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Regulation of phospholipase D activity and phosphatidic acid production after purinergic (P2Y6) receptor stimulation.
Scott SA, Xiang Y, Mathews TP, Cho HP, Myers DS, Armstrong MD, Tallman KA, O'Reilly MC, Lindsley CW, Brown HA
(2013) J Biol Chem 288: 20477-87
MeSH Terms: 1-Butanol, Blotting, Western, Cell Line, Tumor, Diacylglycerol Kinase, Diglycerides, Dose-Response Relationship, Drug, Enzyme Inhibitors, Humans, Hydrolysis, Isoenzymes, Mass Spectrometry, Models, Biological, Phosphatidic Acids, Phosphatidylcholines, Phospholipase C delta, Phospholipase D, Protein Kinase C-alpha, RNA Interference, Receptors, Purinergic P2, Signal Transduction, Uridine Diphosphate
Show Abstract · Added March 7, 2014
Phosphatidic acid (PA) is a lipid second messenger located at the intersection of several lipid metabolism and cell signaling events including membrane trafficking, survival, and proliferation. Generation of signaling PA has long been primarily attributed to the activation of phospholipase D (PLD). PLD catalyzes the hydrolysis of phosphatidylcholine into PA. A variety of both receptor-tyrosine kinase and G-protein-coupled receptor stimulations have been shown to lead to PLD activation and PA generation. This study focuses on profiling the PA pool upon P2Y6 receptor signaling manipulation to determine the major PA producing enzymes. Here we show that PLD, although highly active, is not responsible for the majority of stable PA being produced upon UDP stimulation of the P2Y6 receptor and that PA levels are tightly regulated. By following PA flux in the cell we show that PLD is involved in an initial increase in PA upon receptor stimulation; however, when PLD is blocked, the cell compensates by increasing PA production from other sources. We further delineate the P2Y6 signaling pathway showing that phospholipase Cβ3 (PLCβ3), PLCδ1, DGKζ and PLD are all downstream of receptor activation. We also show that DGKζ is a novel negative regulator of PLD activity in this system that occurs through an inhibitory mechanism with PKCα. These results further define the downstream events resulting in PA production in the P2Y6 receptor signaling pathway.
1 Communities
2 Members
0 Resources
21 MeSH Terms
Protease-activated receptor signaling in platelets activates cytosolic phospholipase A2α differently for cyclooxygenase-1 and 12-lipoxygenase catalysis.
Holinstat M, Boutaud O, Apopa PL, Vesci J, Bala M, Oates JA, Hamm HE
(2011) Arterioscler Thromb Vasc Biol 31: 435-42
MeSH Terms: 1-Butanol, 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid, Arachidonate 12-Lipoxygenase, Arachidonic Acid, Blood Platelets, Calcium, Chromones, Cyclooxygenase 1, Cytosol, Eicosanoids, Enzyme Inhibitors, Group IV Phospholipases A2, Humans, In Vitro Techniques, Morpholines, Propranolol, Protein Kinase C, Receptors, Proteinase-Activated, Signal Transduction, Thromboxane A2, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added March 20, 2014
OBJECTIVE - The rate-limiting step in the biosynthesis of thromboxane A(2) (TxA(2)) and 12-hydroxyeicosatetraenoic acid (12-HETE) by platelets is activation of cytosolic phospholipase A(2α) (cPLA(2α)), which releases arachidonic acid, which is the substrate for cyclooxygenase-1 (COX-1) and 12-lipoxygenase. We evaluated signaling via the human platelet thrombin receptors, protease-activated receptor (PAR) 1 and PAR4, to the activation of cPLA(2α), which provides a substrate for the biosynthesis of TxA(2) and 12-HETE.
METHODS AND RESULTS - Stimulating washed human platelets resulted in delayed biosynthesis of 12-HETE, which continues after maximal formation of TxA(2) is completed, suggesting that 12-HETE is not formed by the same pool of arachidonic acid that provides a substrate to COX-1. PAR1-induced formation of TxA(2) was inhibited by the phosphatidylinositol kinase inhibitor LY294002, whereas this inhibitor did not block 12-HETE biosynthesis. Both 1-butanol and propranolol also blocked TxA(2) biosynthesis but did not inhibit 12-HETE formation.
CONCLUSIONS - The concerted evidence indicates that the platelet thrombin receptors signal activation of cPLA(2α) coupled to COX-1 by a pathway different from that signaling activation of the cPLA(2α) coupled to 12-lipoxygenase.
1 Communities
2 Members
0 Resources
21 MeSH Terms
Phospholipase D1 is required for angiogenesis of intersegmental blood vessels in zebrafish.
Zeng XX, Zheng X, Xiang Y, Cho HP, Jessen JR, Zhong TP, Solnica-Krezel L, Brown HA
(2009) Dev Biol 328: 363-76
MeSH Terms: 1-Butanol, Animals, Animals, Genetically Modified, Body Patterning, Cell Differentiation, Embryo, Nonmammalian, Liver, Neovascularization, Physiologic, Notochord, Phosphatidic Acids, Phospholipase D, Somites, Zebrafish, Zebrafish Proteins
Show Abstract · Added March 19, 2013
Phospholipase D (PLD) hydrolyzes phosphatidylcholine to generate phosphatidic acid and choline. Studies in cultured cells and Drosophila melanogaster have implicated PLD in the regulation of many cellular functions, including intracellular vesicle trafficking, cell proliferation and differentiation. However, the function of PLD in vertebrate development has not been explored. Here we report cloning and characterization of a zebrafish PLD1 (pld1) homolog. Like mammalian PLDs, zebrafish Pld1 contains two conservative HKD motifs. Maternally contributed pld1 transcripts are uniformly distributed in early embryo. Localized expression of pld1 is observed in the notochord during early segmentation, in the somites during later segmentation and in the liver at the larval stages. Studies in intact and cell-free preparations demonstrate evolutionary conservation of regulation. Inhibition of Pld1 expression using antisense morpholino oligonucleotides (MO) interfering with the translation or splicing of pld1 impaired intersegmental vessel (ISV) development. Incubating embryos with 1-butanol, which diverts production of phosphatidic acid to a phosphatidylalcohol, caused similar ISV defects. To determine where Pld1 is required for ISV development we performed transplantation experiments. Analyses of the mosaic Pld1 deficient embryos showed partial suppression of ISV defects in the segments containing transplanted wild-type notochord cells but not in the ones containing wild-type somitic cells. These results provide the first evidence that function of Pld1 in the developing notochord is essential for vascular development in vertebrates.
0 Communities
2 Members
0 Resources
14 MeSH Terms