title: Inhibition of lipid phosphate phosphatase activity by VPC32183 suppresses the ability of diacylglycerol pyrophosphate to activate ERK(1/2) MAP kinases.
abstract: The lipidic metabolite, diacylglycerol pyrophosphate (DGPP), in its dioctanoyl form (DGPP 8:0), has been described as an antagonist for mammalian lysophosphatidic acid (LPA) receptors LPA1 and LPA3. In this study we show that DGPP 8:0 does not antagonize LPA dependent activation of ERK(1/2) MAP kinases but strongly stimulated them in various mammalian cell lines. LPA and DGPP 8:0 stimulation of ERK(1/2) occurred through different pathways. The DGPP 8:0 effect appeared to be dependent on PKC, Raf and MEK but was insensitive to pertussis toxin and did not involve G protein activation. Finally we showed that DGPP 8:0 effect on ERK(1/2) was dependent on its dephosphorylation by a phosphatase activity sharing lipid phosphate phosphatase properties. The inhibition of this phosphatase activity by VPC32183, a previously characterized LPA receptor antagonist, blocked the DGPP 8:0 effect on ERK(1/2) activation. Moreover, down-regulation of lipid phosphate phosphatase 1 (LPP1) expression by RNA interference technique also reduced DGPP 8:0-induced ERK(1/2) activation. Consistently, over expression of LPP1 in HEK293 cells increases DGPP 8:0 hydrolysis and this increased activity was inhibited by VPC32183. In conclusion, DGPP 8:0 does not exert its effect by acting on a G protein coupled receptor, but through its dephosphorylation by LPP1, generating dioctanoyl phosphatidic acid which in turn activates PKC. These results suggest that LPP1 could have a positive regulatory function on cellular signaling processes such as ERK(1/2) activation.
authors: Université Paris-Sud 11, Institut de Biochimie et de Biophysique Moléculaire et Cellulaire, CNRS UMR 8619, 91405 Orsay CEDEX, France.
authors: Pierre-Christian
authors: PC
authors: Violet
authors: Emmanuelle
authors: E
authors: Billon-Denis
authors: Philippe
authors: P
authors: Robin
mesh_terms: D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D011756:Diphosphates / Q000494:pharmacology*; D005990:Glycerol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D010755:Organophosphates / Q000494:pharmacology*; D010711:Phosphatidate Phosphatase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010712:Phosphatidic Acids / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D011756:Diphosphates; D008246:Lysophospholipids; D010755:Organophosphates; D010712:Phosphatidic Acids; D011725:Pyridines; D012333:RNA, Messenger; D049368:Receptors, Lysophosphatidic Acid; C529824:VPC32183; C408642:diacylglycerol pyrophosphate; C084527:dioctanoylphosphatidic acid; D048490:raf Kinases; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C112948:lipid phosphate phosphatase; D010711:Phosphatidate Phosphatase; D005990:Glycerol; C032881:lysophosphatidic acid