Lysophosphatidic acids

Edg receptors are a group of recently discovered G-protein coupled receptors, which mediate the action of lysophospholipids (sphingosine-1 -phosphate, lysophosphatidic acid). Tachykinins and their Receptors... 

Lipid phosphate phosphohydrolases (LPPs), formerly called type 2 phosphatidate phosphohydrolases (PAP-2), catalyse the dephosphorylation of bioactive phospholipids (phosphatidic acid, ceramide-1-phosphate) and lysophospholipids (lysophosphatidic acid, sphingosine-1-phosphate). The substrate selectivity of individual LPPs is broad in contrast to the related sphingosine-1-phosphate phosphatase. LPPs are characterized by a lack of requirement for Mg2+ and insensitivity to N-ethylmaleimide. Three subtypes (LPP-1, LPP-2, LPP-3) have been identified in mammals. These enzymes have six putative transmembrane domains and three highly conserved domains that are characteristic of a phosphatase superfamily. Whether LPPs cleave extracellular mediators or rather have an influence on intracellular lipid phosphate concentrations is still a matter of debate. 

Moolenaar WH, Meeteren LA, van Giepmans BN (2004) The ins and outs of lysophosphatidic acid signaling. Bioessays 26 870-881... 

Parrill AL, Sardar VM, Yuan H (2004) Sphingosine 1-phosphate and lysophosphatidic acid receptors agonist and antagonist binding and progress toward development of receptor-specific ligands. Semin Cell Dev Biol 15 467-476... 

Edwards, J.G., Cambell, G., Carr, M Edwards, C.C. (1993). Shapes of cells spreading on fibronectin Measurement of the stellation of BHK21 cells induced by raising cyclic AMP, and of its reversal by erum and lysophosphatidic acid. J. Cell Sci. 104,399-407. 

Two possible pathways for the biosynthesis of 2-AG have been proposed (1) a phospholipase C (PLC) hydrolysis of membrane phospholipids followed by a second hydrolysis of the resulting 1,2-diacylglycerol by diacylglycerol lipase or (2) a phospholipase Ai (PLA,) activity that generates a lysophospholipid, which in turn is hydrolyzed to 2-AG by lysophospholipase C (Fig. 5) (Piomelli, 1998). Alternative pathways may also exist from either triacylglycerols by a neutral lipase activity or lysophosphatidic acid by a dephosphorylase. The fact that PLC and diacylglycerol lipase inhibitors inhibit 2-AG formation in cortical neurons supports the contention that 2-AG is, at least predominantly, biosynthesized by the PLC pathway (Stella, 1997). However, a mixed pathway may also be plausible. 

Hecht, J. H., Weiner,J. A., Post, S.R. and Chun. /Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex. /. Cell Biol. 135 1071-1083,1996. 

Guo, Z., Liliom, K., Fischer, D. J. etal. Molecular cloning of a high-affinity receptor for the growth factor-like mediator lysophosphatidic acid from Xenopus oocytes. Proc. Natl Acad. Sci. U.S.A. 93 14367-14372,1996. 

An, S., Dickens, M. A., Bleu, T., Hallmark, O. G. and Goetzl, E. J. Molecular cloning of the human EDG2 protein and its identification as a functional cellular receptor for lysophosphatidic acid. Biochem. Biophys. Res. Commun. 231 619-622, 1997. 

Westermann AM, Havik E, Postma FR, Beijnen JH, Dalesio O, Moolenaar WH, Roden-huis S (1998) Malignant effusions contain lysophosphatidic acid (LPA)-like activity. Ann Oncol 9 437-442... 

Cunnick, J.M., Dorsey, J.F., Standley, T., Turkson, J., Kraker, A.J., Fry, D.W., Jove, R., and Wu, J., 1998, Role of tyrosine kinase activity of epidermal growth factor receptor in the lysophosphatidic acid-stimulated mitogen-activated protein kinase pathway, J. Biol. Chem. 273 14468-14475. 

Siess, W., Zangl, K.J., Essler, M., Bauer, M., Brandi, R., Corrinth, C., Bittman, R., Tigyi, G.,and Aepfelbacher, M., 1999, Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions, Proc. Natl. Acad. Sci. USA 96 6931-6936. 

An, S., Goetzl, E.J. and Lee, H., 1998, Signaling mechanisms and molecular characteristics of G protein-coupled receptors for lysophosphatidic acid and sphingosine 1-phosphate. J. 

Goetzl, E.J., Kong, Y. and Mei, B., 1999, Lysophosphatidic acid and sphingosine 1-phosphate protection ofT cells from apoptosis in association with suppression of Bax, J. Immunol. 162 2049-2056. 

Yang, L., Yatomi, Y., Hisano, N., Qi, R., Asazuma, N., Satoh, K.., Igarashi, Y., Ozaki, Y. and Kume, S., 1996, Activation of protein-tyrosine kinase Syk in human platelets stimulated with lysophosphatidic acid or sphingosine 1 -phosphate. Biochem. Biophys. 

Young, K.W., Bootman, M.D., Channing, D.R., Lipp, P., Maycox, P.R., Meakin, J., ChaUis, J.A. andNahorski, S.R., 2000, Lysophosphatidic acid-induced mobihsation requires intracellular sphingosine 1-phospahte production, J. Biol. Ghent. 275 38532-38539. 

Ahmed S, Lee J, Kozma R, Best A, Monfries C, Lim LA (1993) A novel functional target for tumor-promoting phorbol esters and lysophosphatidic acid. The p21rac-GTPase activating protein n-chimaerin. J Biol Chem 268 10709-10712... 

Messenger substances derived from phospholipids can also function as hormones and serve for communication between cells. An important extracellular messenger substance formed from phospholipids is lysophosphatidic acid (l-acyl-sn-glycerine-3-phos-phate). Lysophosphatidic acid (lysophosphatidic acid, LPA) is released by platelets and other cells and reaches its target cells via the circulation. As a product of the blood clotting process, LPA is an abimdant constituent of serum, where it is found in an albu-min-boimd form. 

Moolenaar, WH., Kranenburg, O., Postma, FR. and Zondag, G.C.M. Lysophosphatidic acid G-protein signalling and cellular responses (1997) Curr. Op. Cell Biol. 9, 168-173... 

Lecithins and related phospholipids usually contain a saturated fatty acid in the C-l position but an unsaturated acid, which may contain from one to four double bonds, at C-2. Arachidonic acid is often present here. Hydrolysis of the ester linkage at C-2 yields a l-acyl-3-phosphoglycerol, better known as a Iysophosphatidylcholine. The name comes from the powerful detergent action of these substances which leads to lysis of cells. Some snake venoms contain phospholipases that form Iysophosphatidylcholine. Lysophosphatidic acid (l-acyl-glycerol-3-phosphate) is both an intermediate in phospholipid biosynthesis (Chapter 21) and also a signaling molecule released into the bloodstream by activated platelets.15... 

Figure 21-3 Major pathways of synthesis of fatty acids and glycerolipids in the green plant Arabidopsis. The major site of fatty acid synthesis is chloroplasts. Most is exported to the cytosol as oleic acid (18 1). After conversion to its coenzyme A derivative it is converted to phosphatidic acid (PA), diacylglycerol (DAG), and the phospholipids phosphatidylcholine (PC), phosphatidylinositol (PI), phosphatidylglycerol (PG), and phosphatidylethanolamine (PE). Desaturation also occurs, and some linoleic and linolenic acids are returned to the chloroplasts. See text also. From Sommerville and Browse.106 See also Figs. 21-4 and 21-5. Other abbreviations monogalactosyldiacylglycerol (MGD), digalactosyldiacylglycerol (DGD), sulfolipid (SL), glycerol 3-phosphate (G3P), lysophosphatidic acid (LPA), acyl carrier protein (ACP), cytidine diphosphate-DAG (CDP-DAG).

Thrombin and lysophosphatidic acid receptors utilize distinct rhoGEFs in prostate cancer cells. /. Biol. Chem. 279, 28831-28834. 

Yamada, T., Ohoka, Y., Kogo, M., and Inagaki, S. (2005). Physical and functional interactions of the lysophosphatidic acid receptors with PDZ domain-containing Rho guanine nucleotide exchange factors (RhoGEFs)./ Biol. Chem. 280,19358-19363. 

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