Lysophosphatidate

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... 

Most GPCRs interact with and activate more than one G-protein subfamily, e.g., with Gs plus Gq/n (histamine H2, parathyroid hormone and calcitonin recqrtors), Gs plus G (luteinising hormone receptor, 32-adrenoceptor) or Gq/11 plus G12/13 (thromboxane A2, angiotensin ATb endothelin ETA receptors). Some receptors show even broader G-protein coupling, e.g., to Gi, Gq/n plus Gi n ( protease-activated receptors, lysophosphatidate and sphingosine-1-phosphate receptors) or even to all four G-protein subfamilies (thyrotropin receptor). This multiple coupling results in multiple signaling via different pathways and in a concerted reaction of the cell to the stimulus. 

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. 

Siess, W., Essler, M., and Brandi, R., 2000, Lysophosphatidic add and sphingosine 1-phosphate two hpid villains provoking cardiovascular diseases , lUBMB Life 49 167-171. 

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. 

Durieux, M.E., Carlisle, S.J., Salafranca, M.N. and Lynch, K.R., 1993, Responses to sphingosine-1 -phosphate in X. laevis oocytes Similarities with lysophosphatidic add signaling. Am. J. Physiol. 264 C1360-C1364. 

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. 

Esterification of glycerol 3-phosphate with a long-chain fatty acid produces a strongly amphipathic lysophosphatidate (enzyme glycerol-3-phosphate acyltransferase 2.3.1.15). In this reaction, an acyl residue is transferred from the activated precursor acyl-CoA to the hydroxy group at C-1. 

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... 

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