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http://dx.doi.org/10.4062/biomolther.2014.109

Promising Pharmacological Directions in the World of Lysophosphatidic Acid Signaling  

Stoddard, Nicole C. (Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute)
Chun, Jerold (Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute)
Publication Information
Biomolecules & Therapeutics / v.23, no.1, 2015 , pp. 1-11 More about this Journal
Abstract
Lysophosphatidic acid (LPA) is a signaling lipid that binds to six known lysophosphatidic acid receptors (LPARs), named $LPA_1-LPA_6$. These receptors initiate signaling cascades relevant to development, maintenance, and healing processes throughout the body. The diversity and specificity of LPA signaling, especially in relation to cancer and autoimmune disorders, makes LPA receptor modulation an attractive target for drug development. Several LPAR-specific analogues and small molecules have been synthesized and are efficacious in attenuating pathology in disease models. To date, at least three compounds have passed phase I and phase II clinical trials for idiopathic pulmonary fibrosis and systemic sclerosis. This review focuses on the promising therapeutic directions emerging in LPA signaling toward ameliorating several diseases, including cancer, fibrosis, arthritis, hydrocephalus, and traumatic injury.
Keywords
Lysophosphatidic acid receptor; Pharmacology; Autotaxin; Cancer; Autoimmune disease; Fibrosis;
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1 Bandoh, K., Aoki, J., Hosono, H., Kobayashi, S., Kobayashi, T., Murakami- Murofushi, K., Tsujimoto, M., Arai, H. and Inoue, K. (1999) Molecular cloning and characterization of a novel human G-protein- coupled receptor, EDG7, for lysophosphatidic acid. J. Biol. Chem. 274, 27776-27785.   DOI
2 Beck, H. P., Kohn, T., Rubenstein, S., Hedberg, C., Schwandner, R., Hasslinger, K., Dai, K., Li, C., Liang, L., Wesche, H., Frank, B., An, S., Wickramasinghe, D., Jaen, J., Medina, J., Hungate, R. and Shen, W. (2008) Discovery of potent LPA2 (EDG4) antagonists as potential anticancer agents. Bioorg. Med. Chem. Lett. 18, 1037-1041.   DOI
3 Benesch, M. G., Tang, X., Maeda, T., Ohhata, A., Zhao, Y. Y., Kok, B. P., Dewald, J., Hitt, M., Curtis, J. M., McMullen, T. P. and Brindley, D. N. (2014) Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice. FASEB J. 28, 2655-2666.   DOI
4 Bhave, S. R., Dadey, D. Y., Karvas, R. M., Ferraro, D. J., Kotipatruni, R. P., Jaboin, J. J., Hallahan, A. N., Dewees, T. A., Linkous, A. G., Hallahan, D. E. and Thotala, D. (2013) Autotaxin inhibition with PF- 8380 enhances the radiosensitivity of human and murine glioblastoma cell lines. Front. Oncol. 3, 236.
5 BMS (2011) Bristol-myers squibb to acquire amira pharmaceuticals. Bristol-Myers Squibb, Online. http://news.bms.com/press-release/ partnering-news/bristol-myers-squibb-acquire-amira-pharmaceuticals, Access Date: 2014/09/15.
6 BMS (2014) Safety and efficacy of a lysophosphatidic acid receptor antagonist in idiopathic pulmonary fibrosis. https://clinicaltrials.gov/ ct2/show/NCT01766817, Access Date: 2014/09/15.
7 Bradford, W. Z. (2012) Pirfenidone and anti-fibrotic therapy in selected patients, International Patent: WO/2012/162592 A1. Intermune, Inc., International. http://www.google.im/patents/WO2012162592A1, Access Date: 2014/09/15.
8 Fukushima, N., Ishii, I., Contos, J. J., Weiner, J. A. and Chun, J. (2001) Lysophospholipid receptors. Annu. Rev. Pharmacol. Toxicol. 41, 507-534.   DOI
9 Geng, H., Lan, R., Singha, P. K., Gilchrist, A., Weinreb, P. H., Violette, S. M., Weinberg, J. M., Saikumar, P. and Venkatachalam, M. A. (2012) Lysophosphatidic acid increases proximal tubule cell secretion of profibrotic cytokines PDGF-B and CTGF through LPA2- and Galphaq-mediated Rho and alphavbeta6 integrin-dependent activation of TGF-beta. Am. J. Pathol. 181, 1236-1249.   DOI
10 Gerrard, J. M., Kindom, S. E., Peterson, D. A., Peller, J., Krantz, K. E. and White, J. G. (1979) Lysophosphatidic acids. Influence on platelet aggregation and intracellular calcium flux. Am. J. Pathol. 96, 423-438.
11 Gierse, J., Thorarensen, A., Beltey, K., Bradshaw-Pierce, E., Cortes- Burgos, L., Hall, T., Johnston, A., Murphy, M., Nemirovskiy, O., Ogawa, S., Pegg, L., Pelc, M., Prinsen, M., Schnute, M., Wendling, J., Wene, S., Weinberg, R., Wittwer, A., Zweifel, B. and Masferrer, J. (2010) A novel autotaxin inhibitor reduces lysophosphatidic acid levels in plasma and the site of inflammation. J. Pharmacol. Exp. Ther. 334, 310-317.   DOI
12 Goldshmit, Y., Matteo, R., Sztal, T., Ellett, F., Frisca, F., Moreno, K., Crombie, D., Lieschke, G. J., Currie, P. D., Sabbadini, R. A. and Pebay, A. (2012) Blockage of lysophosphatidic acid signaling improves spinal cord injury outcomes. Am. J. Pathol. 181, 978-992.   DOI   ScienceOn
13 Gotoh, M., Fujiwara, Y., Yue, J., Liu, J., Lee, S., Fells, J., Uchiyama, A., Murakami-Murofushi, K., Kennel, S., Wall, J., Patil, R., Gupte, R., Balazs, L., Miller, D. D. and Tigyi, G. J. (2012) Controlling cancer through the autotaxin-lysophosphatidic acid receptor axis. Biochem. Soc. Trans. 40, 31-36.   DOI
14 Lin, D. A. and Boyce, J. A. (2006) Lysophospholipids as mediators of immunity. Ad. Immunol. 89, 141-167.   DOI
15 Lee, H., Goetzl, E. J. and An, S. (2000) Lysophosphatidic acid and sphingosine 1-phosphate stimulate endothelial cell wound healing. American journal of physiology. Am. J. Physiol. Cell Physiol. 278, C612-618.   DOI
16 Lee, Z., Cheng, C. T., Zhang, H., Subler, M. A., Wu, J., Mukherjee, A., Windle, J. J., Chen, C. K. and Fang, X. (2008) Role of LPA4/ p2y9/GPR23 in negative regulation of cell motility. Mol. Biol. Cell 19, 5435-5445.   DOI
17 Liao, Y., Mu, G., Zhang, L., Zhou, W., Zhang, J. and Yu, H. (2013) Lysophosphatidic acid stimulates activation of focal adhesion kinase and paxillin and promotes cell motility, via LPA1-3, in human pancreatic cancer. Dig. Dis. Sci. 58, 3524-3533.   DOI
18 Lu, W. Y., Xiong, Z. G., Lei, S., Orser, B. A., Dudek, E., Browning, M. D. and MacDonald, J. F. (1999) G-protein-coupled receptors act via protein kinase C and Src to regulate NMDA receptors. Nat. Neurosci. 2, 331-338.   DOI
19 Lundequist, A. and Boyce, J. A. (2011) Lundequist, A. and Boyce is abundantly expressed by human mast cells and important for lysophosphatidic acid induced MIP-1beta release. PloS ONE 6, e18192.   DOI
20 Marshall, J. C., Collins, J. W., Nakayama, J., Horak, C. E., Liewehr, D. J., Steinberg, S. M., Albaugh, M., Vidal-Vanaclocha, F., Palmieri, D., Barbier, M., Murone, M. and Steeg, P. S. (2012) Effect of inhibition of the lysophosphatidic acid receptor 1 on metastasis and metastatic dormancy in breast cancer. J. Natl. Cancer Inst. 104, 1306-1319.   DOI
21 Okusa, M. D., Ye, H., Huang, L., Sigismund, L., Macdonald, T. and Lynch, K. R. (2003) Selective blockade of lysophosphatidic acid LPA3 receptors reduces murine renal ischemia-reperfusion injury. American journal of physiology. Am. J. Physol. Renal Physiol. 285, F565-574.   DOI
22 Nogueira, E. S. and Vales, R. L. (2013) Methods for treating spinal cord injury with lpa receptor antagonists, International Patent: WO/2013/070879 A1. Bristol-Myers Squibb, International. http://www.google.com/patents/WO2013070879A, Access Date: 2014/09/15.
23 Norman, D. D., Ibezim, A., Scott, W. E., White, S., Parrill, A. L. and Baker, D. L. (2013) Autotaxin inhibition: development and application of computational tools to identify site-selective lead compounds. Bioorg. Med. Chem. 21, 5548-5560.   DOI
24 Oikonomou, N., Mouratis, M. A., Tzouvelekis, A., Kaffe, E., Valavanis, C., Vilaras, G., Karameris, A., Prestwich, G. D., Bouros, D. and Aidinis, V. (2012) Pulmonary autotaxin expression contributes to the pathogenesis of pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 47, 566-574.   DOI
25 Orosa, B., Garcia, S., Martinez, P., Gonzalez, A., Gomez-Reino, J. J. and Conde, C. (2014) Lysophosphatidic acid receptor inhibition as a new multipronged treatment for rheumatoid arthritis. Am. Rheum. Dis. 73, 298-305.   DOI
26 Park, G. Y., Lee, Y. G., Berdyshev, E., Nyenhuis, S., Du, J., Fu, P., Gorshkova, I. A., Li, Y., Chung, S., Karpurapu, M., Deng, J., Ranjan, R., Xiao, L., Jaffe, H. A., Corbridge, S. J., Kelly, E. A., Jarjour, N. N., Chun, J., Prestwich, G. D., Kaffe, E., Ninou, I., Aidinis, V., Morris, A. J., Smyth, S. S., Ackerman, S. J., Natarajan, V. and Christman, J. W. (2013) Autotaxin production of lysophosphatidic acid mediates allergic asthmatic inflammation. Am. J. Respir. Crit. Care Med. 188, 928-940.   DOI
27 Sonoda, H., Aoki, J., Hiramatsu, T., Ishida, M., Bandoh, K., Nagai, Y., Taguchi, R., Inoue, K. and Arai, H. (2002) A novel phosphatidic acid- selective phospholipase A1 that produces lysophosphatidic acid. J. Biol. Chem. 277, 34254-34263.   DOI
28 Schleicher, S. M., Thotala, D. K., Linkous, A. G., Hu, R., Leahy, K. M., Yazlovitskaya, E. M. and Hallahan, D. E. (2011) Autotaxin and LPA receptors represent potential molecular targets for the radiosensitization of murine glioma through effects on tumor vasculature. PloS ONE 6, e22182.   DOI
29 Sedlakova, I., Vavrova, J., Tosner, J. and Hanousek, L. (2011) Lysophosphatidic acid (LPA)-a perspective marker in ovarian cancer. Tumor Biol. 32, 311-316.   DOI
30 Seewald, S., Schmitz, U., Seul, C., Ko, Y., Sachinidis, A. and Vetter, H. (1999) Lysophosphatidic acid stimulates protein kinase C isoforms alpha, beta, epsilon, and zeta in a pertussis toxin sensitive pathway in vascular smooth muscle cells. Am. J. Hypertens. 12, 532-537.   DOI
31 Sotiropoulos, A., Gineitis, D., Copeland, J. and Treisman, R. (1999) Signal-regulated activation of serum response factor is mediated by changes in actin dynamics. Cell 98, 159-169.   DOI
32 St-Coeur, P. D., Ferguson, D., Morin, P., Jr. and Touaibia, M. (2013) PF-8380 and closely related analogs: synthesis and structure-activity relationship towards autotaxin inhibition and glioma cell viability. Arch. Pharm. 346, 91-97.   DOI
33 Su, S. C., Hu, X., Kenney, P. A., Merrill, M. M., Babaian, K. N., Zhang, X. Y., Maity, T., Yang, S. F., Lin, X. and Wood, C. G. (2013) Autotaxin- lysophosphatidic acid signaling axis mediates tumorigenesis and development of acquired resistance to sunitinib in renal cell carcinoma. Clin. Cancer Res. 19, 6461-6472.   DOI
34 Xu, X. and Prestwich, G. D. (2010) Inhibition of tumor growth and angiogenesis by a lysophosphatidic acid antagonist in an engineered three-dimensional lung cancer xenograft model. Cancer 116, 1739-1750.   DOI
35 Umezu-Goto, M., Kishi, Y., Taira, A., Hama, K., Dohmae, N., Takio, K., Yamori, T., Mills, G. B., Inoue, K., Aoki, J. and Arai, H. (2002) Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. J. Cell Biol. 158, 227-233.   DOI
36 Valet, P., Pages, C., Jeanneton, O., Daviaud, D., Barbe, P., Record, M., Saulnier-Blache, J. S. and Lafontan, M. (1998) Alpha2-adrenergic receptor-mediated release of lysophosphatidic acid by adipocytes. A paracrine signal for preadipocyte growth. J. Clin. Invest. 101, 1431-1438.   DOI
37 van Meeteren, L. A., Ruurs, P., Stortelers, C., Bouwman, P., van Rooijen, M. A., Pradere, J. P., Pettit, T. R., Wakelam, M. J., Saulnier- Blache, J. S., Mummery, C. L., Moolenaar, W. H. and Jonkers, J. (2006) Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development. Mol. Cell. Biol. 26, 5015-5022.   DOI
38 Yanagida, K., Masago, K., Nakanishi, H., Kihara, Y., Hamano, F., Tajima, Y., Taguchi, R., Shimizu, T. and Ishii, S. (2009) Identification and Characterization of a Novel Lysophosphatidic Acid Receptor, p2y5/LPA6. J. Biol. Chem. 284, 17731-17741.   DOI
39 Ye, X., Hama, K., Contos, J. J., Anliker, B., Inoue, A., Skinner, M. K., Suzuki, H., Amano, T., Kennedy, G., Arai, H., Aoki, J. and Chun, J. (2005) LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing. Nature 435, 104-108.   DOI
40 Ye, X., Ishii, I., Kingsbury, M. A. and Chun, J. (2002) Lysophosphatidic acid as a novel cell survival/apoptotic factor. Biochim. Biophys. Acta 1585, 108-113.   DOI
41 Choi, J. W., Herr, D. R., Noguchi, K., Yung, Y. C., Lee, C. W., Mutoh, T., Lin, M. E., Teo, S. T., Park, K. E., Mosley, A. N. and Chun, J. (2010) LPA receptors: subtypes and biological actions. Annu. Rev. Pharmacol. Toxicol. 50, 157-186.   DOI
42 Brinkmann, V., Davis, M. D., Heise, C. E., Albert, R., Cottens, S., Hof, R., Bruns, C., Prieschl, E., Baumruker, T., Hiestand, P., Foster, C. A., Zollinger, M. and Lynch, K. R. (2002) The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem. 277, 21453-21457.   DOI
43 Calabresi, P. A., Radue, E. W., Goodin, D., Jeffery, D., Rammohan, K. W., Reder, A. T., Vollmer, T., Agius, M. A., Kappos, L., Stites, T., Li, B., Cappiello, L., von Rosenstiel, P. and Lublin, F. D. (2014) Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo- controlled, phase 3 trial. Lancet Neurol. 13, 545-556.   DOI
44 Castelino, F. V., Seiders, J., Bain, G., Brooks, S. F., King, C. D., Swaney, J. S., Lorrain, D. S., Chun, J., Luster, A. D. and Tager, A. M. (2011) Amelioration of dermal fibrosis by genetic deletion or pharmacologic antagonism of lysophosphatidic acid receptor 1 in a mouse model of scleroderma. Arthritis Rheum. 63, 1405-1415.   DOI
45 Chun, J. and Hartung, H. P. (2010) Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin. Neuropharmacol. 33, 91-101.   DOI
46 Chun, J., Hla, T., Lynch, K. R., Spiegel, S. and Moolenaar, W. H. (2010) International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid receptor nomenclature. Pharmacol. Rev. 62, 579-587.   DOI
47 Gupte, R., Patil, R., Liu, J., Wang, Y., Lee, S. C., Fujiwara, Y., Fells, J., Bolen, A. L., Emmons-Thompson, K., Yates, C. R., Siddam, A., Panupinthu, N., Pham, T. C., Baker, D. L., Parrill, A. L., Mills, G. B., Tigyi, G. and Miller, D. D. (2011) Benzyl and naphthalene methylphosphonic acid inhibitors of autotaxin with anti-invasive and anti-metastatic activity. ChemMedChem 6, 922-935.   DOI
48 Yung, Y. C., Mutoh, T., Lin, M. E., Noguchi, K., Rivera, R. R., Choi, J. W., Kingsbury, M. A. and Chun, J. (2011) Lysophosphatidic acid signaling may initiate fetal hydrocephalus. Sci. Transl. Med. 3, 99ra87.
49 Yung, Y. C., Stoddard, N. C. and Chun, J. (2014) LPA receptor signaling: pharmacology, physiology, and pathophysiology. J. Lipid Res. 55, 1192-1214.   DOI
50 Zhang, H., Xu, X., Gajewiak, J., Tsukahara, R., Fujiwara, Y., Liu, J., Fells, J. I., Perygin, D., Parrill, A. L., Tigyi, G. and Prestwich, G. D. (2009) Dual activity lysophosphatidic acid receptor pan-antagonist/ autotaxin inhibitor reduces breast cancer cell migration in vitro and causes tumor regression in vivo. Cancer Res. 69, 5441-5449.   DOI
51 Hama, K., Aoki, J., Fukaya, M., Kishi, Y., Sakai, T., Suzuki, R., Ohta, H., Yamori, T., Watanabe, M., Chun, J. and Arai, H. (2004) Lysophosphatidic acid and autotaxin stimulate cell motility of neoplastic and non-neoplastic cells through LPA1. J. Biol. Chem. 279, 17634-17639.   DOI
52 Hayashi, M., Okabe, K., Kato, K., Okumura, M., Fukui, R., Fukushima, N. and Tsujiuchi, T. (2012) Differential function of lysophosphatidic acid receptors in cell proliferation and migration of neuroblastoma cells. Cancer Lett. 316, 91-96.   DOI
53 Hecht, J. H., Weiner, J. A., Post, S. R. and Chun, J. (1996) Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex. J. Cell Biol. 135, 1071-1083.   DOI
54 Hoelzinger, D. B., Nakada, M., Demuth, T., Rosensteel, T., Reavie, L. B. and Berens, M. E. (2008) Autotaxin: a secreted autocrine/ paracrine factor that promotes glioma invasion. J. Neurooncol. 86, 297-309.   DOI
55 Hwang, S. H., Lee, B. H., Kim, H. J., Cho, H. J., Shin, H. C., Im, K. S., Choi, S. H., Shin, T. J., Lee, S. M., Nam, S. W., Kim, H. C., Rhim, H. and Nah, S. Y. (2013) Suppression of metastasis of intravenouslyinoculated B16/F10 melanoma cells by the novel ginseng-derived ingredient, gintonin: involvement of autotaxin inhibition. Int. J. Oncol. 42, 317-326.   DOI
56 Im, D. S. (2010) Pharmacological tools for lysophospholipid GPCRs: development of agonists and antagonists for LPA and S1P receptors. Acta Pharmacol. Sin. 31, 1213-1222.   DOI
57 Jimenez, C., Portela, R. A., Mellado, M., Rodriguez-Frade, J. M., Collard, J., Serrano, A., Martinez, A. C., Avila, J. and Carrera, A. C. (2000) Role of the PI3K regulatory subunit in the control of actin organization and cell migration. J. Cell Biol. 151, 249-262.   DOI
58 Ishii, I., Fukushima, N., Ye, X. and Chun, J. (2004) Lysophospholipid receptors: signaling and biology. Annu. Rev. Biochem. 73, 321-354.   DOI
59 Iyer, P., Lalane, R., 3rd, Morris, C., Challa, P., Vann, R. and Rao, P. V. (2012) Autotaxin-lysophosphatidic acid axis is a novel molecular target for lowering intraocular pressure. PloS ONE 7, e42627.   DOI
60 Jeong, K. J., Park, S. Y., Cho, K. H., Sohn, J. S., Lee, J., Kim, Y. K., Kang, J., Park, C. G., Han, J. W. and Lee, H. Y. (2012) The Rho/ ROCK pathway for lysophosphatidic acid-induced proteolytic enzyme expression and ovarian cancer cell invasion. Oncogene 31, 4279-4289.   DOI
61 Jongsma, M., Matas-Rico, E., Rzadkowski, A., Jalink, K. and Mool enaar, W. H. (2011) LPA is a chemorepellent for B16 melanoma cells: action through the cAMP-elevating LPA5 receptor. PloS ONE 6, e29260.   DOI
62 Kanda, H., Newton, R., Klein, R., Morita, Y., Gunn, M. D. and Rosen, S. D. (2008) Autotaxin, an ectoenzyme that produces lysophosphatidic acid, promotes the entry of lymphocytes into secondary lymphoid organs. Nat. Immunol. 9, 415-423.   DOI
63 Kang, Y. C., Kim, K. M., Lee, K. S., Namkoong, S., Lee, S. J., Han, J. A., Jeoung, D., Ha, K. S., Kwon, Y. G. and Kim, Y. M. (2004) Serum bioactive lysophospholipids prevent TRAIL-induced apoptosis via PI3K/Akt-dependent cFLIP expression and Bad phosphorylation. Cell Death Differ. 11, 1287-1298.   DOI
64 Bai, C. Q., Yao, Y. W., Liu, C. H., Zhang, H., Xu, X. B., Zeng, J. L., Liang, W. J., Yang, W. and Song, Y. (2014) Diagnostic and prognostic significance of lysophosphatidic acid in malignant pleural effusions. J. Thorac. Dis. 6, 483-490.
65 An, S., Bleu, T., Hallmark, O. G. and Goetzl, E. J. (1998) Characterization of a novel subtype of human G protein-coupled receptor for lysophosphatidic acid. J. Biol. Chem. 273, 7906-7910.   DOI
66 Azeem, Z., Jelani, M., Naz, G., Tariq, M., Wasif, N., Kamran-Ul-Hassan Naqvi, S., Ayub, M., Yasinzai, M., Amin-Ud-Din, M., Wali, A., Ali, G., Chishti, M. S. and Ahmad, W. (2008) Novel mutations in G proteincoupled receptor gene (P2RY5) in families with autosomal recessive hypotrichosis (LAH3). Hum. Genet. 123, 515-519.   DOI
67 Bachner, D., Ahrens, M., Betat, N., Schroder, D. and Gross, G. (1999) Developmental expression analysis of murine autotaxin (ATX). Mech. Dev. 84, 121-125.   DOI
68 Cummings, R., Zhao, Y., Jacoby, D., Spannhake, E. W., Ohba, M., Garcia, J. G., Watkins, T., He, D., Saatian, B. and Natarajan, V. (2004) Protein kinase Cdelta mediates lysophosphatidic acid-induced NF-kappaB activation and interleukin-8 secretion in human bronchial epithelial cells. J. Biol. Chem. 279, 41085-41094.   DOI
69 Contos, J. J., Ishii, I., Fukushima, N., Kingsbury, M. A., Ye, X., Kawamura, S., Brown, J. H. and Chun, J. (2002) Characterization of lpa(2) (Edg4) and lpa(1)/lpa(2) (Edg2/Edg4) lysophosphatidic acid receptor knockout mice: signaling deficits without obvious phenotypic abnormality attributable to lpa(2). Mol. Cell. Biol. 22, 6921-6929.   DOI
70 Crack, P. J., Zhang, M., Morganti-Kossmann, M. C., Morris, A. J., Wojciak, J. M., Fleming, J. K., Karve, I., Wright, D., Sashindranath, M., Goldshmit, Y., Conquest, A., Daglas, M., Johnston, L. A., Medcalf, R. L., Sabbadini, R. A. and Pebay, A. (2014) Anti-lysophosphatidic acid antibodies improve traumatic brain injury outcomes. J. Neuroinflammation 11, 37.   DOI
71 Eichholtz, T., Jalink, K., Fahrenfort, I. and Moolenaar, W. H. (1993) The bioactive phospholipid lysophosphatidic acid is released from activated platelets. Biochem. J. 291 (Pt 3), 677-680.   DOI
72 Fells, J. I., Lee, S. C., Fujiwara, Y., Norman, D. D., Lim, K. G., Tsukahara, R., Liu, J., Patil, R., Miller, D. D., Kirby, R. J., Nelson, S., Seibel, W., Papoian, R., Parrill, A. L., Baker, D. L., Bittman, R. and Tigyi, G. (2013) Hits of a high-throughput screen identify the hydrophobic pocket of autotaxin/lysophospholipase D as an inhibitory surface. Mol. Pharmacol. 84, 415-424.   DOI
73 Fourcade, O., Simon, M. F., Viode, C., Rugani, N., Leballe, F., Ragab, A., Fournie, B., Sarda, L. and Chap, H. (1995) Secretory phospholipase A2 generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells. Cell 80, 919-927.   DOI
74 Kotarsky, K., Boketoft, A., Bristulf, J., Nilsson, N. E., Norberg, A., Hansson, S., Owman, C., Sillard, R., Leeb-Lundberg, L. M. and Olde, B. (2006) Lysophosphatidic acid binds to and activates GPR92, a G protein-coupled receptor highly expressed in gastrointestinal lymphocytes. J. Pharmacol. Exp. Ther. 318, 619-628.   DOI
75 Kawaguchi, M., Okabe, T., Okudaira, S., Nishimasu, H., Ishitani, R., Kojima, H., Nureki, O., Aoki, J. and Nagano, T. (2013) Screening and X-ray crystal structure-based optimization of autotaxin (ENPP2) inhibitors, using a newly developed fluorescence probe. ACS Chem. Biol. 8, 1713-1721.   DOI
76 Kim, J. H. and Adelstein, R. S. (2011) LPA(1) -induced migration requires nonmuscle myosin II light chain phosphorylation in breast cancer cells. J. Cell. Physiol. 226, 2881-2893.   DOI
77 Komachi, M., Sato, K., Tobo, M., Mogi, C., Yamada, T., Ohta, H., Tomura, H., Kimura, T., Im, D. S., Yanagida, K., Ishii, S., Takeyoshi, I. and Okajima, F. (2012) Orally active lysophosphatidic acid receptor antagonist attenuates pancreatic cancer invasion and metastasis in vivo. Cancer Sci. 103, 1099-1104.   DOI
78 Kranenburg, O. and Moolenaar, W. H. (2001) Ras-MAP kinase signaling by lysophosphatidic acid and other G protein-coupled receptor agonists. Oncogene 20, 1540-1546.   DOI
79 Lafyatis, R. (2014) Transforming growth factor beta-at the centre of systemic sclerosis. Nat. Rev. Rheumatol. 10, 706-719.   DOI
80 Lee, C. W., Rivera, R., Gardell, S., Dubin, A. E. and Chun, J. (2006) GPR92 as a new G12/13- and Gq-coupled lysophosphatidic acid receptor that increases cAMP, $LPA_{5}$. J. Biol. Chem. 281, 23589-23597.   DOI
81 Morimoto, T. (2012) Tetrahydrocarboline derivative, International Patent: WO/2012/ 005227 A1. Ono Pharmaceutical Co., Ltd., International. http://www.google.com/patents/WO2012005227A1, Access Date: 2014/ 09/15.
82 Mills, G. B., Eder, A., Fang, X., Hasegawa, Y., Mao, M., Lu, Y., Tanyi, J., Tabassam, F. H., Wiener, J., Lapushin, R., Yu, S., Parrott, J. A., Compton, T., Tribley, W., Fishman, D., Stack, M. S., Gaudette, D., Jaffe, R., Furui, T., Aoki, J. and Erickson, J. R. (2002) Critical role of lysophospholipids in the pathophysiology, diagnosis, and management of ovarian cancer. Cancer Treat. Res. 107, 259-283.
83 Mirendil, H., Lin, M.-E. and Chun, J. (2013) Lysophospholipid receptors: signaling and biochemistry. In lysophospholipid receptors: signaling and biochemistry (J. Chun, T. Hla, S. Spiegel and W. H. Moolenaar, Eds.) John Wiley & Sons, Inc., Hoboken, NJ.
84 Moolenaar, W. H. and van Corven, E. J. (1990) Growth factor-like action of lysophosphatidic acid: mitogenic signalling mediated by G proteins. Ciba Found. Symp. 150, 99-106.
85 NCI (2014) A pilot study of a protein profile test in ovarian cancer patients in remission to see if protein changes can predict relapse. https://clinicaltrials.gov/ct2/show/NCT00001938, Access Date: 2014/09/15.
86 Nikitopoulou, I., Kaffe, E., Sevastou, I., Sirioti, I., Samiotaki, M., Madan, D., Prestwich, G. D. and Aidinis, V. (2013) A metabolicallystabilized phosphonate analog of lysophosphatidic acid attenuates collagen-induced arthritis. PloS ONE 8, e70941.   DOI
87 Noguchi, K., Ishii, S. and Shimizu, T. (2003) Identification of p2y9/ GPR23 as a novel G protein-coupled receptor for lysophosphatidic acid, structurally distant from the Edg family. J. Biol. Chem. 278, 25600-25606.   DOI
88 Ruisanchez, E., Dancs, P., Kerek, M., Nemeth, T., Farago, B., Balogh, A., Patil, R., Jennings, B. L., Liliom, K., Malik, K. U., Smrcka, A. V., Tigyi, G. and Benyo, Z. (2014) Lysophosphatidic acid induces vasodilation mediated by LPA1 receptors, phospholipase C, and endothelial nitric oxide synthase. FASEB J. 28, 880-890.   DOI
89 Pasternack, S. M., von Kugelgen, I., Al Aboud, K., Lee, Y. A., Ruschendorf, F., Voss, K., Hillmer, A. M., Molderings, G. J., Franz, T., Ramirez, A., Nurnberg, P., Nothen, M. M. and Betz, R. C. (2008) G protein-coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth. Nat. Genet. 40, 329-334.   DOI
90 Petukhova, L., Sousa, E. C., Jr., Martinez-Mir, A., Vitebsky, A., Dos Santos, L. G., Shapiro, L., Haynes, C., Gordon, D., Shimomura, Y. and Christiano, A. M. (2008) Genome-wide linkage analysis of an autosomal recessive hypotrichosis identifies a novel P2RY5 mutation. Genomics 92, 273-278.   DOI
91 Sando, J. J. and Chertihin, O. I. (1996) Activation of protein kinase C by lysophosphatidic acid: dependence on composition of phospholipid vesicles. Biochem. J. 317 (Pt 2), 583-588.   DOI
92 Sano, T., Baker, D., Virag, T., Wada, A., Yatomi, Y., Kobayashi, T., Igarashi, Y. and Tigyi, G. (2002) Multiple mechanisms linked to platelet activation result in lysophosphatidic acid and sphingosine 1-phosphate generation in blood. J. Biol. Chem. 277, 21197-21206.   DOI
93 Sanofi (2014) Proof of Biological Activity of SAR100842 in Systemic Sclerosis. https://clinicaltrials.gov/ct2/show/NCT01651143, Access Date: 2014/09/15.
94 Savaskan, N. E., Rocha, L., Kotter, M. R., Baer, A., Lubec, G., van Meeteren, L. A., Kishi, Y., Aoki, J., Moolenaar, W. H., Nitsch, R. and Brauer, A. U. (2007) Autotaxin (NPP-2) in the brain: cell typespecific expression and regulation during development and after neurotrauma. Cell. Mol. Life Sci. 64, 230-243.   DOI
95 Tokumura, A., Fukuzawa, K., Akamatsu, Y., Yamada, S., Suzuki, T. and Tsukatani, H. (1978) Identification of vasopressor phospholipid in crude soybean lecithin. Lipids 13, 468-472.   DOI
96 Swaney, J. S., Chapman, C., Correa, L. D., Stebbins, K. J., Broadhead, A. R., Bain, G., Santini, A. M., Darlington, J., King, C. D., Baccei, C. S., Lee, C., Parr, T. A., Roppe, J. R., Seiders, T. J., Ziff, J., Prasit, P., Hutchinson, J. H., Evans, J. F. and Lorrain, D. S. (2011) Pharmacokinetic and pharmacodynamic characterization of an oral lysophosphatidic acid type 1 receptor-selective antagonist. J. Pharmacol. Exp. Ther. 336, 693-700.   DOI
97 Swaney, J. S., Chapman, C., Correa, L. D., Stebbins, K. J., Bundey, R. A., Prodanovich, P. C., Fagan, P., Baccei, C. S., Santini, A. M., Hutchinson, J. H., Seiders, T. J., Parr, T. A., Prasit, P., Evans, J. F. and Lorrain, D. S. (2010) A novel, orally active LPA(1) receptor antagonist inhibits lung fibrosis in the mouse bleomycin model. Br. J. Pharmacol. 160, 1699-1713.   DOI
98 Tanaka, M., Okudaira, S., Kishi, Y., Ohkawa, R., Iseki, S., Ota, M., Noji, S., Yatomi, Y., Aoki, J. and Arai, H. (2006) Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid. J. Biol. Chem. 281, 25822-25830.   DOI
99 Tokumura, A., Majima, E., Kariya, Y., Tominaga, K., Kogure, K., Yasuda, K. and Fukuzawa, K. (2002) Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase. J. Biol. Chem. 277, 39436-39442.   DOI
100 Ueda, H., Matsunaga, H., Olaposi, O. I. and Nagai, J. (2013) Lysophosphatidic acid: chemical signature of neuropathic pain. Biochim. Biophys. Acta 1831, 61-73.   DOI