Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

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)
  • Received : 2014.09.29
  • Accepted : 2014.12.02
  • Published : 2015.01.01
Download PDF
⟨ Previous Next ⟩

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

References

  1. 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. https://doi.org/10.1074/jbc.273.14.7906
  2. 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. https://doi.org/10.1007/s00439-008-0507-7
  3. Bachner, D., Ahrens, M., Betat, N., Schroder, D. and Gross, G. (1999) Developmental expression analysis of murine autotaxin (ATX). Mech. Dev. 84, 121-125. https://doi.org/10.1016/S0925-4773(99)00048-9
  4. 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.
  5. 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. https://doi.org/10.1074/jbc.274.39.27776
  6. 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. https://doi.org/10.1016/j.bmcl.2007.12.024
  7. 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. https://doi.org/10.1096/fj.13-248641
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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. https://doi.org/10.1074/jbc.C200176200
  13. 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. https://doi.org/10.1016/S1474-4422(14)70049-3
  14. 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. https://doi.org/10.1002/art.30262
  15. 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. https://doi.org/10.1146/annurev.pharmtox.010909.105753
  16. Chun, J. and Hartung, H. P. (2010) Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin. Neuropharmacol. 33, 91-101. https://doi.org/10.1097/WNF.0b013e3181cbf825
  17. 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. https://doi.org/10.1124/pr.110.003111
  18. 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. https://doi.org/10.1128/MCB.22.19.6921-6929.2002
  19. 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. https://doi.org/10.1186/1742-2094-11-37
  20. 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. https://doi.org/10.1074/jbc.M404045200
  21. 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. https://doi.org/10.1042/bj2910677
  22. 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. https://doi.org/10.1124/mol.113.087080
  23. 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. https://doi.org/10.1016/0092-8674(95)90295-3
  24. Fukushima, N., Ishii, I., Contos, J. J., Weiner, J. A. and Chun, J. (2001) Lysophospholipid receptors. Annu. Rev. Pharmacol. Toxicol. 41, 507-534. https://doi.org/10.1146/annurev.pharmtox.41.1.507
  25. 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. https://doi.org/10.1016/j.ajpath.2012.06.035
  26. 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.
  27. 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. https://doi.org/10.1124/jpet.110.165845
  28. 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. https://doi.org/10.1016/j.ajpath.2012.06.007
  29. 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. https://doi.org/10.1042/BST20110608
  30. 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. https://doi.org/10.1002/cmdc.201000425
  31. 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. https://doi.org/10.1074/jbc.M313927200
  32. 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. https://doi.org/10.1016/j.canlet.2011.10.030
  33. 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. https://doi.org/10.1083/jcb.135.4.1071
  34. 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. https://doi.org/10.1007/s11060-007-9480-6
  35. 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. https://doi.org/10.3892/ijo.2012.1709
  36. 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. https://doi.org/10.1038/aps.2010.135
  37. Ishii, I., Fukushima, N., Ye, X. and Chun, J. (2004) Lysophospholipid receptors: signaling and biology. Annu. Rev. Biochem. 73, 321-354. https://doi.org/10.1146/annurev.biochem.73.011303.073731
  38. 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. https://doi.org/10.1371/journal.pone.0042627
  39. 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. https://doi.org/10.1038/onc.2011.595
  40. 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. https://doi.org/10.1083/jcb.151.2.249
  41. 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. https://doi.org/10.1371/journal.pone.0029260
  42. 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. https://doi.org/10.1038/ni1573
  43. 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. https://doi.org/10.1038/sj.cdd.4401489
  44. 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. https://doi.org/10.1021/cb400150c
  45. 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. https://doi.org/10.1002/jcp.22631
  46. 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. https://doi.org/10.1111/j.1349-7006.2012.02246.x
  47. 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. https://doi.org/10.1124/jpet.105.098848
  48. 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. https://doi.org/10.1038/sj.onc.1204187
  49. Lafyatis, R. (2014) Transforming growth factor beta-at the centre of systemic sclerosis. Nat. Rev. Rheumatol. 10, 706-719. https://doi.org/10.1038/nrrheum.2014.137
  50. 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. https://doi.org/10.1074/jbc.M603670200
  51. 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. https://doi.org/10.1152/ajpcell.2000.278.3.C612
  52. 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. https://doi.org/10.1091/mbc.E08-03-0316
  53. 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. https://doi.org/10.1007/s10620-013-2878-4
  54. Lin, D. A. and Boyce, J. A. (2006) Lysophospholipids as mediators of immunity. Ad. Immunol. 89, 141-167. https://doi.org/10.1016/S0065-2776(05)89004-2
  55. 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. https://doi.org/10.1038/7243
  56. 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. https://doi.org/10.1371/journal.pone.0018192
  57. 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. https://doi.org/10.1093/jnci/djs319
  58. 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.
  59. 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.
  60. 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.
  61. 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.
  62. 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.
  63. 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. https://doi.org/10.1371/journal.pone.0070941
  64. 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. https://doi.org/10.1074/jbc.M302648200
  65. 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.
  66. 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. https://doi.org/10.1016/j.bmc.2013.05.061
  67. 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. https://doi.org/10.1165/rcmb.2012-0004OC
  68. 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. https://doi.org/10.1152/ajprenal.00023.2003
  69. 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. https://doi.org/10.1136/annrheumdis-2012-202832
  70. 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. https://doi.org/10.1164/rccm.201306-1014OC
  71. 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. https://doi.org/10.1038/ng.84
  72. 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. https://doi.org/10.1016/j.ygeno.2008.06.009
  73. 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. https://doi.org/10.1096/fj.13-234997
  74. 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. https://doi.org/10.1042/bj3170583
  75. 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. https://doi.org/10.1074/jbc.M201289200
  76. Sanofi (2014) Proof of Biological Activity of SAR100842 in Systemic Sclerosis. https://clinicaltrials.gov/ct2/show/NCT01651143, Access Date: 2014/09/15.
  77. 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. https://doi.org/10.1007/s00018-006-6412-0
  78. 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. https://doi.org/10.1371/journal.pone.0022182
  79. Sedlakova, I., Vavrova, J., Tosner, J. and Hanousek, L. (2011) Lysophosphatidic acid (LPA)-a perspective marker in ovarian cancer. Tumor Biol. 32, 311-316. https://doi.org/10.1007/s13277-010-0123-8
  80. 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. https://doi.org/10.1016/S0895-7061(98)00269-6
  81. 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. https://doi.org/10.1074/jbc.M201659200
  82. 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. https://doi.org/10.1016/S0092-8674(00)81011-9
  83. 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. https://doi.org/10.1002/ardp.201200395
  84. 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. https://doi.org/10.1158/1078-0432.CCR-13-1284
  85. 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. https://doi.org/10.1124/jpet.110.175901
  86. 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. https://doi.org/10.1111/j.1476-5381.2010.00828.x
  87. 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. https://doi.org/10.1074/jbc.M605142200
  88. 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. https://doi.org/10.1007/BF02533615
  89. 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. https://doi.org/10.1074/jbc.M205623200
  90. Ueda, H., Matsunaga, H., Olaposi, O. I. and Nagai, J. (2013) Lysophosphatidic acid: chemical signature of neuropathic pain. Biochim. Biophys. Acta 1831, 61-73. https://doi.org/10.1016/j.bbalip.2012.08.014
  91. 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. https://doi.org/10.1083/jcb.200204026
  92. 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. https://doi.org/10.1172/JCI806
  93. 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. https://doi.org/10.1128/MCB.02419-05
  94. 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. https://doi.org/10.1002/cncr.24907
  95. 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. https://doi.org/10.1074/jbc.M808506200
  96. 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. https://doi.org/10.1038/nature03505
  97. 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. https://doi.org/10.1016/S1388-1981(02)00330-X
  98. 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.
  99. Yung, Y. C., Stoddard, N. C. and Chun, J. (2014) LPA receptor signaling: pharmacology, physiology, and pathophysiology. J. Lipid Res. 55, 1192-1214. https://doi.org/10.1194/jlr.R046458
  100. 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. https://doi.org/10.1158/0008-5472.CAN-09-0302

Cited by

  1. The autotaxin-lysophosphatidic acid–lysophosphatidic acid receptor cascade: proposal of a novel potential therapeutic target for treating glioblastoma multiforme vol.14, pp.1, 2015, https://doi.org/10.1186/s12944-015-0059-5
  2. Discovery, Structure–Activity Relationship, and Binding Mode of an Imidazo[1,2-a]pyridine Series of Autotaxin Inhibitors vol.60, pp.17, 2017, https://doi.org/10.1021/acs.jmedchem.7b00647
  3. Autotaxin inhibitors: a patent review (2012-2016) vol.27, pp.7, 2017, https://doi.org/10.1080/13543776.2017.1323331
  4. Lysophosphatidic acid (LPA) signaling via LPA4 and LPA6 negatively regulates cell motile activities of colon cancer cells vol.483, pp.1, 2017, https://doi.org/10.1016/j.bbrc.2016.12.088
  5. Lysophosphatidic acid signaling via LPA1 and LPA3 regulates cellular functions during tumor progression in pancreatic cancer cells vol.352, pp.1, 2017, https://doi.org/10.1016/j.yexcr.2017.02.007
  6. Discovery and synthetic optimization of a novel scaffold for hydrophobic tunnel-targeted autotaxin inhibition vol.24, pp.19, 2016, https://doi.org/10.1016/j.bmc.2016.08.004
  7. Investigational drugs for idiopathic pulmonary fibrosis vol.26, pp.9, 2017, https://doi.org/10.1080/13543784.2017.1364361
  8. Local effect of lysophosphatidic acid on prostaglandin production in the bovine oviduct vol.29, pp.5, 2017, https://doi.org/10.1071/RD15409
  9. Bleb Formation in Human Fibrosarcoma HT1080 Cancer Cell Line Is Positively Regulated by the Lipid Signalling Phospholipase D2 (PLD2) vol.10, pp.2, 2016, https://doi.org/10.1016/j.als.2016.11.001
  10. Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression vol.57, pp.1, 2016, https://doi.org/10.1194/jlr.R060020
  11. Discovery of Novel Gq-Biased LPA1 Negative Allosteric Modulators vol.22, pp.7, 2017, https://doi.org/10.1177/2472555217691719
  12. The critical role and potential target of the autotaxin/lysophosphatidate axis in pancreatic cancer vol.39, pp.3, 2017, https://doi.org/10.1177/1010428317694544
  13. Chitinase 3-like 1 expression by human (MG63) osteoblasts in response to lysophosphatidic acid and 1,25-dihydroxyvitamin D3 vol.128-129, 2016, https://doi.org/10.1016/j.biochi.2016.08.011
  14. Enhanced cellular functions through induction of LPA2 by cisplatin in fibrosarcoma HT1080 cells vol.431, pp.1-2, 2017, https://doi.org/10.1007/s11010-017-2971-7
  15. Diverse effects of LPA4, LPA5 and LPA6 on the activation of tumor progression in pancreatic cancer cells vol.461, pp.1, 2015, https://doi.org/10.1016/j.bbrc.2015.03.169
  16. Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis vol.60, pp.9, 2017, https://doi.org/10.1021/acs.jmedchem.7b00032
  17. Therapeutic targets in idiopathic pulmonary fibrosis vol.131, 2017, https://doi.org/10.1016/j.rmed.2017.07.062
  18. Nonsurgical therapy for hydrocephalus: a comprehensive and critical review vol.13, pp.1, 2015, https://doi.org/10.1186/s12987-016-0025-2
  19. Lysophosphatidic Acid Receptor 4 Activation Augments Drug Delivery in Tumors by Tightening Endothelial Cell-Cell Contact vol.20, pp.9, 2017, https://doi.org/10.1016/j.celrep.2017.07.080
  20. on the regulation of colony formation activity in colon cancer cells treated with anticancer drugs vol.38, pp.1, 2018, https://doi.org/10.1080/10799893.2018.1426608
  21. Promotion of cell-invasive activity through the induction of LPA receptor-1 in pancreatic cancer cells vol.38, pp.4, 2018, https://doi.org/10.1080/10799893.2018.1531889
  22. Mechanisms of Lysophosphatidic Acid-Mediated Lymphangiogenesis in Prostate Cancer vol.10, pp.11, 2018, https://doi.org/10.3390/cancers10110413
  23. Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism vol.59, pp.10, 2018, https://doi.org/10.1194/jlr.M082008
  24. Lysophospholipid Signaling in the Epithelial Ovarian Cancer Tumor Microenvironment vol.10, pp.7, 2018, https://doi.org/10.3390/cancers10070227
  25. Comprehensive Analysis of Non-Synonymous Natural Variants of G Protein-Coupled Receptors vol.26, pp.2, 2018, https://doi.org/10.4062/biomolther.2017.073
  26. Extracellular Vesicles as Conveyors of Membrane-Derived Bioactive Lipids in Immune System vol.19, pp.4, 2018, https://doi.org/10.3390/ijms19041227
  27. Lysophosphatidic Acid Signaling in Obesity and Insulin Resistance vol.10, pp.4, 2018, https://doi.org/10.3390/nu10040399
  28. Fingolimod: Lessons Learned and New Opportunities for Treating Multiple Sclerosis and Other Disorders vol.59, pp.1, 2019, https://doi.org/10.1146/annurev-pharmtox-010818-021358
  29. Inhibition of lysophosphatidic acid receptor ameliorates Sjögren's syndrome in NOD mice vol.8, pp.16, 2015, https://doi.org/10.18632/oncotarget.15916
  30. Chemical Tools for Studying Lipid-Binding Class A G Protein–Coupled Receptors vol.69, pp.3, 2017, https://doi.org/10.1124/pr.116.013243
  31. Alpha conotoxin-BuIA globular isomer is a competitive antagonist for oleoyl-L-alpha-lysophosphatidic acid binding to LPAR6; A molecular dynamics study vol.12, pp.12, 2015, https://doi.org/10.1371/journal.pone.0189154
  32. Tissue-resident mesenchymal stromal cells: Implications for tissue-specific antifibrotic therapies vol.10, pp.426, 2015, https://doi.org/10.1126/scitranslmed.aan5174
  33. Therapeutic targets and early stage clinical trials for pulmonary fibrosis vol.28, pp.1, 2015, https://doi.org/10.1080/13543784.2019.1554054
  34. Rapid establishment of highly migratory cells from cancer cells for investigating cellular functions vol.39, pp.3, 2019, https://doi.org/10.1080/10799893.2019.1638399
  35. Lipid metabolism and Calcium signaling in epithelial ovarian cancer vol.81, pp.None, 2015, https://doi.org/10.1016/j.ceca.2019.06.002
  36. Recent Advances in Rational Diagnosis and Treatment of Normal Pressure Hydrocephalus: A Critical Appraisal on Novel Diagnostic, Therapy Monitoring and Treatment Modalities vol.20, pp.10, 2015, https://doi.org/10.2174/1389450120666190214121342
  37. Safety, Pharmacokinetics, and Pharmacodynamics of the Autotaxin Inhibitor GLPG1690 in Healthy Subjects: Phase 1 Randomized Trials vol.59, pp.10, 2015, https://doi.org/10.1002/jcph.1424
  38. LPA 1/3 overactivation induces neonatal posthemorrhagic hydrocephalus through ependymal loss and ciliary dysfunction vol.5, pp.10, 2015, https://doi.org/10.1126/sciadv.aax2011
  39. Benzoxaboroles-Novel Autotaxin Inhibitors vol.24, pp.19, 2015, https://doi.org/10.3390/molecules24193419
  40. Antifibrotic effects of 2-carba cyclic phosphatidic acid (2ccPA) in systemic sclerosis: contribution to the novel treatment vol.21, pp.None, 2015, https://doi.org/10.1186/s13075-019-1881-3
  41. microRNA‐501‐5p promotes cell proliferation and migration in gastric cancer by downregulating LPAR1 vol.121, pp.2, 2015, https://doi.org/10.1002/jcb.29426
  42. Lysophosphatidic Acid and Hematopoiesis: From Microenvironmental Effects to Intracellular Signaling vol.21, pp.6, 2015, https://doi.org/10.3390/ijms21062015
  43. A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA1), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration vol.63, pp.5, 2015, https://doi.org/10.1021/acs.jmedchem.9b01287
  44. Lysophosphatidic acid receptor-2 (LPA2)-mediated signaling enhances chemoresistance in melanoma cells treated with anticancer drugs vol.469, pp.1, 2015, https://doi.org/10.1007/s11010-020-03730-w
  45. Lysophosphatidic Acid Receptor 5 Contributes to Imiquimod-Induced Psoriasis-Like Lesions through NLRP3 Inflammasome Activation in Macrophages vol.9, pp.8, 2015, https://doi.org/10.3390/cells9081753
  46. NLRP3 Inflammasome Activation Is Involved in LPA 1 -Mediated Brain Injury after Transient Focal Cerebral Ischemia vol.21, pp.22, 2015, https://doi.org/10.3390/ijms21228595
  47. BMS-986020, a Specific LPA 1 Antagonist, Provides Neuroprotection against Ischemic Stroke in Mice vol.9, pp.11, 2015, https://doi.org/10.3390/antiox9111097
  48. Different effects of lysophosphatidic acid receptor-2 (LPA2) and LPA5 on the regulation of chemoresistance in colon cancer cells vol.41, pp.1, 2015, https://doi.org/10.1080/10799893.2020.1794002
  49. LPAR5 promotes thyroid carcinoma cell proliferation and migration by activating class IA PI3K catalytic subunit p110β vol.112, pp.4, 2021, https://doi.org/10.1111/cas.14837
  50. Lysophosphatidic Acid: Promoter of Cancer Progression and of Tumor Microenvironment Development. A Promising Target for Anticancer Therapies? vol.10, pp.6, 2015, https://doi.org/10.3390/cells10061390
  51. The lysophosphatidic acid axis in fibrosis: Implications for glaucoma vol.29, pp.4, 2021, https://doi.org/10.1111/wrr.12929
  52. Lysophosphatidic Acid Signaling in Cancer Cells: What Makes LPA So Special? vol.10, pp.8, 2015, https://doi.org/10.3390/cells10082059
  53. Lysophosphatidic acid (LPA) receptor modulators: Structural features and recent development vol.222, pp.None, 2015, https://doi.org/10.1016/j.ejmech.2021.113574
  54. Lysophosphatidic acid (LPA) receptor modulators: Structural features and recent development vol.222, pp.None, 2015, https://doi.org/10.1016/j.ejmech.2021.113574
  55. Changes in Plasma Phospholipid Metabolism Are Associated with Clinical Manifestations of Systemic Sclerosis vol.11, pp.11, 2015, https://doi.org/10.3390/diagnostics11112116
  56. Emerging therapeutic targets for idiopathic pulmonary fibrosis: preclinical progress and therapeutic implications vol.25, pp.11, 2021, https://doi.org/10.1080/14728222.2021.2006186
  57. Role of lysophosphatidic acid and its receptors in health and disease: novel therapeutic strategies vol.6, pp.1, 2015, https://doi.org/10.1038/s41392-020-00367-5
  58. Interfering with lysophosphatidic acid receptor edg2/lpa1 signalling slows down disease progression in SOD1‐G93A transgenic mice vol.47, pp.7, 2015, https://doi.org/10.1111/nan.12699