Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Journal of Lipid Research

Volumn 57, Issue 1, 2016, Pages 25-35

  Federico, Lorenzo ^a   Jeong, Kang Jin ^a   Vellano, Christopher P ^a   Mills, Gordon B ^a  

^a UNIVERSITY OF TEXAS   (United States)

Author keywords

Inflammation; Metabolism; The Cancer Genome Atlas

Indexed keywords

AUTOTAXIN; LYSOPHOSPHOLIPASE; LYSOPHOSPHOLIPASE D; UNCLASSIFIED DRUG; ALKYLGLYCEROPHOSPHOETHANOLAMINE PHOSPHODIESTERASE; INORGANIC PYROPHOSPHATASE; PHOSPHODIESTERASE;

CANCER GROWTH; CARCINOGENESIS; ENZYME ACTIVITY; HUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN SECRETION; PROTEIN STRUCTURE; REVIEW; STRUCTURE ACTIVITY RELATION; TRANSCRIPTION REGULATION; ANIMAL; CELL TRANSFORMATION; DISEASE COURSE; ENZYMOLOGY; GENETICS; METABOLISM; NEOPLASM; PATHOLOGY;

ANIMALS; CARCINOGENESIS; CELL TRANSFORMATION, NEOPLASTIC; DISEASE PROGRESSION; HUMANS; NEOPLASMS; PHOSPHORIC DIESTER HYDROLASES; PYROPHOSPHATASES;

EID: 84956723700     PISSN: 00222275     EISSN: 15397262     Source Type: Journal    
DOI: 10.1194/jlr.R060020     Document Type: Review

References (183)

1. Stracke, M. L., H. C. Krutzsch, E. J. Unsworth, A. Arestad, V. Cioce, E. Schiffmann, and L. A. Liotta. 1992. Identifi cation, purifi-cation, and partial sequence analysis of autotaxin, a novel motilitystimulating protein. J. Biol. Chem. 267: 2524-2529.
2. Lee, H. Y., J. Murata, T. Clair, M. H. Polymeropoulos, R. Torres, R. E. Manrow, L. A. Liotta, and M. L. Stracke. 1996. Cloning, chromosomal localization, and tissue expression of autotaxin from human teratocarcinoma cells. Biochem. Biophys. Res. Commun. 218: 714-719.
3. Murata, J., H. Y. Lee, T. Clair, H. C. Krutzsch, A. A. Arestad, M. E. Sobel, L. A. Liotta, and M. L. Stracke. 1994. cDNA cloning of the human tumor motility-stimulating protein, autotaxin, reveals a homology with phosphodiesterases. J. Biol. Chem. 269: 30479-30484.
4. Kawagoe, H., O. Soma, J. Goji, N. Nishimura, M. Narita, J. Inazawa, H. Nakamura, and K. Sano. 1995. Molecular cloning and chromosomal assignment of the human brain-type phosphodiesterase I/nucleotide pyrophosphatase gene (PDNP2). Genomics. 30: 380-384.
5. Piao, J. H., Y. Matsuda, H. Nakamura, and K. Sano. 1999. Assignment of Pdnp2, the gene encoding phosphodiesterase I/ nucleotide pyrophosphatase 2, to mouse chromosome 15D2. Cytogenet. Cell Genet. 87: 172-174.
6. Narita, M., J. Goji, H. Nakamura, and K. Sano. 1994. Molecular cloning, expression, and localization of a brain-specifi c phosphodiesterase I/nucleotide pyrophosphatase (PD-I alpha) from rat brain. J. Biol. Chem. 269: 28235-28242.
7. Giganti, A., M. Rodriguez, B. Fould, N. Moulharat, F. Coge, P. Chomarat, J. P. Galizzi, P. Valet, J. S. Saulnier-Blache, J. A. Boutin, et al. 2008. Murine and human autotaxin alpha, beta, and gamma isoforms: gene organization, tissue distribution, and biochemical characterization. J. Biol. Chem. 283: 7776-7789.
8. Hashimoto, T., S. Okudaira, K. Igarashi, K. Hama, Y. Yatomi, and J. Aoki. 2012. Identifi cation and biochemical characterization of a novel autotaxin isoform, ATXdelta, with a four-amino acid deletion. J. Biochem. 151: 89-97.
9. Barbayianni, E., E. Kaffe, V. Aidinis, and G. Kokotos. 2015. Autotaxin, a secreted lysophospholipase D, as a promising therapeutic target in chronic infl ammation and cancer. Prog. Lipid Res. 58: 76-96.
10. Tokumura, A., E. Majima, Y. Kariya, K. Tominaga, K. Kogure, K. Yasuda, and K. Fukuzawa. 2002. Identifi cation of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase. J. Biol. Chem. 277: 39436-39442.
11. Houben, A. J., X. M. van Wijk, L. A. van Meeteren, L. van Zeijl, E. M. van de Westerlo, J. Hausmann, A. Fish, A. Perrakis, T. H. van Kuppevelt, and W. H. Moolenaar. 2013. The polybasic insertion in autotaxin alpha confers specifi c binding to heparin and cell surface heparan sulfate proteoglycans. J. Biol. Chem. 288: 510-519.
12. Goding, J. W., B. Grobben, and H. Slegers. 2003. Physiological and pathophysiological functions of the ecto-nucleotide pyrophosphatase/ phosphodiesterase family. Biochim. Biophys. Acta. 1638: 1-19.
13. Stefan, C., S. Jansen, and M. Bollen. 2006. Modulation of purinergic signaling by NPP-type ectophosphodiesterases. Purinergic Signal. 2: 361-370.
14. Stefan, C., S. Jansen, and M. Bollen. 2005. NPP-type ectophosphodiesterases: unity in diversity. Trends Biochem. Sci. 30: 542-550.
15. Hausmann, J., S. Kamtekar, E. Christodoulou, J. E. Day, T. Wu, Z. Fulkerson, H. M. Albers, L. A. van Meeteren, A. J. Houben, L. van Zeijl, et al. 2011. Structural basis of substrate discrimination and integrin binding by autotaxin. Nat. Struct. Mol. Biol. 18: 198-204.
16. Nishimasu, H., S. Okudaira, K. Hama, E. Mihara, N. Dohmae, A. Inoue, R. Ishitani, J. Takagi, J. Aoki, and O. Nureki. 2011. Crystal structure of autotaxin and insight into GPCR activation by lipid mediators. Nat. Struct. Mol. Biol. 18: 205-212.
17. Clair, T., H. Y. Lee, L. A. Liotta, and M. L. Stracke. 1997. Autotaxin is an exoenzyme possessing 5 '-nucleotide phosphodiesterase/ ATP pyrophosphatase and ATPase activities. J. Biol. Chem. 272: 996-1001.
18. Lee, H. Y., T. Clair, P. T. Mulvaney, E. C. Woodhouse, S. Aznavoorian, L. A. Liotta, and M. L. Stracke. 1996. Stimulation of tumor cell motility linked to phosphodiesterase catalytic site of autotaxin. J. Biol. Chem. 271: 24408-24412.
19. Lee, J., I. D. Jung, S. W. Nam, T. Clair, E. M. Jeong, S. Y. Hong, J. W. Han, H. W. Lee, M. L. Stracke, and H. Y. Lee. 2001. Enzymatic activation of autotaxin by divalent cations without EF-hand loop region involvement. Biochem. Pharmacol. 62: 219-224.
20. Umezu-Goto, M., Y. Kishi, A. Taira, K. Hama, N. Dohmae, K. Takio, T. Yamori, G. B. Mills, K. Inoue, J. Aoki, et al. 2002. Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. J. Cell Biol. 158: 227-233.
21. Fang, X., M. Schummer, M. Mao, S. Yu, F. H. Tabassam, R. Swaby, Y. Hasegawa, J. L. Tanyi, R. LaPushin, A. Eder, et al. 2002. Lysophosphatidic acid is a bioactive mediator in ovarian cancer. Biochim. Biophys. Acta. 1582: 257-264.
22. Mills, G. B., and W. H. Moolenaar. 2003. The emerging role of lysophosphatidic acid in cancer. Nat. Rev. Cancer. 3: 582-591.
23. Murph, M., and G. B. Mills. 2007. Targeting the lipids LPA and S1P and their signalling pathways to inhibit tumour progression. Expert Rev. Mol. Med. 9: 1-18.
24. Murph, M., T. Tanaka, S. Liu, and G. B. Mills. 2006. Of spiders and crabs: the emergence of lysophospholipids and their metabolic pathways as targets for therapy in cancer. Clin. Cancer Res. 12: 6598-6602.
25. Panupinthu, N., H. Y. Lee, and G. B. Mills. 2010. Lysophosphatidic acid production and action: critical new players in breast cancer initiation and progression. Br. J. Cancer. 102: 941-946.
26. Madan, D., C. G. Ferguson, W. Y. Lee, G. D. Prestwich, and C. A. Testa. 2013. Non-invasive imaging of tumors by monitoring autotaxin activity using an enzyme-activated near-infrared fl uorogenic substrate. PLoS ONE. 8: e79065.
27. Gijsbers, R., J. Aoki, H. Arai, and M. Bollen. 2003. The hydrolysis of lysophospholipids and nucleotides by autotaxin (NPP2) involves a single catalytic site. FEBS Lett. 538: 60-64.
28. Cimpean, A., C. Stefan, R. Gijsbers, W. Stalmans, and M. Bollen. 2004. Substrate-specifying determinants of the nucleotide pyrophosphatases/ phosphodiesterases NPP1 and NPP2. Biochem. J. 381: 71-77.
29. Jansen, S., M. Andries, R. Derua, E. Waelkens, and M. Bollen. 2009. Domain interplay mediated by an essential disulfi de linkage is critical for the activity and secretion of the metastasis-promoting enzyme autotaxin. J. Biol. Chem. 284: 14296-14302.
30. Gijsbers, R., H. Ceulemans, and M. Bollen. 2003. Functional characterization of the non-catalytic ectodomains of the nucleotide pyrophosphatase/phosphodiesterase NPP1. Biochem. J. 371: 321-330.
31. Stracke, M. L., A. Arestad, M. Levine, H. C. Krutzsch, and L. A. Liotta. 1995. Autotaxin is an N-linked glycoprotein but the sugar moieties are not needed for its stimulation of cellular motility. Melanoma Res. 5: 203-209.
32. Pradère, J. P., E. Tarnus, S. Grès, P. Valet, and J. S. Saulnier-Blache. 2007. Secretion and lysophospholipase D activity of autotaxin by adipocytes are controlled by N-glycosylation and signal peptidase. Biochim. Biophys. Acta. 1771: 93-102.
33. Jansen, S., N. Callewaert, I. Dewerte, M. Andries, H. Ceulemans, and M. Bollen. 2007. An essential oligomannosidic glycan chain in the catalytic domain of autotaxin, a secreted lysophospholipase-D. J. Biol. Chem. 282: 11084-11091.
34. Koyama, M., H. Nishimasu, R. Ishitani, and O. Nureki. 2012. Molecular dynamics simulation of Autotaxin: roles of the nuclease-like domain and the glycan modifi cation. J. Phys. Chem. B. 116: 11798-11808.
35. Tabchy, A., G. Tigyi, and G. B. Mills. 2011. Location, location, location: a crystal-clear view of autotaxin saturating LPA receptors. Nat. Struct. Mol. Biol. 18: 117-118.
36. Zhou, A. 2007. Functional structure of the somatomedin B domain of vitronectin. Protein Sci. 16: 1502-1508.
37. Zhou, A., J. A. Huntington, N. S. Pannu, R. W. Carrell, and R. J. Read. 2003. How vitronectin binds PAI-1 to modulate fi brinolysis and cell migration. Nat. Struct. Biol. 10: 541-544.
38. Ruoslahti, E. 1996. RGD and other recognition sequences for integrins. Annu. Rev. Cell Dev. Biol. 12: 697-715.
39. Fulkerson, Z., T. Wu, M. Sunkara, C. V. Kooi, A. J. Morris, and S. S. Smyth. 2011. Binding of autotaxin to integrins localizes lysophosphatidic acid production to platelets and mammalian cells. J. Biol. Chem. 286: 34654-34663.
40. Kawagoe, H., M. L. Stracke, H. Nakamura, and K. Sano. 1997. Expression and transcriptional regulation of the PD-Ialpha/autotaxin gene in neuroblastoma. Cancer Res. 57: 2516-2521.
41. Farina, A. R., L. Cappabianca, P. Ruggeri, N. Di Ianni, M. Ragone, S. Merolle, K. Sano, M. L. Stracke, J. M. Horowitz, A. Gulino, et al. 2012. Constitutive autotaxin transcription by Nmyc-amplifi ed and non-amplifi ed neuroblastoma cells is regulated by a novel AP-1 and SP-mediated mechanism and abrogated by curcumin. FEBS Lett. 586: 3681-3691.
42. Sioletic, S., J. Czaplinski, L. Hu, J. A. Fletcher, C. D. Fletcher, A. J. Wagner, M. Loda, G. D. Demetri, E. T. Sicinska, and E. L. Snyder. 2014. c-Jun promotes cell migration and drives expression of the motility factor ENPP2 in soft tissue sarcomas. J. Pathol. 234: 190-202.
43. Chen, M., and K. L. O'Connor. 2005. Integrin alpha6beta4 promotes expression of autotaxin/ENPP2 autocrine motility factor in breast carcinoma cells. Oncogene. 24: 5125-5130.
44. Fric, J., T. Zelante, A. Y. Wong, A. Mertes, H. B. Yu, and P. Ricciardi-Castagnoli. 2012. NFAT control of innate immunity. Blood. 120: 1380-1389.
45. Pan, M. G., Y. Xiong, and F. Chen. 2013. NFAT gene family in infl ammation and cancer. Curr. Mol. Med. 13: 543-554.
46. Qin, J. J., S. Nag, W. Wang, J. Zhou, W. D. Zhang, H. Wang, and R. Zhang. 2014. NFAT as cancer target: mission possible? Biochim. Biophys. Acta. 1846: 297-311.
47. Shou, J., J. Jing, J. Xie, L. You, Z. Jing, J. Yao, W. Han, and H. Pan. 2015. Nuclear factor of activated T cells in cancer development and treatment. Cancer Lett. 361: 174-184.
48. Braeuer, R. R., M. Zigler, T. Kamiya, A. S. Dobroff, L. Huang, W. Choi, D. J. McConkey, E. Shoshan, A. K. Mobley, R. Song, et al. 2012. Galectin-3 contributes to melanoma growth and metastasis via regulation of NFAT1 and autotaxin. Cancer Res. 72: 5757-5766.
49. Thijssen, V. L., R. Heusschen, J. Caers, and A. W. Griffi oen. 2015. Galectin expression in cancer diagnosis and prognosis: A systematic review. Biochim. Biophys. Acta. 1855: 235-247
50. Seifert, A., S. Rau, G. Kullertz, B. Fischer, and A. N. Santos. 2009. TCDD induces cell migration via NFATc1/ATX-signaling in MCF-7 cells. Toxicol. Lett. 184: 26-32.
51. Benesch, M. G., Y. Y. Zhao, J. M. Curtis, T. P. McMullen, and D. N. Brindley. Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine-1-phosphate. J. Lipid Res. Epub ahead of print. April 20, 2015; doi:10.1194/jlr.M057661.
52. Moolenaar, W. H. 2002. Lysophospholipids in the limelight: autotaxin takes center stage. J. Cell Biol. 158: 197-199.
53. Jansen, S., C. Stefan, J. W. Creemers, E. Waelkens, A. Van Eynde, W. Stalmans, and M. Bollen. 2005. Proteolytic maturation and activation of autotaxin (NPP2), a secreted metastasis-enhancing lysophospholipase D. J. Cell Sci. 118: 3081-3089.
54. Koike, S., K. Keino-Masu, T. Ohto, and M. Masu. 2006. The N-terminal hydrophobic sequence of autotaxin (ENPP2) functions as a signal peptide. Genes Cells. 11: 133-142.
55. Pamuklar, Z., L. Federico, S. Liu, M. Umezu-Goto, A. Dong, M. Panchatcharam, Z. Fulkerson, E. Berdyshev, V. Natarajan, X. Fang, et al. 2009. Autotaxin/lysopholipase D and lysophosphatidic acid regulate murine hemostasis and thrombosis. J. Biol. Chem. 284: 7385-7394.
56. [Erratum. 2009. J. Biol. Chem. 284: 21100.]
57. Boucher, J., D. Quilliot, J. P. Praderes, M. F. Simon, S. Gres, C. Guigne, D. Prevot, G. Ferry, J. A. Boutin, C. Carpene, et al. 2005. Potential involvement of adipocyte insulin resistance in obesityassociated up-regulation of adipocyte lysophospholipase D/autotaxin expression. Diabetologia. 48: 569-577.
58. Dusaulcy, R., C. Rancoule, S. Gres, E. Wanecq, A. Colom, C. Guigne, L. A. van Meeteren, W. H. Moolenaar, P. Valet, and J. S. Saulnier-Blache. 2011. Adipose-specifi c disruption of autotaxin enhances nutritional fattening and reduces plasma lysophosphatidic acid. J. Lipid Res. 52: 1247-1255.
59. Ferry, G., E. Tellier, A. Try, S. Gres, I. Naime, M. F. Simon, M. Rodriguez, J. Boucher, I. Tack, S. Gesta, et al. 2003. Autotaxin is released from adipocytes, catalyzes lysophosphatidic acid synthesis, and activates preadipocyte proliferation. Up-regulated expression with adipocyte differentiation and obesity. J. Biol. Chem. 278: 18162-18169.
60. Nishimura, S., M. Nagasaki, S. Okudaira, J. Aoki, T. Ohmori, R. Ohkawa, K. Nakamura, K. Igarashi, H. Yamashita, K. Eto, et al. 2014. ENPP2 contributes to adipose tissue expansion and insulin resistance in diet-induced obesity. Diabetes. 63: 4154-4164.
61. Savaskan, N. E., L. Rocha, M. R. Kotter, A. Baer, G. Lubec, L. A. van Meeteren, Y. Kishi, J. Aoki, W. H. Moolenaar, R. Nitsch, et al. 2007. Autotaxin (NPP-2) in the brain: cell type-specifi c expression and regulation during development and after neurotrauma. Cell. Mol. Life Sci. 64: 230-243.
62. Ohuchi, H., Y. Hayashibara, H. Matsuda, M. Onoi, M. Mitsumori, M. Tanaka, J. Aoki, H. Arai, and S. Noji. 2007. Diversifi ed expression patterns of autotaxin, a gene for phospholipid-generating enzyme during mouse and chicken development. Dev. Dyn. 236: 1134-1143.
63. Ma, L., H. Uchida, J. Nagai, M. Inoue, J. Aoki, and H. Ueda. 2010. Evidence for de novo synthesis of lysophosphatidic acid in the spinal cord through phospholipase A2 and autotaxin in nerve injury-induced neuropathic pain. J. Pharmacol. Exp. Ther. 333: 540-546.
64. Dennis, J., L. Nogaroli, and B. Fuss. 2005. Phosphodiesterase-Ialpha/autotaxin (PD-Ialpha/ATX): a multifunctional protein involved in central nervous system development and disease. J. Neurosci. Res. 82: 737-742.
65. Sato, K., E. Malchinkhuu, T. Muraki, K. Ishikawa, K. Hayashi, M. Tosaka, A. Mochiduki, K. Inoue, H. Tomura, C. Mogi, et al. 2005. Identifi cation of autotaxin as a neurite retraction-inducing factor of PC12 cells in cerebrospinal fl uid and its possible sources. J. Neurochem. 92: 904-914.
66. Jansen, S., M. Andries, K. Vekemans, H. Vanbilloen, A. Verbruggen, and M. Bollen. 2009. Rapid clearance of the circulating metastatic factor autotaxin by the scavenger receptors of liver sinusoidal endothelial cells. Cancer Lett. 284: 216-221.
67. Clair, T., J. Aoki, E. Koh, R. W. Bandle, S. W. Nam, M. M. Ptaszynska, G. B. Mills, E. Schiffmann, L. A. Liotta, and M. L. Stracke. 2003. Autotaxin hydrolyzes sphingosylphosphorylcholine to produce the regulator of migration, sphingosine-1-phosphate. Cancer Res. 63: 5446-5453.
68. Aoki, J., A. Inoue, and S. Okudaira. 2008. Two pathways for lysophosphatidic acid production. Biochim. Biophys. Acta. 1781: 513-518.
69. Tanaka, M., S. Okudaira, Y. Kishi, R. Ohkawa, S. Iseki, M. Ota, S. Noji, Y. Yatomi, J. Aoki, and H. Arai. 2006. Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid. J. Biol. Chem. 281: 25822-25830.
70. Liu, S., M. Murph, N. Panupinthu, and G. B. Mills. 2009. ATX-LPA receptor axis in infl ammation and cancer. Cell Cycle. 8: 3695-3701.
71. Teo, K., and V. G. Brunton. 2014. The role and therapeutic potential of the autotaxin-lysophosphatidate signalling axis in breast cancer. Biochem. J. 463: 157-165.
72. Leblanc, R., and O. Peyruchaud. 2015. New insights into the autotaxin/ LPA axis in cancer development and metastasis. Exp. Cell Res. 333: 183-189.
73. Kamikubo, Y., R. De Guzman, G. Kroon, S. Curriden, J. G. Neels, M. J. Churchill, P. Dawson, S. Oldziej, A. Jagielska, H. A. Scheraga, et al. 2004. Disulfi de bonding arrangements in active forms of the somatomedin B domain of human vitronectin. Biochemistry. 43: 6519-6534.
74. Felding-Habermann, B., and D. A. Cheresh. 1993. Vitronectin and its receptors. Curr. Opin. Cell Biol. 5: 864-868.
75. Wu, T., C. V. Kooi, P. Shah, R. Charnigo, C. Huang, S. S. Smyth, and A. J. Morris. 2014. Integrin-mediated cell surface recruitment of autotaxin promotes persistent directional cell migration. FASEB J. 28: 861-870.
76. Turing, A. M. 1952. The chemical basis of morphogenesis. Philos. Trans. R. Soc. Lond. B.. 237: 37-72.
77. Moolenaar, W. H., A. J. Houben, S. J. Lee, and L. A. van Meeteren. 2013. Autotaxin in embryonic development. Biochim. Biophys. Acta. 1831: 13-19.
78. van Meeteren, L. A., P. Ruurs, C. Stortelers, P. Bouwman, M. A. van Rooijen, J. P. Pradere, T. R. Pettit, M. J. Wakelam, J. S. Saulnier-Blache, C. L. Mummery, et al. 2006. Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development. Mol. Cell. Biol. 26: 5015-5022.
79. Ferry, G., A. Giganti, F. Coge, F. Bertaux, K. Thiam, and J. A. Boutin. 2007. Functional invalidation of the autotaxin gene by a single amino acid mutation in mouse is lethal. FEBS Lett. 581: 3572-3578.
80. Sumida, H., K. Noguchi, Y. Kihara, M. Abe, K. Yanagida, F. Hamano, S. Sato, K. Tamaki, Y. Morishita, M. R. Kano, et al. 2010. LPA4 regulates blood and lymphatic vessel formation during mouse embryogenesis. Blood. 116: 5060-5070.
81. Yukiura, H., K. Hama, K. Nakanaga, M. Tanaka, Y. Asaoka, S. Okudaira, N. Arima, A. Inoue, T. Hashimoto, H. Arai, et al. 2011. Autotaxin regulates vascular development via multiple lysophosphatidic acid (LPA) receptors in zebrafi sh. J. Biol. Chem. 286: 43972-43983.
82. Li, H., R. Yue, B. Wei, G. Gao, J. Du, and G. Pei. 2014. Lysophosphatidic acid acts as a nutrient-derived developmental cue to regulate early hematopoiesis. EMBO J. 33: 1383-1396.
83. Im, E., R. Motiejunaite, J. Aranda, E. Y. Park, L. Federico, T. I. Kim, T. Clair, M. L. Stracke, S. Smyth, and A. Kazlauskas. 2010. Phospholipase Cgamma activation drives increased production of autotaxin in endothelial cells and lysophosphatidic acid-dependent regression. Mol. Cell. Biol. 30: 2401-2410.
84. Siess, W., K. J. Zangl, M. Essler, M. Bauer, R. Brandl, C. Corrinth, R. Bittman, G. Tigyi, and M. Aepfelbacher. 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.
85. Inoue, M., L. Ma, J. Aoki, J. Chun, and H. Ueda. 2008. Autotaxin, a synthetic enzyme of lysophosphatidic acid (LPA), mediates the induction of nerve-injured neuropathic pain. Mol. Pain. 4: 6.
86. Inoue, M., W. Xie, Y. Matsushita, J. Chun, J. Aoki, and H. Ueda. 2008. Lysophosphatidylcholine induces neuropathic pain through an action of autotaxin to generate lysophosphatidic acid. Neuroscience. 152: 296-298.
87. Inoue, M., M. H. Rashid, R. Fujita, J. J. Contos, J. Chun, and H. Ueda. 2004. Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling. Nat. Med. 10: 712-718.
88. Katakai, T., N. Kondo, Y. Ueda, and T. Kinashi. 2014. Autotaxin produced by stromal cells promotes LFA-1-independent and Rhodependent interstitial T cell motility in the lymph node paracortex. J. Immunol. 193: 617-626.
89. Morris, A. J., and S. S. Smyth. 2014. Lipid phosphate phosphatases: more than one way to put the brakes on LPA signaling? J. Lipid Res. 55: 2195-2197.
90. Smyth, S. S., V. A. Sciorra, Y. J. Sigal, Z. Pamuklar, Z. Wang, Y. Xu, G. D. Prestwich, and A. J. Morris. 2003. Lipid phosphate phosphatases regulate lysophosphatidic acid production and signaling in platelets: studies using chemical inhibitors of lipid phosphate phosphatase activity. J. Biol. Chem. 278: 43214-43223.
91. Tanyi, J. L., A. J. Morris, J. K. Wolf, X. Fang, Y. Hasegawa, R. Lapushin, N. Auersperg, Y. J. Sigal, R. A. Newman, E. A. Felix, et al. 2003. The human lipid phosphate phosphatase-3 decreases the growth, survival, and tumorigenesis of ovarian cancer cells: validation of the lysophosphatidic acid signaling cascade as a target for therapy in ovarian cancer. Cancer Res. 63: 1073-1082.
92. Tomsig, J. L., A. H. Snyder, E. V. Berdyshev, A. Skobeleva, C. Mataya, V. Natarajan, D. N. Brindley, and K. R. Lynch. 2009. Lipid phosphate phosphohydrolase type 1 (LPP1) degrades extracellular lysophosphatidic acid in vivo. Biochem. J. 419: 611-618.
93. Ryu, J. M., and H. J. Han. 2015. Autotaxin-LPA axis regulates hMSC migration by adherent junction disruption and cytoskeletal rearrangement via LPAR1/3-dependent PKC/GSK3 β / β-catenin and PKC/Rho GTPase pathways. Stem Cells. 33: 819-832.
94. Oude Elferink, R. P., R. Bolier, and U. H. Beuers. 2015. Lysophosphatidic acid and signaling in sensory neurons. Biochim. Biophys. Acta. 1851: 61-65.
95. Contos, J. J., N. Fukushima, J. A. Weiner, D. Kaushal, and J. Chun. 2000. Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behavior. Proc. Natl. Acad. Sci. USA. 97: 13384-13389.
96. Kishi, Y., S. Okudaira, M. Tanaka, K. Hama, D. Shida, J. Kitayama, T. Yamori, J. Aoki, T. Fujimaki, and H. Arai. 2006. Autotaxin is overexpressed in glioblastoma multiforme and contributes to cell motility of glioblastoma by converting lysophosphatidylcholine to lysophosphatidic acid. J. Biol. Chem. 281: 17492-17500.
97. Yang, Y., L. Mou, N. Liu, and M. S. Tsao. 1999. Autotaxin expression in non-small-cell lung cancer. Am. J. Respir. Cell Mol. Biol. 21: 216-222.
98. Kehlen, A., N. Englert, A. Seifert, T. Klonisch, H. Dralle, J. Langner, and C. Hoang-Vu. 2004. Expression, regulation and function of autotaxin in thyroid carcinomas. Int. J. Cancer. 109: 833-838.
99. Seifert, A., T. Klonisch, J. Wulfaenger, F. Haag, H. Dralle, J. Langner, C. Hoang-Vu, and A. Kehlen. 2008. The cellular localization of autotaxin impacts on its biological functions in human thyroid carcinoma cells. Oncol. Rep. 19: 1485-1491.
100. Masuda, A., K. Nakamura, K. Izutsu, K. Igarashi, R. Ohkawa, M. Jona, K. Higashi, H. Yokota, S. Okudaira, T. Kishimoto, et al. 2008. Serum autotaxin measurement in haematological malignancies: a promising marker for follicular lymphoma. Br. J. Haematol. 143: 60-70.
101. Tokumura, A., T. Kume, K. Fukuzawa, M. Tahara, K. Tasaka, J. Aoki, H. Arai, K. Yasuda, and H. Kanzaki. 2007. Peritoneal fl uids from patients with certain gynecologic tumor contain elevated levels of bioactive lysophospholipase D activity. Life Sci. 80: 1641-1649.
102. Hanahan, D., and R. A. Weinberg. 2008. Retrospective: Judah Folkman (1933-2008). Science. 319: 1055.
103. Hanahan, D., and R. A. Weinberg. 2011. Hallmarks of cancer: the next generation. Cell. 144: 646-674.
104. David, M., E. Wannecq, F. Descotes, S. Jansen, B. Deux, J. Ribeiro, C. M. Serre, S. Gres, N. Bendriss-Vermare, M. Bollen, et al. 2010. Cancer cell expression of autotaxin controls bone metastasis formation in mouse through lysophosphatidic acid-dependent activation of osteoclasts. PLoS ONE. 5: e9741.
105. Federico, L., H. Ren, P. A. Mueller, T. Wu, S. Liu, J. Popovic, E. M. Blalock, M. Sunkara, H. Ovaa, H. M. Albers, et al. 2012. Autotaxin and its product lysophosphatidic acid suppress brown adipose differentiation and promote diet-induced obesity in mice. Mol. Endocrinol. 26: 786-797.
106. Mazzocca, A., F. Dituri, L. Lupo, M. Quaranta, S. Antonaci, and G. Giannelli. 2011. Tumor-secreted lysophostatidic acid accelerates hepatocellular carcinoma progression by promoting differentiation of peritumoral fi broblasts in myofi broblasts. Hepatology. 54: 920-930.
107. Yuelling, L. W., C. T. Waggener, F. S. Afshari, J. A. Lister, and B. Fuss. 2012. Autotaxin/ENPP2 regulates oligodendrocyte differentiation in vivo in the developing zebrafi sh hindbrain. Glia. 60: 1605-1618.
108. Baumforth, K. R., J. R. Flavell, G. M. Reynolds, G. Davies, T. R. Pettit, W. Wei, S. Morgan, T. Stankovic, Y. Kishi, H. Arai, et al. 2005. Induction of autotaxin by the Epstein-Barr virus promotes the growth and survival of Hodgkin lymphoma cells. Blood. 106: 2138-2146.
109. Brindley, D. N., F. T. Lin, and G. J. Tigyi. 2013. Role of the autotaxin-lysophosphatidate axis in cancer resistance to chemotherapy and radiotherapy. Biochim. Biophys. Acta. 1831: 74-85.
110. Samadi, N., R. T. Bekele, I. S. Goping, L. M. Schang, and D. N. Brindley. 2011. Lysophosphatidate induces chemo-resistance by releasing breast cancer cells from taxol-induced mitotic arrest. PLoS ONE. 6: e20608.
111. Satoh, Y., R. Ohkawa, K. Nakamura, K. Higashi, M. Kaneko, H. Yokota, J. Aoki, H. Arai, Y. Yuasa, and Y. Yatomi. 2007. Lysophosphatidic acid protection against apoptosis in the human pre-B-cell line Nalm-6. Eur. J. Haematol. 78: 510-517.
112. Song, J., T. Clair, J. H. Noh, J. W. Eun, S. Y. Ryu, S. N. Lee, Y. M. Ahn, S. Y. Kim, S. H. Lee, W. S. Park, et al. 2005. Autotaxin (lyso-PLD/NPP2) protects fi broblasts from apoptosis through its enzymatic product, lysophosphatidic acid, utilizing albumin-bound substrate. Biochem. Biophys. Res. Commun. 337: 967-975.
113. Vidot, S., J. Witham, R. Agarwal, S. Greenhough, H. S. Bamrah, G. J. Tigyi, S. B. Kaye, and A. Richardson. 2010. Autotaxin delays apoptosis induced by carboplatin in ovarian cancer cells. Cell. Signal. 22: 926-935.
114. Billon-Denis, E., Z. Tanfi n, and P. Robin. 2008. Role of lysophosphatidic acid in the regulation of uterine leiomyoma cell proliferation by phospholipase D and autotaxin. J. Lipid Res. 49: 295-307.
115. Conrotto, P., U. Andreasson, V. Kuci, C. A. Borrebaeck, and S. Ek. 2011. Knock-down of SOX11 induces autotaxin-dependent increase in proliferation in vitro and more aggressive tumors in vivo. Mol. Oncol. 5: 527-537.
116. Ortlepp, C., C. Steudel, C. Heiderich, S. Koch, A. Jacobi, M. Ryser, S. Brenner, M. Bornhäuser, B. Brors, W. K. Hofmann, et al. 2013. Autotaxin is expressed in FLT3-ITD positive acute myeloid leukemia and hematopoietic stem cells and promotes cell migration and proliferation. Exp. Hematol. 41: 444-461.
117. Xia, Q., A. M. Deng, S. S. Wu, and M. Zheng. 2011. Cholera toxin inhibits human hepatocarcinoma cell proliferation in vitro via suppressing ATX/LPA axis. Acta Pharmacol. Sin. 32: 1055-1062.
118. Dai, W., F. Wang, L. He, C. Lin, S. Wu, P. Chen, Y. Zhang, M. Shen, D. Wu, C. Wang, et al. 2015. Genistein inhibits hepatocellular carcinoma cell migration by reversing the epithelial-mesenchymal transition: Partial mediation by the transcription factor NFAT1. Mol. Carcinog. 54: 301-311.
119. Gaetano, C. G., N. Samadi, J. L. Tomsig, T. L. Macdonald, K. R. Lynch, and D. N. Brindley. 2009. Inhibition of autotaxin production or activity blocks lysophosphatidylcholine-induced migration of human breast cancer and melanoma cells. Mol. Carcinog. 48: 801-809.
120. Ptaszynska, M. M., M. L. Pendrak, M. L. Stracke, and D. D. Roberts. 2010. Autotaxin signaling via lysophosphatidic acid receptors contributes to vascular endothelial growth factor-induced endothelial cell migration. Mol. Cancer Res. 8: 309-321.
121. Saunders, L. P., A. Ouellette, R. Bandle, W. C. Chang, H. Zhou, R. N. Misra, E. M. De La Cruz, and D. T. Braddock. 2008. Identifi cation of small-molecule inhibitors of autotaxin that inhibit melanoma cell migration and invasion. Mol. Cancer Ther. 7: 3352-3362.
122. Zhang, Y., Y. C. Chen, M. F. Krummel, and S. D. Rosen. 2012. Autotaxin through lysophosphatidic acid stimulates polarization, motility, and transendothelial migration of naive T cells. J. Immunol. 189: 3914-3924.
123. Zhao, J., D. He, E. Berdyshev, M. Zhong, R. Salgia, A. J. Morris, S. S. Smyth, V. Natarajan, and Y. Zhao. 2011. Autotaxin induces lung epithelial cell migration through lysoPLD activity-dependent and-independent pathways. Biochem. J. 439: 45-55.
124. Xu, X., and G. D. Prestwich. 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.
125. Rancoule, C., R. Dusaulcy, K. Treguer, S. Gres, C. Attane, and J. S. Saulnier-Blache. 2014. Involvement of autotaxin/lysophosphatidic acid signaling in obesity and impaired glucose homeostasis. Biochimie. 96: 140-143.
126. Rancoule, C., R. Dusaulcy, K. Treguer, S. Gres, C. Guigne, D. Quilliot, P. Valet, and J. S. Saulnier-Blache. 2012. Depot-specifi c regulation of autotaxin with obesity in human adipose tissue. J. Physiol. Biochem. 68: 635-644.
127. Georas, S. N. 2009. Lysophosphatidic acid and autotaxin: emerging roles in innate and adaptive immunity. Immunol. Res. 45: 229-238.
128. Coussens, L. M., L. Zitvogel, and A. K. Palucka. 2013. Neutralizing tumor-promoting chronic infl ammation: a magic bullet? Science. 339: 286-291.
129. Coussens, L. M., and Z. Werb. 2002. Infl ammation and cancer. Nature. 420: 860-867.
130. Knowlden, S., and S. N. Georas. 2014. The autotaxin-LPA axis emerges as a novel regulator of lymphocyte homing and infl ammation. J. Immunol. 192: 851-857.
131. Sevastou, I., E. Kaffe, M. A. Mouratis, and V. Aidinis. 2013. Lysoglycerophospholipids in chronic infl ammatory disorders: the PLA(2)/LPC and ATX/LPA axes. Biochim. Biophys. Acta. 1831: 42-60.
132. Benesch, M. G., Y. M. Ko, T. P. McMullen, and D. N. Brindley. 2014. Autotaxin in the crosshairs: taking aim at cancer and other infl ammatory conditions. FEBS Lett. 588: 2712-2727.
133. Kanda, H., R. Newton, R. Klein, Y. Morita, M. D. Gunn, and S. D. Rosen. 2008. Autotaxin, an ectoenzyme that produces lysophosphatidic acid, promotes the entry of lymphocytes into secondary lymphoid organs. Nat. Immunol. 9: 415-423.
134. Bai, Z., L. Cai, E. Umemoto, A. Takeda, K. Tohya, Y. Komai, P. T. Veeraveedu, E. Hata, Y. Sugiura, A. Kubo, et al. 2013. Constitutive lymphocyte transmigration across the basal lamina of high endothelial venules is regulated by the autotaxin/lysophosphatidic acid axis. J. Immunol. 190: 2036-2048.
135. Nikitopoulou, I., N. Oikonomou, E. Karouzakis, I. Sevastou, N. Nikolaidou-Katsaridou, Z. Zhao, V. Mersinias, M. Armaka, Y. Xu, M. Masu, et al. 2012. Autotaxin expression from synovial fi broblasts is essential for the pathogenesis of modeled arthritis. J. Exp. Med. 209: 925-933.
136. Wu, J. M., Y. Xu, N. J. Skill, H. Sheng, Z. Zhao, M. Yu, R. Saxena, and M. A. Maluccio. 2010. Autotaxin expression and its connection with the TNF-alpha-NF-kappaB axis in human hepatocellular carcinoma. Mol. Cancer. 9: 71.
137. Pleli, T., D. Martin, B. Kronenberger, F. Brunner, V. Koberle, G. Grammatikos, H. Farnik, Y. Martinez, F. Finkelmeier, S. Labocha, et al. 2014. Serum autotaxin is a parameter for the severity of liver cirrhosis and overall survival in patients with liver cirrhosis-a prospective cohort study. PLoS ONE. 9: e103532.
138. Budd, D. C., and Y. Qian. 2013. Development of lysophosphatidic acid pathway modulators as therapies for fi brosis. Future Med. Chem. 5: 1935-1952.
139. Nakagawa, H., H. Ikeda, K. Nakamura, R. Ohkawa, R. Masuzaki, R. Tateishi, H. Yoshida, N. Watanabe, K. Tejima, Y. Kume, et al. 2011. Autotaxin as a novel serum marker of liver fi brosis. Clin. Chim. Acta. 412: 1201-1206.
140. Oikonomou, N., M. A. Mouratis, A. Tzouvelekis, E. Kaffe, C. Valavanis, G. Vilaras, A. Karameris, G. D. Prestwich, D. Bouros, and V. Aidinis. 2012. Pulmonary autotaxin expression contributes to the pathogenesis of pulmonary fi brosis. Am. J. Respir. Cell Mol. Biol. 47: 566-574.
141. Tager, A. M. 2012. Autotaxin emerges as a therapeutic target for idiopathic pulmonary fi brosis: limiting fi brosis by limiting lysophosphatidic acid synthesis. Am. J. Respir. Cell Mol. Biol. 47: 563-565.
142. Wu, L., F. A. Petrigliano, K. Ba, S. Lee, J. Bogdanov, D. R. McAllister, J. S. Adams, A. K. Rosenthal, B. Van Handel, G. M. Crooks, et al. 2015. Lysophosphatidic acid mediates fi brosis in injured joints by regulating collagen type I biosynthesis. Osteoarthritis Cartilage. 23: 308-318.
143. Hozumi, H., R. Hokari, C. Kurihara, K. Narimatsu, H. Sato, S. Sato, T. Ueda, M. Higashiyama, Y. Okada, C. Watanabe, et al. 2013. Involvement of autotaxin/lysophospholipase D expression in intestinal vessels in aggravation of intestinal damage through lymphocyte migration. Lab. Invest. 93: 508-519.
144. Cooper, A. B., J. Wu, D. Lu, and M. A. Maluccio. 2007. Is autotaxin (ENPP2) the link between hepatitis C and hepatocellular cancer? J. Gastrointest. Surg. 11: 1628-1634; discussion 1634-1625.
145. Liu, S., M. Umezu-Goto, M. Murph, Y. Lu, W. Liu, F. Zhang, S. Yu, L. C. Stephens, X. Cui, G. Murrow, et al. 2009. Expression of autotaxin and lysophosphatidic acid receptors increases mammary tumorigenesis, invasion, and metastases. Cancer Cell. 15: 539-550.
146. Fang, X., S. Yu, R. C. Bast, S. Liu, H. J. Xu, S. X. Hu, R. LaPushin, F. X. Claret, B. B. Aggarwal, Y. Lu, et al. 2004. Mechanisms for lysophosphatidic acid-induced cytokine production in ovarian cancer cells. J. Biol. Chem. 279: 9653-9661.
147. Mu, H., T. L. Calderone, M. A. Davies, V. G. Prieto, H. Wang, G. B. Mills, M. Bar-Eli, and J. E. Gershenwald. 2012. Lysophosphatidic acid induces lymphangiogenesis and IL-8 production in vitro in human lymphatic endothelial cells. Am. J. Pathol. 180: 2170-2181.
148. Ptaszynska, M. M., M. L. Pendrak, R. W. Bandle, M. L. Stracke, and D. D. Roberts. 2008. Positive feedback between vascular endothelial growth factor-A and autotaxin in ovarian cancer cells. Mol. Cancer Res. 6: 352-363.
149. Park, S. Y., K. J. Jeong, N. Panupinthu, S. Yu, J. Lee, J. W. Han, J. M. Kim, J. S. Lee, J. Kang, C. G. Park, et al. 2011. Lysophosphatidic acid augments human hepatocellular carcinoma cell invasion through LPA1 receptor and MMP-9 expression. Oncogene. 30: 1351-1359.
150. Benesch, M. G., X. Tang, T. Maeda, A. Ohhata, Y. Y. Zhao, B. P. Kok, J. Dewald, M. Hitt, J. M. Curtis, T. P. McMullen, et al. 2014. Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice. FASEB J. 28: 2655-2666.
151. Leblanc, R., S. C. Lee, M. David, J. C. Bordet, D. D. Norman, R. Patil, D. Miller, D. Sahay, J. Ribeiro, P. Clezardin, et al. 2014. Interaction of platelet-derived autotaxin with tumor integrin alphaVbeta3 controls metastasis of breast cancer cells to bone. Blood. 124: 3141-3150.
152. Boucharaba, A., C. M. Serre, S. Gres, J. S. Saulnier-Blache, J. C. Bordet, J. Guglielmi, P. Clezardin, and O. Peyruchaud. 2004. Plateletderived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer. J. Clin. Invest. 114: 1714-1725.
153. Venkatraman, G., M. G. Benesch, X. Tang, J. Dewald, T. P. McMullen, and D. N. Brindley. 2015. Lysophosphatidate signaling stabilizes Nrf2 and increases the expression of genes involved in drug resistance and oxidative stress responses: implications for cancer treatment. FASEB J. 29: 772-785.
154. Nam, S. W., T. Clair, C. K. Campo, H. Y. Lee, L. A. Liotta, and M. L. Stracke. 2000. Autotaxin (ATX), a potent tumor motogen, augments invasive and metastatic potential of ras-transformed cells. Oncogene. 19: 241-247.
155. Su, S. C., X. Hu, P. A. Kenney, M. M. Merrill, K. N. Babaian, X. Y. Zhang, T. Maity, S. F. Yang, X. Lin, and C. G. Wood. 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.
156. Yu, F. X., B. Zhao, N. Panupinthu, J. L. Jewell, I. Lian, L. H. Wang, J. Zhao, H. Yuan, K. Tumaneng, H. Li, et al. 2012. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell. 150: 780-791.
157. Panupinthu, N., S. Yu, D. Zhang, F. Zhang, M. Gagea, Y. Lu, J. R. Grandis, S. E. Dunn, H. Y. Lee, and G. B. Mills. 2014. Selfreinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer. Oncogene. 33: 2846-2856.
158. Jeong, K. J., K. H. Cho, N. Panupinthu, H. Kim, J. Kang, C. G. Park, G. B. Mills, and H. Y. Lee. 2013. EGFR mediates LPAinduced proteolytic enzyme expression and ovarian cancer invasion: inhibition by resveratrol. Mol. Oncol. 7: 121-129.
159. Gao, J., B. A. Aksoy, U. Dogrusoz, G. Dresdner, B. Gross, S. O. Sumer, Y. Sun, A. Jacobsen, R. Sinha, E. Larsson, et al. 2013. Integrative analysis of complex cancer genomics and clinical profi les using the cBioPortal. Sci. Signal. 6: pl1.
160. The Cancer Genome Atlas Research Network. 2011. Integrated genomic analyses of ovarian carcinoma. Nature. 474: 609-615.
161. The Cancer Genome Atlas Research Network. 2012. Comprehensive molecular portraits of human breast tumours. Nature. 490: 61-70.
162. The Cancer Genome Atlas Research Network. 2014. Comprehensive molecular profi ling of lung adenocarcinoma. Nature. 511: 543-550.
163. [Erratum. 2014. Nature. 514: 262.]
164. The Cancer Genome Atlas Research Network. 2014. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 507: 315-322.
165. The Cancer Genome Atlas Research Network. 2015. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 517: 576-582.
166. Albers, H. M., L. A. van Meeteren, D. A. Egan, E. W. van Tilburg, W. H. Moolenaar, and H. Ovaa. 2010. Discovery and optimization of boronic acid based inhibitors of autotaxin. J. Med. Chem. 53: 4958-4967.
167. Federico, L., Z. Pamuklar, S. S. Smyth, and A. J. Morris. 2008. Therapeutic potential of autotaxin/lysophospholipase d inhibitors. Curr. Drug Targets. 9: 698-708.
168. Fells, J. I., S. C. Lee, Y. Fujiwara, D. D. Norman, K. G. Lim, R. Tsukahara, J. Liu, R. Patil, D. D. Miller, R. J. Kirby, et al. 2013. Hits of a high-throughput screen identify the hydrophobic pocket of autotaxin/lysophospholipase D as an inhibitory surface. Mol. Pharmacol. 84: 415-424.
169. Fells, J. I., S. C. Lee, D. D. Norman, R. Tsukahara, J. R. Kirby, S. Nelson, W. Seibel, R. Papoian, R. Patil, D. D. Miller, et al. 2014. Targeting the hydrophobic pocket of autotaxin with virtual screening of inhibitors identifi es a common aromatic sulfonamide structural motif. FEBS J. 281: 1017-1028.
170. North, E. J., A. L. Howard, I. W. Wanjala, T. C. Pham, D. L. Baker, and A. L. Parrill. 2010. Pharmacophore development and application toward the identifi cation of novel, small-molecule autotaxin inhibitors. J. Med. Chem. 53: 3095-3105.
171. Albers, H. M., A. Dong, L. A. van Meeteren, D. A. Egan, M. Sunkara, E. W. van Tilburg, K. Schuurman, O. van Tellingen, A. J. Morris, S. S. Smyth, et al. 2010. Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation. Proc. Natl. Acad. Sci. USA. 107: 7257-7262.
172. East, J. E., A. J. Kennedy, J. L. Tomsig, A. R. De Leon, K. R. Lynch, and T. L. Macdonald. 2010. Synthesis and structure-activity relationships of tyrosine-based inhibitors of autotaxin (ATX). Bioorg. Med. Chem. Lett. 20: 7132-7136.
173. Fisher, N., T. Hilton-Bolt, M. G. Edwards, K. J. Haxton, M. McKenzie, S. M. Allin, and A. Richardson. 2013. Dendrimer conjugate of [4-(tetradecanoylamino)benzyl]phosphonic acid (S32826) as an autotaxin inhibitor. ACS Med. Chem. Lett. 5: 34-39.
174. Katsamakas, S., E. Bermperoglou, and D. Hadjipavlou-Litina. 2015. Considering autotaxin inhibitors in terms of 2D-QSAR and 3D-Mapping: review and evaluation. Curr. Med. Chem. 22: 1428-1461.
175. Saga, H., A. Ohhata, A. Hayashi, M. Katoh, T. Maeda, H. Mizuno, Y. Takada, Y. Komichi, H. Ota, N. Matsumura, et al. 2014. A novel highly potent autotaxin/ENPP2 inhibitor produces prolonged decreases in plasma lysophosphatidic acid formation in vivo and regulates urethral tension. PLoS ONE. 9: e93230.
176. Kawaguchi, M., T. Okabe, S. Okudaira, H. Nishimasu, R. Ishitani, H. Kojima, O. Nureki, J. Aoki, and T. Nagano. 2013. Screening and X-ray crystal structure-based optimization of autotaxin (ENPP2) inhibitors, using a newly developed fl uorescence probe. ACS Chem. Biol. 8: 1713-1721.
177. Albers, H. M., L. J. Hendrickx, R. J. van Tol, J. Hausmann, A. Perrakis, and H. Ovaa. 2011. Structure-based design of novel boronic acid-based inhibitors of autotaxin. J. Med. Chem. 54: 4619-4626.
178. Norman, D. D., A. Ibezim, W. E. Scott, S. White, A. L. Parrill, and D. L. Baker. 2013. Autotaxin inhibition: development and application of computational tools to identify site-selective lead compounds. Bioorg. Med. Chem. 21: 5548-5560.
179. Crack, P. J., M. Zhang, M. C. Morganti-Kossmann, A. J. Morris, J. M. Wojciak, J. K. Fleming, I. Karve, D. Wright, M. Sashindranath, Y. Goldshmit, et al. 2014. Anti-lysophosphatidic acid antibodies improve traumatic brain injury outcomes. J. Neuroinfl ammation. 11: 37.
180. Stoddard, N. C., and J. Chun. 2015. Promising pharmacological directions in the world of lysophosphatidic acid signaling. Biomol. Ther. (Seoul). 23: 1-11.
181. Nishimasu, H., R. Ishitani, J. Aoki, and O. Nureki. 2012. A 3D view of autotaxin. Trends Pharmacol. Sci. 33: 138-145.
182. Moolenaar, W. H., and A. Perrakis. 2011. Insights into autotaxin: how to produce and present a lipid mediator. Nat. Rev. Mol. Cell Biol. 12: 674-679.
183. cBioPortal for Cancer Genomics. The Cancer Genome Atlas Research Network. Available at: http://www.cbioportal.org/