Autotaxin

ENPP2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4ZGA, 4ZG6, 4ZG9, 4ZG7
Identifiers
Aliases	ENPP2, ATX, ATX-X, AUTOTAXIN, LysoPLD, NPP2, PD-IALPHA, PDNP2, ectonucleotide pyrophosphatase/phosphodiesterase 2
External IDs	OMIM: 601060 MGI: 1321390 HomoloGene: 4526 GeneCards: ENPP2
Gene ontology Molecular function • nucleotide diphosphatase activity • phosphodiesterase I activity • transcription factor binding • polysaccharide binding • metal ion binding • scavenger receptor activity • catalytic activity • alkylglycerophosphoethanolamine phosphodiesterase activity • nucleic acid binding • hydrolase activity • calcium ion binding • lysophospholipase activity • zinc ion binding Cellular component • plasma membrane • integral component of plasma membrane • extracellular region • extracellular space Biological process • G-protein coupled receptor signaling pathway • movement of cell or subcellular component • regulation of cell migration • positive regulation of lamellipodium morphogenesis • lipid metabolic process • positive regulation of epithelial cell migration • regulation of angiogenesis • receptor-mediated endocytosis • lipid catabolic process • immune response • phospholipid catabolic process • positive regulation of peptidyl-tyrosine phosphorylation • phosphate-containing compound metabolic process • metabolic process • chemotaxis • phosphatidylcholine catabolic process • nucleic acid phosphodiester bond hydrolysis Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5168	18606
Ensembl	ENSG00000136960	ENSMUSG00000022425
UniProt	Q13822	Q9R1E6
RefSeq (mRNA)	NM_001040092 NM_001130863 NM_006209	NM_001136077 NM_015744 NM_001285994 NM_001285995
RefSeq (protein)	NP_001035181.1 NP_001124335.1 NP_006200.3	NP_001129549.1 NP_001272923.1 NP_001272924.1 NP_056559.2
Location (UCSC)	Chr 8: 119.56 – 119.67 Mb	Chr 15: 54.84 – 54.92 Mb
PubMed search	[1]	[2]
Wikidata

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Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (E-NPP 2), is an enzyme that in humans is encoded by the ENPP2 gene.^[3][4]

Function

Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (NPP2 or ENPP2), is a secreted enzyme important for generating the lipid signaling molecule lysophosphatidic acid (LPA). Autotaxin has lysophospholipase D activity that converts lysophosphatidylcholine into LPA.

Autotaxin was originally identified as a tumor cell-motility-stimulating factor; later it was shown to be LPA (which signals through lysophospholipid receptors), the lipid product of the reaction catalyzed by autotaxin, which is responsible for its effects on cell-proliferation.

The protein encoded by this gene functions as a phosphodiesterase. Autotaxin is secreted and further processed to make the biologically active form. Several alternatively spliced transcript variants have been identified. Autotaxin is able to cleave the phosphodiester bond between the α and the β position of triphosphate nucleotides, acting as an ectonucleotide phosphodiesterase producing pyrophosphate, as most members of the ENPP family. Importantly, autotaxin also acts as phospholipase, catalyzing the removal of the head group of various lysolipids. The physiological function of autotaxin is the production of the signalling lipid lysophosphatidic acid (LPA) in extracellular fluids. LPA evokes growth factor-like responses including stimulation of cell proliferation and chemotaxis. This gene product stimulates the motility of tumor cells, has angiogenic properties, and its expression is up-regulated in several kinds of tumours.^[4] Also, autotaxin and LPA are involved in numerous inflammatory-driven diseases such as asthma and arthritis.^[5] Physiologically, LPA helps promote wound healing responses to tissue damage. Under normal circumstances, LPA negatively regulates autotaxin transcription, but in the context of wound repair, cytokines induce autotaxin expression to increase overall LPA concentrations.^[6]

It has been shown that autotaxin's function can be regulated by certain steroids, namely bile acids,.^[7]

As a drug target

Various small molecule inhibitors of autotaxin have been developed for clinical applications. A specific inhibitor against idiopathic pulmonary fibrosis is under phase II trials.^[8] A DNA aptamer inhibitor of Autotaxin has also been described.^[9]

Structure

The crystal structures rat^[10] and mouse autotaxin^[11] have been solved. In each case, the apo structure have been solved along with product or inhibitor bound complexes. Both proteins consist of 4 domains, 2 N-terminal somatomedin-B-like (SMB) domains which may be involved in cell-surface localisation. The catalytic domain follows and contains a deep hydrophobic pocket in which the lipid substrate binds. At the C-terminus is the inactive nuclease domain which may function to aid protein stability.

See also

• Lysophosphatidic acid
• Lysophospholipid receptors
• Lipid signaling
• Phospholipases

References

1. "Human PubMed Reference:".
2. "Mouse PubMed Reference:".
3. Kawagoe H, Soma O, Goji J, Nishimura N, Narita M, Inazawa J, Nakamura H, Sano K (November 1995). "Molecular cloning and chromosomal assignment of the human brain-type phosphodiesterase I/nucleotide pyrophosphatase gene (PDNP2)". Genomics. 30 (2): 380–4. doi:10.1006/geno.1995.0036. PMID 8586446.
4. "Entrez Gene: ENPP2 ectonucleotide pyrophosphatase/phosphodiesterase 2 (autotaxin)".
5. Benesch MG, Ko YM, McMullen TP, Brindley DN (August 2014). "Autotaxin in the crosshairs: taking aim at cancer and other inflammatory conditions". FEBS Letters. 588 (16): 2712–27. doi:10.1016/j.febslet.2014.02.009. PMID 24560789.
6. Benesch MG, Zhao YY, Curtis JM, McMullen TP, Brindley DN (June 2015). "Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate". Journal of Lipid Research. 56 (6): 1134–44. doi:10.1194/jlr.M057661. PMID 25896349.
7. Keune WJ, Hausmann J, Bolier R, Tolenaars D, Kremer A, Heidebrecht T, Joosten RP, Sunkara M, Morris AJ, Matas-Rico E, Moolenaar WH, Oude Elferink RP, Perrakis A (April 2016). "Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling". Nature Communications. 7: 11248. doi:10.1038/ncomms11248. PMC 4834639. PMID 27075612.
8. Clinical trial number NCT02738801 for "Study to Assess Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Properties of GLPG1690" at ClinicalTrials.gov
9. Kato K, Ikeda H, Miyakawa S, Futakawa S, Nonaka Y, Fujiwara M, Okudaira S, Kano K, Aoki J, Morita J, Ishitani R, Nishimasu H, Nakamura Y, Nureki O (May 2016). "Structural basis for specific inhibition of Autotaxin by a DNA aptamer". Nature Structural & Molecular Biology. 23 (5): 395–401. doi:10.1038/nsmb.3200. PMID 27043297.
10. Hausmann J, Kamtekar S, Christodoulou E, Day JE, Wu T, Fulkerson Z, Albers HM, van Meeteren LA, Houben AJ, van Zeijl L, Jansen S, Andries M, Hall T, Pegg LE, Benson TE, Kasiem M, Harlos K, Kooi CW, Smyth SS, Ovaa H, Bollen M, Morris AJ, Moolenaar WH, Perrakis A (February 2011). "Structural basis of substrate discrimination and integrin binding by autotaxin". Nature Structural & Molecular Biology. 18 (2): 198–204. doi:10.1038/nsmb.1980. PMC 3064516. PMID 21240271.
11. Nishimasu H, Okudaira S, Hama K, Mihara E, Dohmae N, Inoue A, Ishitani R, Takagi J, Aoki J, Nureki O (February 2011). "Crystal structure of autotaxin and insight into GPCR activation by lipid mediators". Nature Structural & Molecular Biology. 18 (2): 205–12. doi:10.1038/nsmb.1998. PMID 21240269.

Further reading

• Perrakis A, Moolenaar WH (June 2014). "Autotaxin: structure-function and signaling". Journal of Lipid Research. 55 (6): 1010–8. doi:10.1194/jlr.r046391. PMC 4031933. PMID 24548887.
• Tokumura A, Majima E, Kariya Y, Tominaga K, Kogure K, Yasuda K, Fukuzawa K (October 2002). "Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase". The Journal of Biological Chemistry. 277 (42): 39436–42. doi:10.1074/jbc.M205623200. PMID 12176993.
• Umezu-Goto M, Kishi Y, Taira A, Hama K, Dohmae N, Takio K, Yamori T, Mills GB, Inoue K, Aoki J, Arai H (July 2002). "Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production". The Journal of Cell Biology. 158 (2): 227–33. doi:10.1083/jcb.200204026. PMC 2173129. PMID 12119361.
• Stracke ML, Krutzsch HC, Unsworth EJ, Arestad A, Cioce V, Schiffmann E, Liotta LA (February 1992). "Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein". The Journal of Biological Chemistry. 267 (4): 2524–9. PMID 1733949.
• Stracke ML, Arestad A, Levine M, Krutzsch HC, Liotta LA (August 1995). "Autotaxin is an N-linked glycoprotein but the sugar moieties are not needed for its stimulation of cellular motility". Melanoma Research. 5 (4): 203–9. doi:10.1097/00008390-199508000-00001. PMID 7496154.
• Murata J, Lee HY, Clair T, Krutzsch HC, Arestad AA, Sobel ME, Liotta LA, Stracke ML (December 1994). "cDNA cloning of the human tumor motility-stimulating protein, autotaxin, reveals a homology with phosphodiesterases". The Journal of Biological Chemistry. 269 (48): 30479–84. PMID 7982964.
• Lee HY, Murata J, Clair T, Polymeropoulos MH, Torres R, Manrow RE, Liotta LA, Stracke ML (January 1996). "Cloning, chromosomal localization, and tissue expression of autotaxin from human teratocarcinoma cells". Biochemical and Biophysical Research Communications. 218 (3): 714–9. doi:10.1006/bbrc.1996.0127. PMID 8579579.
• Lee HY, Clair T, Mulvaney PT, Woodhouse EC, Aznavoorian S, Liotta LA, Stracke ML (October 1996). "Stimulation of tumor cell motility linked to phosphodiesterase catalytic site of autotaxin". The Journal of Biological Chemistry. 271 (40): 24408–12. doi:10.1074/jbc.271.40.24408. PMID 8798697.
• Clair T, Lee HY, Liotta LA, Stracke ML (January 1997). "Autotaxin is an exoenzyme possessing 5'-nucleotide phosphodiesterase/ATP pyrophosphatase and ATPase activities". The Journal of Biological Chemistry. 272 (2): 996–1001. doi:10.1074/jbc.272.2.996. PMID 8995394.
• Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W, Zago MA, Bordin S, Costa FF, Goldman GH, Carvalho AF, Matsukuma A, Baia GS, Simpson DH, Brunstein A, de Oliveira PS, Bucher P, Jongeneel CV, O'Hare MJ, Soares F, Brentani RR, Reis LF, de Souza SJ, Simpson AJ (March 2000). "Shotgun sequencing of the human transcriptome with ORF expressed sequence tags". Proceedings of the National Academy of Sciences of the United States of America. 97 (7): 3491–6. doi:10.1073/pnas.97.7.3491. PMC 16267. PMID 10737800.
• Nam SW, Clair T, Kim YS, McMarlin A, Schiffmann E, Liotta LA, Stracke ML (September 2001). "Autotaxin (NPP-2), a metastasis-enhancing motogen, is an angiogenic factor". Cancer Research. 61 (18): 6938–44. PMID 11559573.
• Umezu-Goto M, Kishi Y, Taira A, Hama K, Dohmae N, Takio K, Yamori T, Mills GB, Inoue K, Aoki J, Arai H (July 2002). "Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production". The Journal of Cell Biology. 158 (2): 227–33. doi:10.1083/jcb.200204026. PMC 2173129. PMID 12119361.
• Tokumura A, Majima E, Kariya Y, Tominaga K, Kogure K, Yasuda K, Fukuzawa K (October 2002). "Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase". The Journal of Biological Chemistry. 277 (42): 39436–42. doi:10.1074/jbc.M205623200. PMID 12176993.
• Jung ID, Lee J, Yun SY, Park CG, Choi WS, Lee HW, Choi OH, Han JW, Lee HY (December 2002). "Cdc42 and Rac1 are necessary for autotaxin-induced tumor cell motility in A2058 melanoma cells". FEBS Letters. 532 (3): 351–6. doi:10.1016/S0014-5793(02)03698-0. PMID 12482591.
• Yang SY, Lee J, Park CG, Kim S, Hong S, Chung HC, Min SK, Han JW, Lee HW, Lee HY (2003). "Expression of autotaxin (NPP-2) is closely linked to invasiveness of breast cancer cells". Clinical & Experimental Metastasis. 19 (7): 603–8. doi:10.1023/A:1020950420196. PMID 12498389.
• Gijsbers R, Aoki J, Arai H, Bollen M (March 2003). "The hydrolysis of lysophospholipids and nucleotides by autotaxin (NPP2) involves a single catalytic site". FEBS Letters. 538 (1-3): 60–4. doi:10.1016/S0014-5793(03)00133-9. PMID 12633853.
• Koh E, Clair T, Woodhouse EC, Schiffmann E, Liotta L, Stracke M (May 2003). "Site-directed mutations in the tumor-associated cytokine, autotaxin, eliminate nucleotide phosphodiesterase, lysophospholipase D, and motogenic activities". Cancer Research. 63 (9): 2042–5. PMID 12727817.
• Kehlen A, Englert N, Seifert A, Klonisch T, Dralle H, Langner J, Hoang-Vu C (May 2004). "Expression, regulation and function of autotaxin in thyroid carcinomas". International Journal of Cancer. 109 (6): 833–8. doi:10.1002/ijc.20022. PMID 15027116.
• Boucher J, Quilliot D, Pradères JP, Simon MF, Grès S, Guigné C, Prévot D, Ferry G, Boutin JA, Carpéné C, Valet P, Saulnier-Blache JS (March 2005). "Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression". Diabetologia. 48 (3): 569–77. doi:10.1007/s00125-004-1660-8. PMC 1885462. PMID 15700135.
• van Meeteren LA, Ruurs P, Christodoulou E, Goding JW, Takakusa H, Kikuchi K, Perrakis A, Nagano T, Moolenaar WH (June 2005). "Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate". The Journal of Biological Chemistry. 280 (22): 21155–61. doi:10.1074/jbc.M413183200. PMID 15769751.