Autotaxin

Ectonucleotide pyrophosphatase/phosphodiesterase 2
Mouse autotaxin in complex with lipid. PDB 3nkr
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 3NKR, 2XR9, 2XRG
Identifiers
Symbols	ENPP2 ; ATX; ATX-X; AUTOTAXIN; LysoPLD; NPP2; PD-IALPHA; PDNP2
External IDs	OMIM: 601060 MGI: 1321390 HomoloGene: 4526 ChEMBL: 3691 GeneCards: ENPP2 Gene
EC number	3.1.4.39
Gene ontology Molecular function • nucleic acid binding • phosphodiesterase I activity • nucleotide diphosphatase activity • lysophospholipase activity • scavenger receptor activity • calcium ion binding • transcription factor binding • zinc ion binding • hydrolase activity • polysaccharide binding • alkylglycerophosphoethanolamine phosphodiesterase activity Cellular component • extracellular space • plasma membrane • integral component of plasma membrane Biological process • phosphate-containing compound metabolic process • receptor-mediated endocytosis • movement of cell or subcellular component • chemotaxis • immune response • G-protein coupled receptor signaling pathway • phospholipid catabolic process • positive regulation of epithelial cell migration • regulation of cell migration • phosphatidylcholine catabolic process • regulation of angiogenesis • positive regulation of peptidyl-tyrosine phosphorylation • nucleic acid phosphodiester bond hydrolysis • positive regulation of lamellipodium morphogenesis 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_001136077
RefSeq (protein)	NP_001035181	NP_001129549
Location (UCSC)	Chr 8: 119.56 – 119.67 Mb	Chr 15: 54.84 – 54.92 Mb
PubMed search

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.^[1][2]

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 EMPP family. Importantly, Autotoxin also acts as phospholipase, catalyzing the removal of the head group of various lysolipids. The physiological function of Autotoxin 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 upregulated in several kinds of tumours.^[2]

Various small molecule inhibitors of Autotaxin have been developed for clinical applications. A specific inhibitor against idiopathic pulmonary fibrosis, are currently under phase II trials.^[3] A DNA aptamer inhibitor of Autotaxin has also been described.^[4] It has been shown that Autotaxin's function can be regulated by certain steroids, namely bile acids,.^[5][6]

Structure

The crystal structures rat^[7] and mouse autotaxin^[8] 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. Kawagoe H, Soma O, Goji J, Nishimura N, Narita M, Inazawa J, Nakamura H, Sano K (Nov 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.
2. "Entrez Gene: ENPP2 ectonucleotide pyrophosphatase/phosphodiesterase 2 (autotaxin)".
3. http://www.glpg.com/glpg-1690
4. 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 (4 April 2016). "Structural basis for specific inhibition of Autotaxin by a DNA aptamer.". Nature structural & molecular biology. PMID 27043297.
5. 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 (14 April 2016). "Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling.". Nature communications 7: 11248. PMID 27075612.
6. "Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling".
7. 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 (2011). "Structural basis of substrate discrimination and integrin binding by autotaxin". Nat. Struct. Mol. Biol. 18 (2): 198–204. doi:10.1038/nsmb.1980. PMC 3064516. PMID 21240271.
8. Nishimasu H, Okudaira S, Hama K, Mihara E, Dohmae N, Inoue A, Ishitani R, Takagi J, Aoki J, Nureki O (2011). "Crystal structure of autotaxin and insight into GPCR activation by lipid mediators". Nat. Struct. Mol. Biol. 18 (2): 205–12. doi:10.1038/nsmb.1998. PMID 21240269.

Further reading

• Perrakis, A; Moolenaar, WH (18 February 2014). "Autotaxin: structure-function and signaling.". Journal of lipid research 55 (6): 1010–1018. PMID 24548887.
• Tokumura A, Majima E, Kariya Y, Tominaga K, Kogure K, Yasuda K, Fukuzawa K (Oct 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 (Jul 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 (Feb 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 (Aug 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 (Dec 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 (Jan 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 (Oct 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 (Jan 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 (Mar 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 (Sep 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 (Jul 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 (Oct 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 (Dec 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 (Mar 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. Journal International Du 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 (Mar 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 (Jun 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.