Autotaxin

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ENPP2
3nkr.png
Available structures
PDB Ortholog search: PDBe RCSB
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: 5168
RNA expression pattern
PBB GE ENPP2 209392 at tn.png

PBB GE ENPP2 210839 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
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
View/Edit Human View/Edit Mouse

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[edit]

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, 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]

Various small molecule inhibitors of autotaxin have been developed for clinical applications. A specific inhibitor against idiopathic pulmonary fibrosis are under phase II trials.[5] A DNA aptamer inhibitor of Autotaxin has also been described.[6] It has been shown that autotaxin's function can be regulated by certain steroids, namely bile acids,.[7][8]

Structure[edit]

The crystal structures rat[9] and mouse autotaxin[10] 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[edit]

References[edit]

  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 (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. 
  4. ^ a b "Entrez Gene: ENPP2 ectonucleotide pyrophosphatase/phosphodiesterase 2 (autotaxin)". 
  5. ^ http://www.glpg.com/glpg-1690
  6. ^ 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. 23: 395–401. doi:10.1038/nsmb.3200. PMID 27043297. 
  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 (14 April 2016). "Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling.". Nature Communications. 7: 11248. doi:10.1038/ncomms11248. PMC 4834639free to read. PMID 27075612. 
  8. ^ "Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling". 
  9. ^ 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 3064516free to read. PMID 21240271. 
  10. ^ 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[edit]

  • Perrakis, A; Moolenaar, WH (18 February 2014). "Autotaxin: structure-function and signaling.". Journal of lipid research. 55 (6): 1010–1018. doi:10.1194/jlr.r046391. PMC 4031933free to read. 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 2173129free to read. 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 16267free to read. 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 2173129free to read. 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 1885462free to read. 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.