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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; OMA:ENPP2 - orthologs
Gene location (Human)
Chr.	Chromosome 8 (human)
End	119,673,453 bp
Gene location (Mouse)
Chr.	Chromosome 15 (mouse)
End	54,952,892 bp
RNA expression pattern
	Top expressed in
	retinal pigment epithelium; ; Epithelium of choroid plexus; ; inferior ganglion of vagus nerve; ; corpus callosum; ; endothelial cell; ; subthalamic nucleus; ; Pons; ; superior vestibular nucleus; ; middle frontal gyrus; ; external globus pallidus;
	Top expressed in
	Epithelium of choroid plexus; ; retinal pigment epithelium; ; fourth ventricle; ; choroid plexus of fourth ventricle; ; deep cerebellar nuclei; ; iris; ; mesenteric lymph nodes; ; globus pallidus; ; nucleus of stria terminalis; ; habenula;
	More reference expression data
	; ;
	More reference expression data
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; cytoplasm; Golgi apparatus;
Biological process	G protein-coupled receptor signaling pathway; regulation of cell migration; positive regulation of lamellipodium morphogenesis; lipid metabolism; 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; metabolism; chemotaxis; phosphatidylcholine catabolic process; nucleic acid phosphodiester bond hydrolysis; cell motility; phospholipid metabolic process; negative regulation of cell-matrix adhesion; positive regulation of cell population proliferation; diencephalon development; forebrain development; midbrain development; positive regulation of oligodendrocyte differentiation; positive regulation of focal adhesion assembly; cell chemotaxis; cellular response to cadmium ion; cellular response to estradiol stimulus; positive regulation of substrate adhesion-dependent cell spreading; response to polycyclic arene; vesicle-mediated transport; endocytosis;
	Sources:Amigo / QuickGO
Orthologs
	5168
	18606
	ENSG00000136960
	ENSMUSG00000022425
	Q13822
	Q9R1E6
	NM_001040092; NM_001130863; NM_006209; NM_001330600
	NM_001136077; NM_015744; NM_001285994; NM_001285995
	NP_001035181; NP_001124335; NP_001317529; NP_006200
	NP_001129549; NP_001272923; NP_001272924; NP_056559
	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.^[5]^[6]

Function

Autotaxin 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.^[6] Also, autotaxin and LPA are involved in numerous inflammatory-driven diseases such as asthma and arthritis.^[7] 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.^[8]

As a drug target

Various small molecule inhibitors of autotaxin have been developed for clinical applications. A specific inhibitor against idiopathic pulmonary fibrosis showed promising results in a phase II trial that ended in May 2018.^[9] A DNA aptamer inhibitor of Autotaxin has also been described.^[10]

Recently, it has been shown that THC is also a partial autotaxin inhibitor, with an apparent IC50 of 407 ± 67 nM for the ATX-gamma isoform.^[11] THC was also co-crystallized with autotaxin, deciphering the binding interface of the complex. These results might explain some of the effects of THC on inflammation and neurological diseases, since autotaxin is responsible of LPA generation, a key lipid mediator involved in numerous diseases and physiological processes. However, clinical trials need to be performed in order to assess the importance of ATX inhibition by THC during medicinal cannabis consumption. Development of cannabinoid inspired autotaxin inhibitors could also be an option in the future.

Structure

The crystal structures of rat and mouse autotaxin^[12] have been solved. In each case, the apo structure has been solved along with those of product- or inhibitor-bound complexes. Both proteins consist of 4 domains, including 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.

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000136960 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000022425 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Kawagoe H, Soma O, Goji J, Nishimura N, Narita M, Inazawa J, et al. (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. hdl:20.500.14094/D1001481. PMID 8586446.
^ ^a ^b "Entrez Gene: ENPP2 ectonucleotide pyrophosphatase/phosphodiesterase 2 (autotaxin)".
^ 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. S2CID 35544825.
^ 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. PMC 4442871. PMID 25896349.
^ Clinical trial number NCT02738801 for "Study to Assess Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Properties of GLPG1690" at ClinicalTrials.gov
^ Kato K, Ikeda H, Miyakawa S, Futakawa S, Nonaka Y, Fujiwara M, et al. (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. S2CID 24948842.
^ Eymery MC, McCarthy AA, Hausmann J (February 2023). "Linking medicinal cannabis to autotaxin-lysophosphatidic acid signaling". Life Science Alliance. 6 (2): e202201595. doi:10.26508/lsa.202201595. PMC 9834664. PMID 36623871.
^ Nishimasu H, Okudaira S, Hama K, Mihara E, Dohmae N, Inoue A, et al. (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. S2CID 6336916.