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 location (Human) Chr. Chromosome 8 (human)[1] Band 8q24.12 Start 119,557,086 bp[1] End 119,673,453 bp[1]
Gene location (Mouse) Chr. Chromosome 15 (mouse)[2] Band 15|15 D1 Start 54,838,901 bp[2] End 54,952,892 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in retinal pigment epithelium inferior ganglion of vagus nerve corpus callosum endothelial cell subthalamic nucleus pons superior vestibular nucleus middle frontal gyrus external globus pallidus ventral tegmental area Top expressed in retinal pigment epithelium fourth ventricle iris globus pallidus habenula pontine nuclei ventral tegmental area ciliary body lateral geniculate nucleus superior surface of tongue More reference expression data BioGPS 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 Species Human Mouse Entrez 5168 18606 Ensembl ENSG00000136960 ENSMUSG00000022425 UniProt Q13822 Q9R1E6 RefSeq (mRNA) NM_001040092 NM_001130863 NM_006209 NM_001330600 NM_001136077 NM_015744 NM_001285994 NM_001285995 RefSeq (protein) NP_001035181 NP_001124335 NP_001317529 NP_006200 NP_001129549 NP_001272923 NP_001272924 NP_056559 Location (UCSC) Chr 8: 119.56 – 119.67 Mb Chr 15: 54.84 – 54.95 Mb PubMed search [3] [4]
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.

See also

• Lysophosphatidic acid
• Lysophospholipid receptors
• Lipid signaling
• Phospholipases

References

Further reading

External links

• Human ENPP2 genome location and ENPP2 gene details page in the UCSC Genome Browser.

This page was last edited on 6 April 2024, at 21:14