Autotaxin

Function

Secreted lysophospholipase D that hydrolyzes lysophospholipids to produce the signaling molecule lysophosphatidic acid (LPA) in extracellular fluids. Its major substrate is lysophosphatidylcholine. Can also act on sphingosylphosphorylcholine producing sphingosine-1-phosphate, a modulator of cell motility. Can hydrolyze, in vitro, bis-pNPP, to some extent pNP-TMP, and barely ATP. Involved in several motility-related processes such as angiogenesis and neurite outgrowth. Acts as an angiogenic factor by stimulating migration of smooth muscle cells and microtubule formation. Stimulates migration of melanoma cells, probably via a pertussis toxin-sensitive G protein. May have a role in induction of parturition. Possible involvement in cell proliferation and adipose tissue development (Probable). Required for LPA production in activated platelets, cleaves the sn-1 lysophospholipids to generate sn-1 lysophosphatidic acids containing predominantly 18:2 and 20:4 fatty acids. Shows a preference for the sn-1 to the sn-2 isomer of 1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF).

Classification

Family (Pfam)

PF01223 Endonuclease_NS, PF01663 Phosphodiest, PF01033 Somatomedin_B

InterPro

Alkaline_phosphatase_core_sf, DNA/RNA_non-sp_Endonuclease_sf, Endo_G_ENPP1-like_dom, ENPP1-3/EXOG-like_nuc-like, His-Me_finger_sf, Phosphodiest/P_Trfase, SMB_chordata, Somatomedin_B-like_dom_sf, Somatomedin_B_dom

Functional cluster

M20 Family Metallopeptidases

Experimental structures · PDB · 9

• 4ZG6 X-ray 1.80A
• 4ZG7 X-ray 1.75A
• 4ZG9 X-ray 2.95A
• 4ZGA X-ray 2.60A
• 5KXA X-ray 2.59A
• 5M7M X-ray 2.70A
• 5MHP X-ray 2.43A
• 8C3O X-ray 2.47A
• 8C3P X-ray 2.38A

A predicted model is available from AlphaFold.

Gene Ontology · 20

• GO:0005615 extracellular space
• GO:0005886 plasma membrane
• GO:0047391 alkylglycerophosphoethanolamine phosphodiesterase activity
• GO:0005509 calcium ion binding
• GO:0004630 D-type glycerophospholipase activity
• GO:0016787 hydrolase activity
• GO:0003676 nucleic acid binding
• GO:0004622 phosphatidylcholine lysophospholipase A1 activity
• GO:0004528 phosphodiesterase I activity
• GO:0030247 polysaccharide binding
• GO:0005044 scavenger receptor activity
• GO:0008270 zinc ion binding
• GO:0006935 chemotaxis
• GO:0006955 immune response
• GO:0034638 phosphatidylcholine catabolic process
• GO:0009395 phospholipid catabolic process
• GO:0010634 positive regulation of epithelial cell migration
• GO:2000394 positive regulation of lamellipodium morphogenesis
• GO:0030334 regulation of cell migration
• GO:0030149 sphingolipid catabolic process

Drugs targeting this protein · 1

• ZIRITAXESTAT inhibitor

Related proteins · sequence + function similarity

• Autotaxin 0.99
• Autotaxin 0.99
• Autotaxin 0.99
• Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 0.87
• Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 0.87
• Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 0.85
• Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 0.85
• Venom phosphodiesterase CdcPDE 0.84
• Venom phosphodiesterase 0.83
• Venom phosphodiesterase 0.83
• Venom phosphodiesterase 1 0.83
• Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 0.83

Co-cited proteins · studied together in the literature

• Autotaxin 3 shared papers
• Autotaxin 3 shared papers
• Acyl-protein thioesterase 1 1 shared papers
• Phosphatidylcholine-sterol acyltransferase 1 shared papers

Literature · 18 cited papers

• Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis. J. Med. Chem. · 2017
• Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis. J. Pharmacol. Exp. Ther. · 2017
• Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding. Mol. Pharmacol. · 2015
• The phospholipase A1 activity of lysophospholipase A-I links platelet activation to LPA production during blood coagulation. J. Lipid Res. · 2011
• Structural basis of substrate discrimination and integrin binding by autotaxin. Nat. Struct. Mol. Biol. · 2011
• Murine and human autotaxin alpha, beta, and gamma isoforms: gene organization, tissue distribution, and biochemical characterization. J. Biol. Chem. · 2008
• DNA sequence and analysis of human chromosome 8. Nature · 2006
• Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate. J. Biol. Chem. · 2005
• Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression. Diabetologia · 2005
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
• Autotaxin hydrolyzes sphingosylphosphorylcholine to produce the regulator of migration, sphingosine-1-phosphate. Cancer Res. · 2003
• Serum lysophosphatidic acid is produced through diverse phospholipase pathways. J. Biol. Chem. · 2002
• … and 6 more in the literature graph