title: Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate.
abstract: Autotaxin (ATX) is a secreted enzyme, which produces extracellular lysophosphatidate (LPA) from lysophosphatidylcholine (LPC). LPA activates six G protein-coupled receptors and this is essential for vasculogenesis during embryonic development. ATX is also involved in wound healing and inflammation, and in tumor growth, metastasis, and chemo-resistance. It is, therefore, important to understand how ATX is regulated. It was proposed that ATX activity is inhibited by its product LPA, or a related lipid called sphingosine 1-phosphate (S1P). We now show that this apparent inhibition is ineffective at the high concentrations of LPC that occur in vivo. Instead, feedback regulation by LPA and S1P is mediated by inhibition of ATX expression resulting from phosphatidylinositol-3-kinase activation. Inhibiting ATX activity in mice with ONO-8430506 severely decreased plasma LPA concentrations and increased ATX mRNA in adipose tissue, which is a major site of ATX production. Consequently, the amount of inhibitor-bound ATX protein in the plasma increased. We, therefore, demonstrate the concept that accumulation of LPA in the circulation decreases ATX production. However, this feedback regulation can be overcome by the inflammatory cytokines, TNF-α or interleukin 1β. This enables high LPA and ATX levels to coexist in inflammatory conditions. The results are discussed in terms of ATX regulation in wound healing and cancer.
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Matthew G K
authors.initials: MG
authors.lastname: Benesch
authors.affiliation: Departments of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Yuan Y
authors.initials: YY
authors.lastname: Zhao
authors.affiliation: Departments of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Curtis
authors.affiliation: Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Todd P W
authors.initials: TP
authors.lastname: McMullen
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: David N
authors.initials: DN
authors.lastname: Brindley
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002243:Carbolines / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008246:Lysophospholipids / Q000097:blood* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010727:Phosphoric Diester Hydrolases / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics; D000099189:Lysophospholipase D
chemical_list: D002243:Carbolines; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D043562:Receptors, G-Protein-Coupled; D013110:Sphingosine; D014409:Tumor Necrosis Factor-alpha; D000099189:Lysophospholipase D; C000592118:ONO-8430506; C439524:TNF protein, human; C060506:sphingosine 1-phosphate; C032881:lysophosphatidic acid
keywords: autotaxin inhibition; cytokines; fluorescent substrate-3 assay; inflammation; lysophosphatidylcholine