Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate

J Biol Chem. 2005 Jun 3;280(22):21155-61. doi: 10.1074/jbc.M413183200. Epub 2005 Mar 15.

Abstract

Autotaxin (ATX) or nucleotide pyrophosphatase/phosphodiesterase 2 (NPP2) is an NPP family member that promotes tumor cell motility, experimental metastasis, and angiogenesis. ATX primarily functions as a lysophospholipase D, generating the lipid mediator lysophosphatidic acid (LPA) from lysophosphatidylcholine. ATX uses a single catalytic site for the hydrolysis of both lipid and non-lipid phosphodiesters, but its regulation is not well understood. Using a new fluorescence resonance energy transfer-based phosphodiesterase sensor that reports ATX activity with high sensitivity, we show here that ATX is potently and specifically inhibited by LPA and sphingosine 1-phosphate (S1P) in a mixed-type manner (Ki approximately 10(-7) M). The homologous ecto-phosphodiesterase NPP1, which lacks lysophospholipase D activity, is insensitive to LPA and S1P. Our results suggest that, by repressing ATX activity, LPA can regulate its own biosynthesis in the extracellular environment, and they reveal a novel role for S1P as an inhibitor of ATX, in addition to its well established role as a receptor ligand.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site
  • Binding Sites
  • Biosensing Techniques
  • Blotting, Western
  • Catalysis
  • Catalytic Domain
  • Cell Line
  • Cell Movement
  • DNA, Complementary / metabolism
  • Dose-Response Relationship, Drug
  • Fluorescence Resonance Energy Transfer
  • Glucose-6-Phosphate Isomerase / antagonists & inhibitors*
  • Glycoproteins / antagonists & inhibitors*
  • Humans
  • Hydrolysis
  • Kinetics
  • Ligands
  • Lipid Metabolism
  • Lipids / chemistry
  • Lysophosphatidylcholines / chemistry
  • Lysophospholipids / chemistry*
  • Lysophospholipids / metabolism
  • Models, Chemical
  • Multienzyme Complexes / antagonists & inhibitors*
  • Mutagenesis
  • Neoplasm Metastasis
  • Neoplasms / metabolism
  • Neovascularization, Pathologic
  • Phosphodiesterase I
  • Phospholipase D / chemistry
  • Phosphoric Diester Hydrolases / chemistry
  • Phosphoric Diester Hydrolases / metabolism
  • Pyrophosphatases
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Proteins / chemistry
  • Sphingosine / analogs & derivatives*
  • Sphingosine / chemistry*
  • Sphingosine / metabolism
  • Transfection

Substances

  • DNA, Complementary
  • Glycoproteins
  • Ligands
  • Lipids
  • Lysophosphatidylcholines
  • Lysophospholipids
  • Multienzyme Complexes
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • sphingosine 1-phosphate
  • Phosphoric Diester Hydrolases
  • Phosphodiesterase I
  • alkylglycerophosphoethanolamine phosphodiesterase
  • Phospholipase D
  • Pyrophosphatases
  • Glucose-6-Phosphate Isomerase
  • Sphingosine
  • lysophosphatidic acid