Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate.

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.

• Authors: Laurens A van Meeteren, Paula Ruurs, Evangelos Christodoulou, James W Goding, Hideo Takakusa, Kazuya Kikuchi, Anastassis Perrakis, Tetsuo Nagano, Wouter H Moolenaar
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 280 Issue 22 Pg. 21155-61 (Jun 03 2005) ISSN: 0021-9258 [Print] United States
• PMID: 15769751 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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, metabolism)
• Models, Chemical
• Multienzyme Complexes (antagonists & inhibitors)
• Mutagenesis
• Neoplasm Metastasis
• Neoplasms (metabolism)
• Neovascularization, Pathologic
• Phosphodiesterase I
• Phospholipase D (chemistry)
• Phosphoric Diester Hydrolases (chemistry, metabolism)
• Pyrophosphatases
• Recombinant Fusion Proteins (metabolism)
• Recombinant Proteins (chemistry)
• Sphingosine (analogs & derivatives, chemistry, metabolism)
• Transfection