Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate.
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.
van Meeteren
Laurens A
LA
Division of Cellular Biochemistry and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Ruurs
Paula
P
Christodoulou
Evangelos
E
Goding
James W
JW
Takakusa
Hideo
H
Kikuchi
Kazuya
K
Perrakis
Anastassis
A
Nagano
Tetsuo
T
Moolenaar
Wouter H
WH
D000495:Allosteric Site; D001665:Binding Sites; D015374:Biosensing Techniques; D015153:Blotting, Western; D002384:Catalysis; D020134:Catalytic Domain; D002460:Cell Line; D002465:Cell Movement; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D031541:Fluorescence Resonance Energy Transfer; D005956:Glucose-6-Phosphate Isomerase / Q000037:antagonists & inhibitors*; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D008024:Ligands; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008244:Lysophosphatidylcholines / Q000737:chemistry; D008246:Lysophospholipids / Q000737:chemistry* / Q000378:metabolism; D008956:Models, Chemical; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D016296:Mutagenesis; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism; D009389:Neovascularization, Pathologic; D043264:Phosphodiesterase I; D010739:Phospholipase D / Q000737:chemistry; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism; D011755:Pyrophosphatases; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D014162:Transfection; D000099189:Lysophospholipase D
D018076:DNA, Complementary; D005956:Glucose-6-Phosphate Isomerase; D006023:Glycoproteins; D008024:Ligands; D008055:Lipids; D008244:Lysophosphatidylcholines; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D010739:Phospholipase D; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D013110:Sphingosine; D000099189:Lysophospholipase D; C060506:sphingosine 1-phosphate; C032881:lysophosphatidic acid