van Meeteren Laurens A, Ruurs Paula, Christodoulou Evangelos, Goding James W, Takakusa Hideo, Kikuchi Kazuya, Perrakis Anastassis, Nagano Tetsuo, Moolenaar Wouter H
Division of Cellular Biochemistry and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
J Biol Chem. 2005 Jun 3;280(22):21155-61. doi: 10.1074/jbc.M413183200. Epub 2005 Mar 15.
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.
自分泌运动因子（ATX）或核苷酸焦磷酸酶/磷酸二酯酶2（NPP2）是NPP家族成员，可促进肿瘤细胞的运动、实验性转移和血管生成。ATX主要作为溶血磷脂酶D发挥作用，从溶血磷脂酰胆碱生成脂质介质溶血磷脂酸（LPA）。ATX使用单一催化位点水解脂质和非脂质磷酸二酯，但其调节机制尚不清楚。我们使用一种基于荧光共振能量转移的新型磷酸二酯酶传感器，能够高灵敏度地报告ATX活性，结果表明，LPA和1-磷酸鞘氨醇（S1P）以混合型方式有效且特异性地抑制ATX（抑制常数约为10^(-7) M）。缺乏溶血磷脂酶D活性的同源胞外磷酸二酯酶NPP1对LPA和S1P不敏感。我们的结果表明，通过抑制ATX活性，LPA可以在细胞外环境中调节自身的生物合成，并且揭示了S1P作为ATX抑制剂的新作用，此外它作为受体配体的作用已得到充分证实。
