Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate
Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate
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DOI：
10.1074/jbc.m413183200
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发表时间：
2005-06-03
影响因子：
4.8
通讯作者：
Moolenaar, WH
中科院分区：
文献类型：
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作者：
van Meeteren, LA;Ruurs, P;Moolenaar, WH
自分泌运动因子（ATX）或核苷酸焦磷酸酶/磷酸二酯酶2（NPP 2）是促进肿瘤细胞运动性、实验性转移和血管生成的NPP家族成员。ATX主要用作溶血磷脂酶D，从溶血磷脂酰胆碱产生脂质介质溶血磷脂酸（LPA）。ATX使用单个催化位点来水解脂质和非脂质磷酸二酯，但其调控尚不清楚。使用一种新的基于荧光共振能量转移的磷酸二酯酶传感器，以高灵敏度报告ATX活性，我们在这里显示ATX被LPA和1-磷酸鞘氨醇（S1 P）以混合型方式有效且特异性地抑制（Ki类似于10（-7）M）。同源胞外磷酸二酯酶NPP 1缺乏溶血磷脂酶D活性，对LPA和S1 P不敏感。我们的研究结果表明，通过抑制ATX活性，LPA可以调节其自身的生物合成在细胞外环境中，他们揭示了一个新的作用，S1 P作为ATX的抑制剂，除了其公认的作用作为受体配体。
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 (K-i similar to 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.