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J. Biol. Chem., Vol. 280, Issue 22, 21155-21161, June 3, 2005

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Inhibition of Autotaxin by Lysophosphatidic Acid and Sphingosine 1-Phosphate^*

Laurens A. van Meeteren, Paula Ruurs, Evangelos Christodoulou, James W. Goding¶, Hideo Takakusa||, Kazuya Kikuchi||, Anastassis Perrakis, Tetsuo Nagano||, and Wouter H. Moolenaar**

From the Division of Cellular Biochemistry and Center for Biomedical Genetics and Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands, ^¶Department of Pathology and Immunology, Monash Medical School, Alfred Hospital, Prahran 3181, Victoria, Australia, and ^||Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan

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 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.

Received for publication, November 22, 2004 , and in revised form, February 18, 2005.

^* This work was supported by the Dutch Cancer Society. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

^** To whom correspondence should be addressed. Tel.: 31-20-512-1971; Fax: 31-20-512-1989; E-mail: w.moolenaar{at}nki.nl.

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