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Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate

Laurens A van Meeteren1, Paula Ruurs, Evangelos Christodoulou

  • 1Division of Cellular Biochemistry and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

The Journal of Biological Chemistry
|March 17, 2005
PubMed

Insights

Autotaxin (ATX), an enzyme promoting tumor growth, is potently inhibited by lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). This finding reveals a new regulatory mechanism for LPA biosynthesis and a novel inhibitory role for S1P.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Autotaxin (ATX), also known as nucleotide pyrophosphatase/phosphodiesterase 2 (NPP2), is crucial for tumor cell motility, metastasis, and angiogenesis.
  • ATX functions as a lysophospholipase D, producing lysophosphatidic acid (LPA) from lysophosphatidylcholine, and its regulatory mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the regulation of Autotaxin (ATX) activity.
  • To identify potential inhibitors of ATX and understand their mechanism of action.

Main Methods:

  • Utilized a novel, highly sensitive fluorescence resonance energy transfer (FRET)-based phosphodiesterase sensor to monitor ATX activity.
  • Assessed the inhibitory effects of lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) on ATX activity in vitro.
  • Compared the sensitivity of ATX to LPA and S1P with the homologous ecto-phosphodiesterase NPP1.

Main Results:

  • ATX activity was potently and specifically inhibited by both LPA and S1P in a mixed-type manner, with inhibition constants (Ki) around 10(-7) M.
  • The related enzyme NPP1, lacking lysophospholipase D activity, showed no sensitivity to LPA or S1P.
  • These findings indicate that LPA can regulate its own extracellular biosynthesis by inhibiting ATX.

Conclusions:

  • Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are potent inhibitors of Autotaxin (ATX).
  • LPA's inhibition of ATX suggests a feedback mechanism for regulating its own production.
  • Sphingosine 1-phosphate (S1P) exhibits a novel inhibitory role on ATX, distinct from its known receptor-ligand functions.

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