Autotaxin hydrolyzes sphingosylphosphorylcholine to produce the regulator of migration, sphingosine-1-phosphate

Timothy Clair, Junken Aoki, Eunjin Koh, Russell W. Bandle, Suk Woo Nam, Malgorzata M. Ptaszynska, Gordon B. Mills, Elliott Schiffmann, Lance A. Liotta, Mary L. Stracke

Research output: Contribution to journalArticle

193 Scopus citations

Abstract

Autotaxin (ATX) is an exoenzyme that potently induces tumor cell motility, and enhances experimental metastasis and angiogenesis. ATX was shown recently to be identical to serum lysophospholipase D activity, producing lysophosphatidic acid (LPA) from lyso-glycerophospholipids. LPA, itself a strong chemoattractant for tumor cells, may mediate the actions of ATX. We now extend the substrate specificity to sphingosylphosphorylcholine (SPC), which ATX hydrolyzes to sphingosine-1-phosphate (S1P). Under migration assay conditions, this novel reaction for the production of S1P has a substrate (SPC) Km = 0.23 ± 0.07 mM. In our responder cell lines (NIH3T3 clone7 and A2058), S1P exerts maximal biological effects at concentrations of 10-100 nM and is mimicked in its biological effects by ATX plus SPC. These effects include inhibition of ATX- and LPA-stimulated motility, and elevation of activated Rho. In NIH3T3 clone7 cells stimulated with platelet-derived growth factor and treated with 10-25 nM S1P, motility is not inhibited and activation of Rho is unaffected, indicating that S1P possesses specificity in its effects. The exoenzyme ATX can potentially regulate diverse processes such as motility and angiogenesis via the S1P family of receptors. Because ATX hydrolyzes nucleotides, lyso-glycerophospholipids, and phosphosphingolipids into bioactive products, it possesses the ability, depending on the availability of substrates, to act as positive or negative regulator of receptor-mediated activity in the cellular microenvironment.

Original languageEnglish (US)
Pages (from-to)5446-5453
Number of pages8
JournalCancer Research
Volume63
Issue number17
StatePublished - Sep 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Clair, T., Aoki, J., Koh, E., Bandle, R. W., Nam, S. W., Ptaszynska, M. M., Mills, G. B., Schiffmann, E., Liotta, L. A., & Stracke, M. L. (2003). Autotaxin hydrolyzes sphingosylphosphorylcholine to produce the regulator of migration, sphingosine-1-phosphate. Cancer Research, 63(17), 5446-5453.