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J. Biol. Chem. 275 (36): 27520-27530

© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

Lipid Phosphate Phosphatase-1 and Ca2+ Control Lysophosphatidate Signaling through EDG-2 Receptors*

James Xu, Lana M. LoveDagger , Indrapal Singh, Qiu-Xia Zhang, Jay Dewald, De-An Wang§, David J. Fischer§, Gabor Tigyi§, Luc G. Berthiaume||, David W. Waggoner**, and David N. BrindleyDagger Dagger

From the Departments of Biochemistry (Signal Transduction Laboratories and Lipid Biology Research Group) and || Cell Biology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada, the § Department of Physiology, University of Tennessee, Memphis, Tennessee 38163, and ** Cell Therapeutics Inc., Seattle, Washington 98119

The serum-derived phospholipid growth factor, lysophosphatidate (LPA), activates cells through the EDG family of G protein-coupled receptors. The present study investigated mechanisms by which dephosphorylation of exogenous LPA by lipid phosphate phosphatase-1 (LPP-1) controls cell signaling. Overexpressing LPP-1 decreased the net specific cell association of LPA with Rat2 fibroblasts by approximately 50% at 37 °C when less than 10% of LPA was dephosphorylated. This attenuated cell activation as indicated by diminished responses, including cAMP, Ca2+, activation of phospholipase D and ERK, DNA synthesis, and cell division. Conversely, decreasing LPP-1 expression increased net LPA association, ERK stimulation, and DNA synthesis. Whereas changing LPP-1 expression did not alter the apparent Kd and Bmax for LPA binding at 4 °C, increasing Ca2+ from 0 to 50 µM increased the Kd from 40 to 900 nM. Decreasing extracellular Ca2+ from 1.8 mM to 10 µM increased LPA binding by 20-fold, shifting the threshold for ERK activation to the nanomolar range. Hence the Ca2+ dependence of the apparent Kd values explains the long-standing discrepancy of why micromolar LPA is often needed to activate cells at physiological Ca2+ levels. In addition, the work demonstrates that LPP-1 can regulate specific LPA association with cells without significantly depleting bulk LPA concentrations in the extracellular medium. This identifies a novel mechanism for controlling EDG-2 receptor activation.


* This work was supported by grants (to D. N. B.) from Cell Therapeutics Inc., by the Alberta Heritage Foundation for Medical Research, by Medical Research Council of Canada Grant MT 10504, and by National Institutes of Health Grant RO1 61751 (to D. English and D. N. B.) and United States Public Health Service Grant HL 61469 (to G. T.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Recipient of a Graduate Studentship from the Alberta Heritage Foundation for Medical Research.

Established Investigator of the American Heart Association.

Dagger Dagger Recipient of a Medical Scientist Award. To whom correspondence should be addressed: Dept. of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Tel.: 780-492-2078; Fax: 780-492-3383; E-mail: david.brindley@ualberta.ca.


Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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