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© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
Lipid Phosphate Phosphatase-1 and Ca2+ Control Lysophosphatidate Signaling through EDG-2 Receptors* , ,
From the Departments of Biochemistry (Signal Transduction
Laboratories and Lipid Biology Research Group) and 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.
Recipient of a Graduate Studentship from the Alberta Heritage
Foundation for Medical Research.
¶
Established Investigator of the American Heart Association.
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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