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Originally published In Press as doi:10.1074/jbc.M306709200 on August 8, 2003
J. Biol. Chem., Vol. 278, Issue 44, 43214-43223, October 31, 2003
Lipid Phosphate Phosphatases Regulate Lysophosphatidic Acid Production and Signaling in Platelets
STUDIES USING CHEMICAL INHIBITORS OF LIPID PHOSPHATE PHOSPHATASE ACTIVITY*
Susan S. Smyth  ,
Vicki A. Sciorra¶,
Yury J. Sigal||,
Zehra Pamuklar,
Zuncai Wang||,
Yong Xu**,
Glenn D. Prestwich**, and
Andrew J. Morris||
From the
¶Howard Hughes Medical Institute, University of California, San Diego, La Jolla, California 92093-0668, the **Department of Medicinal Chemistry, The University of Utah, Salt Lake City, Utah 84108, and the Departments of Medicine, Division of Cardiology and ||Cell and Developmental Biology, University of North Carolina, Chapel Hill, North Carolina 27599-7090
Blood platelets play an essential role in ischemic heart disease and stroke contributing to acute thrombotic events by release of potent inflammatory agents within the vasculature. Lysophosphatidic acid (LPA) is a bioactive lipid mediator produced by platelets and found in the blood and atherosclerotic plaques. LPA receptors on platelets, leukocytes, endothelial cells, and smooth muscle cells regulate growth, differentiation, survival, motility, and contractile activity. Definition of the opposing pathways of synthesis and degradation that control extracellular LPA levels is critical to understanding how LPA bioactivity is regulated. We show that intact platelets and platelet membranes actively dephosphorylate LPA and identify the major enzyme responsible as lipid phosphate phosphatase 1 (LPP1). Localization of LPP1 to the platelet surface is increased by exposure to LPA. A novel receptor-inactive sn-3-substituted difluoromethylenephosphonate analog of phosphatidic acid that is a potent competitive inhibitor of LPP1 activity potentiates platelet aggregation and shape change responses to LPA and amplifies LPA production by agonist-stimulated platelets. Our results identify LPP1 as a pivotal regulator of LPA signaling in the cardiovascular system. These findings are consistent with genetic and cell biological evidence implicating LPPs as negative regulators of lysophospholipid signaling and suggest that the mechanisms involve both attenuation of lysophospholipid actions at cell surface receptors and opposition of lysophospholipid production.
Received for publication, June 24, 2003
, and in revised form, August 7, 2003.
* This work was supported in part by National Institutes of Health Grants GM 50388 and CA 12451 (to A. J. M.), HL070304 and DK064183 (to S. S. S.), and NS029632 (to G. D. P.). 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.
 A Scholar of the American Society of Hematology.
To whom correspondence should be addressed. Tel.: 919-843-5001; Fax: 919-966-1856; E-mail: ajmorris{at}med.unc.edu.
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Copyright © 2003 by the American Society for Biochemistry and Molecular Biology.
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