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J. Biol. Chem., Vol. 281, Issue 50, 38418-38429, December 15, 2006

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 281/50/38418    most recent M601670200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pilquil, C. Articles by Brindley, D. N. Search for Related Content PubMed PubMed Citation Articles by Pilquil, C. Articles by Brindley, D. N. Social Bookmarking                      What's this?

Lipid Phosphate Phosphatase-1 Regulates Lysophosphatidate-induced Fibroblast Migration by Controlling Phospholipase D₂-dependent Phosphatidate Generation^*

Carlos Pilquil¹, Jay Dewald, Anton Cherney, Irina Gorshkova, Gabor Tigyi^¶, Denis English^||, Viswanathan Natarajan, and David N. Brindley²

From the Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada, the ^¶Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, the ^||Department of Neurosurgery Center of Excellence for Aging and Brain Repair, University of South Florida College of Medicine, MDC-78, Tampa, Florida 36112, and the Department of Medicine, Section of Pulmonary and Critical Care, University of Chicago, Chicago, Illinois 60637

Lysophosphatidate (LPA) stimulates cell migration and division through a family of G-protein-coupled receptors. Lipid phosphate phosphatase-1 (LPP1) regulates the degradation of extracellular LPA as well as the intracellular accumulation of lipid phosphates. Here we show that increasing the catalytic activity of LPP1 decreased the pertussis toxin-sensitive stimulation of fibroblast migration by LPA and an LPA-receptor agonist that could not be dephosphorylated. Conversely, knockdown of endogenous LPP1 activity increased LPA-induced migration. However, LPP1 did not affect PDGF- or endothelin-induced migration of fibroblasts in Transwell chamber and "wound healing" assays. Thus, in addition to degrading exogenous LPA, LPP1 controls signaling downstream of LPA receptors. Consistent with this conclusion, LPP1 expression decreased phospholipase D (PLD) stimulation by LPA and PDGF, and phosphatidate accumulation. This LPP1 effect was upstream of PLD activation in addition to the possible metabolism of phosphatidate to diacylglycerol. PLD₂ activation was necessary for LPA-, but not PDGF-induced migration. Increased LPP1 expression also decreased the LPA-, but not the PDGF-induced activation of important proteins involved in fibroblast migration. These included decreased LPA-induced activation of ERK and Rho, and the basal activities of Rac and Cdc42. However, ERK and Rho activation were not downstream targets of LPA-induced PLD₂ activity. We conclude that the intracellular actions of LPP1 play important functions in regulating LPA-induced fibroblast migration through PLD2. LPP1 also controls PDGF-induced phosphatidate formation. These results shed new light on the roles of LPP1 in controlling wound healing and the growth and metastasis of tumors.

Received for publication, February 22, 2006 , and in revised form, October 17, 2006.

^* This work was supported in part by Canadian Institutes of Health Research Grants MOP 10504 and 49491 (to D. N. B.), United States Public Health Serivce Grants NHBLI 61469 and CA-92160 (to G. T.), and National Institutes of Health Grants RO1 HL061751 (to D. E.) and RO1 HL 71152 and HL 079396 (to V. N.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. i.

¹ Received a Graduate Student Research Award from the Alberta Heritage Foundation for Medical Research.

² Supported by a Medical Scientist award from the Alberta Heritage Foundation for Medical Research. To whom correspondence should be addressed: 357 Heritage Medical Research Center, Edmonton, Alberta T6G 2S2, Canada. Tel.: 780-492-2078; Fax: 780-492-3383; E-mail: david.brindley{at}ualberta.ca.

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