Abstract
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. PLD(2) 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 PLD(2) 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.
Highlights
Intracellular actions of lipid phosphate phosphatase-1 (LPP1) play important functions in regulating LPA-induced fibroblast migration through PLD2
These LPP1 overexpressing fibroblasts showed a severe inhibition of LPA-induced migration in a wound healing assay (Fig. 1, C and D)
LPA-induced ERK phosphorylation was decreased by an aver- inhibited fibroblast migration by controlling PA production, we age of 62% by stable overexpression of LPP1 (Fig. 5, A and B). stimulated the fibroblasts with LPA, or PDGF to increase phospholipase D (PLD)
Summary
Intracellular actions of LPP1 play important functions in regulating LPA-induced fibroblast migration through PLD2. Fibroblasts in which LPP1 activity was knocked down showed increased (p Ͻ 0.05) LPA-induced migration compared with cells treated with control siRNA (Fig. 3C). To investigate the role of the ecto-LPP activity more directly The concentration of Rac-GTP under basal conditions was we used the ␣-hydroxyphosphonate analogue (wls-31) of LPA decreased in the LPP1 overexpressing fibroblasts compared to promote cell migration.
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