G-protein-coupled Receptor Stimulation of the p42/p44 Mitogen-activated Protein Kinase Pathway Is Attenuated by Lipid Phosphate Phosphatases 1, 1a, and 2 in Human Embryonic Kidney 293 Cells

Abstract

Sphingosine 1-phosphate, lysophosphatidic acid, and phosphatidic acid bind to G-protein-coupled receptors to stimulate intracellular signaling in mammalian cells. Lipid phosphate phosphatases (1, 1a, 2, and 3) are a group of enzymes that catalyze de-phosphorylation of these lipid agonists. It has been proposed that the lipid phosphate phosphatases exhibit ecto activity that may function to limit bioavailability of these lipid agonists at their receptors. In this study, we show that the stimulation of the p42/p44 mitogen-activated protein kinase pathway by sphingosine 1-phosphate, lysophosphatidic acid, and phosphatidic acid, all of which bind to G i/ocoupled receptors, is substantially reduced in human embyronic kidney 293 cells transfected with lipid phosphate phosphatases 1, 1a, and 2 but not 3. This was correlated with reduced basal intracellular phosphatidic acid and not ecto lipid phosphate phosphatase activity. These findings were supported by results showing that lipid phosphate phosphatases 1, 1a, and 2 also abrogate the stimulation of p42/p44 mitogen-activated protein kinase by thrombin, a peptide G i/o -coupled receptor agonist whose bioavailability at its receptor is not subject to regulation by the phosphatases. Furthermore, the lipid phosphate phosphatases have no effect on the stimulation of p42/p44 mitogen-activated protein kinase by other agents that do not use G-proteins to signal, such as serum factors and phorbol ester. Therefore, these findings show that the lipid phosphate phosphatases 1, 1a, and 2 may function to perturb G-proteincoupled receptor signaling per se rather than limiting bioavailability of lipid agonists at their respective receptors.

Lipid phosphate phosphatase-1 expression in cancer cells attenuates tumor growth and metastasis in mice

“…LPP1 also attenuates signaling downstream of G-protein-coupled receptors and receptor tyrosine kinases. This effect depends on the catalytic activity of LPP1 and presumably results from the degradation of an intracellular lipid phosphate(s) formed downstream of receptor activation ( 14,15,20,21 ). These combined actions are consistent with reports that increasing LPP1 activity in cells suppresses signals that promote cell growth and migration ( 2,15,16 ).…”

Lack of sphingosine 1-phosphate-degrading enzymes in erythrocytes

“…On the other hand, LPP family members are localized in the plasma membrane and also in the internal membranes [23,24], and Sph kinase is localized in the cytosol (primarily) and plasma membrane [25]. Thus the lack of ceramide synthase and S1P lyase activities in erythrocytes would seem reasonable, since erythrocytes have no ER.…”

Lipid Phosphate Phosphatases Regulate Lysophosphatidic Acid Production and Signaling in Platelets

“…At the cellular level, overexpression studies suggest that LPPs 1-3 act as both negative regulators of LPA and S1P signaling and have roles in metabolism of intracellular lipid messengers (23,37). At the organismal level, inactivation or misexpression of two Drosophila LPP enzymes alters gem cell migration in early development, which has been suggested to involve localized changes in LPP-catalyzed degradation of an as yet unidentified lipid signaling molecule (21).…”

“…When in the plasma membrane, the active sites of these enzymes are oriented toward the extracellular space (18 -20). Genetic and cell biological evidence identifies roles for LPPs in both intracellular lipid metabolism and as negative regulators of lysophospholipid signaling, although the mechanisms involved remain to be firmly established (19,(21)(22)(23)(24)(25).Here we show that a specific LPP isoform, LPP1, is strongly * 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.…”

“…When in the plasma membrane, the active sites of these enzymes are oriented toward the extracellular space (18 -20). Genetic and cell biological evidence identifies roles for LPPs in both intracellular lipid metabolism and as negative regulators of lysophospholipid signaling, although the mechanisms involved remain to be firmly established (19,(21)(22)(23)(24)(25).…”