Lipid phosphate phosphatase-1 and Ca2+ control lysophosphatidate signaling through EDG-2 receptors

James Xu, Lana M. Love, Indrapal Singh, Qiu Xia Zhang, Jay W. Dewald, De An Wang, David J. Fischer, Gabor Tigyi, Luc G. Berthiaume, David W. Waggoner, David N. Brindley

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

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 K(d) and B(max) for LPA binding at 4°C, increasing Ca2+ from 0 to 50 μM increased the K(d) 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 K(d) 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.

Original languageEnglish (US)
Pages (from-to)27520-27530
Number of pages11
JournalJournal of Biological Chemistry
Volume275
Issue number36
DOIs
StatePublished - Sep 8 2000

Fingerprint

Chemical activation
Association reactions
Cell signaling
Phospholipase D
DNA
Fibroblasts
G-Protein-Coupled Receptors
Phospholipids
Intercellular Signaling Peptides and Proteins
Cell Division
Cells
lipid phosphate phosphatase
Serum

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Xu, J., Love, L. M., Singh, I., Zhang, Q. X., Dewald, J. W., Wang, D. A., ... Brindley, D. N. (2000). Lipid phosphate phosphatase-1 and Ca2+ control lysophosphatidate signaling through EDG-2 receptors. Journal of Biological Chemistry, 275(36), 27520-27530. https://doi.org/10.1074/jbc.M003211200

Lipid phosphate phosphatase-1 and Ca2+ control lysophosphatidate signaling through EDG-2 receptors. / Xu, James; Love, Lana M.; Singh, Indrapal; Zhang, Qiu Xia; Dewald, Jay W.; Wang, De An; Fischer, David J.; Tigyi, Gabor; Berthiaume, Luc G.; Waggoner, David W.; Brindley, David N.

In: Journal of Biological Chemistry, Vol. 275, No. 36, 08.09.2000, p. 27520-27530.

Research output: Contribution to journalArticle

Xu, J, Love, LM, Singh, I, Zhang, QX, Dewald, JW, Wang, DA, Fischer, DJ, Tigyi, G, Berthiaume, LG, Waggoner, DW & Brindley, DN 2000, 'Lipid phosphate phosphatase-1 and Ca2+ control lysophosphatidate signaling through EDG-2 receptors', Journal of Biological Chemistry, vol. 275, no. 36, pp. 27520-27530. https://doi.org/10.1074/jbc.M003211200
Xu, James ; Love, Lana M. ; Singh, Indrapal ; Zhang, Qiu Xia ; Dewald, Jay W. ; Wang, De An ; Fischer, David J. ; Tigyi, Gabor ; Berthiaume, Luc G. ; Waggoner, David W. ; Brindley, David N. / Lipid phosphate phosphatase-1 and Ca2+ control lysophosphatidate signaling through EDG-2 receptors. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 36. pp. 27520-27530.
@article{f0d47dc7cc184ca69cd81e3328debbf7,
title = "Lipid phosphate phosphatase-1 and Ca2+ control lysophosphatidate signaling through EDG-2 receptors",
abstract = "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 K(d) and B(max) for LPA binding at 4°C, increasing Ca2+ from 0 to 50 μM increased the K(d) 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 K(d) 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.",
author = "James Xu and Love, {Lana M.} and Indrapal Singh and Zhang, {Qiu Xia} and Dewald, {Jay W.} and Wang, {De An} and Fischer, {David J.} and Gabor Tigyi and Berthiaume, {Luc G.} and Waggoner, {David W.} and Brindley, {David N.}",
year = "2000",
month = "9",
day = "8",
doi = "10.1074/jbc.M003211200",
language = "English (US)",
volume = "275",
pages = "27520--27530",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "36",

}

TY - JOUR

T1 - Lipid phosphate phosphatase-1 and Ca2+ control lysophosphatidate signaling through EDG-2 receptors

AU - Xu, James

AU - Love, Lana M.

AU - Singh, Indrapal

AU - Zhang, Qiu Xia

AU - Dewald, Jay W.

AU - Wang, De An

AU - Fischer, David J.

AU - Tigyi, Gabor

AU - Berthiaume, Luc G.

AU - Waggoner, David W.

AU - Brindley, David N.

PY - 2000/9/8

Y1 - 2000/9/8

N2 - 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 K(d) and B(max) for LPA binding at 4°C, increasing Ca2+ from 0 to 50 μM increased the K(d) 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 K(d) 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.

AB - 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 K(d) and B(max) for LPA binding at 4°C, increasing Ca2+ from 0 to 50 μM increased the K(d) 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 K(d) 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.

UR - http://www.scopus.com/inward/record.url?scp=0034623053&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034623053&partnerID=8YFLogxK

U2 - 10.1074/jbc.M003211200

DO - 10.1074/jbc.M003211200

M3 - Article

C2 - 10849424

AN - SCOPUS:0034623053

VL - 275

SP - 27520

EP - 27530

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 36

ER -