Lysophosphatidic acid prevents apoptosis in fibroblasts via G(i)-protein-mediated activation of mitogen-activated protein kinase

X. Fang, S. Yu, R. Lapushin, Y. Lu, T. Furui, L. Z. Penn, D. Stokoe, J. R. Erickson, Jr Bast, Gordon Mills

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Abstract

Lysophosphatidic acid (LPA) is a naturally occurring phospholipid with multiple biological functions. In the present study, we demonstrate that, besides its mitogenic activity, LPA is a potent survival factor, preventing serum-deprivation-induced apoptosis in fibroblasts and other cell types. Both the proliferative effect and survival activity of LPA are sensitive to the action of pertussis toxin (PTX), indicating that both processes are mediated by G(i) protein(s). We therefore focused on the role of G(i)-protein-mediated signalling events in the promotion of cell survival by LPA. In addition to activation of mitogen-activated protein kinase (MAPK), LPA stimulates a modest PTX-sensitive phosphorylation/activation of the serine/threonine kinase Akt, a survival mediator downstream of phosphoinositide 3-kinase (PI3K). Inhibition of PI3K with LY 294002 or wortmannin resulted in a marked inhibition of LPA-induced DNA synthesis, and yet the survival activity of LPA decreased by only 20-30%, suggesting a limited input of the PI3K-Akt cascade in LPA-induced cell survival. In contrast, inhibition of MAPK activation by the MEK-1 inhibitor, PD 98059, blocked both the proliferative and survival effects of LPA. These results indicate that LPA promotes cell survival largely via G(i)-protein-mediated activation of ERK1/ERK2, or other PD 98059-sensitive member(s) of the MAPK family.

Original languageEnglish (US)
Pages (from-to)135-143
Number of pages9
JournalBiochemical Journal
Volume352
Issue number1
DOIs
Publication statusPublished - Nov 15 2000
Externally publishedYes

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Keywords

  • Cell proliferation
  • Cell survival
  • Extracellular-signal-regulated kinase (ERK)
  • NIH 3T3 cells
  • Phosphatidylinositol 3-kinase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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