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Lysophosphatidic Acid Signals through Mitogen-Activated Protein Kinase-Extracellular Signal Regulated Kinase in Ovarian Theca Cells Expressing the LP_A1/edg2-Receptor: Involvement of a Nonclassical Pathway?

Institute for Hormone and Fertility Research, University of Hamburg, D-20251 Hamburg, Germany

Address all correspondence and requests for reprints to: Dr. Lygia T. Budnik, Institute for Hormone and Fertility Research, University of Hamburg, Centrum for Innovative Medicine, Falkenried 88, D-20251 Hamburg, Germany. E-mail: Budnik{at}IHF.de.

We investigated the mechanism of lysophosphatidic acid (LPA) signaling in ovarian theca cells and observed that stimulation with this bioactive lipid markedly enhanced Thr/Tyr phosphorylation of the MAPK ERK1/2. Activation of ERK was transient, showing a peak at 5 min that declined thereafter, and was not associated with a concomitant nuclear translocation of the enzyme, suggesting that a cytosolic tyrosine phosphatase may be responsible for switching off the signal. Epidermal growth factor (EGF)-induced activation of the enzyme in the same cell system was more rapid (peaking at 1 min), sustainable for at least 60 min, and could be suppressed by prior treatment with either pertussis toxin or a noncompetitive inhibitor of Ras acceptor protein, manumycin A. This functional inhibition of either Gi or Ras failed, however, to affect the LPA-induced ERK-phosphorylation. Surprisingly, functional inhibition of Rho-GTPase, in C3-exotoxin-lipofected cells, markedly reduced LPA-stimulated phosphorylation of ERK, without affecting the EGF-induced stimulation of MAPK. Theca cells labeled with anti-LP_A1/edg2-type antibody showed a distinct cell surface labeling, which is reflected in the expression of (LP_A1)-type LPA receptors at both mRNA and protein levels. The findings indicate that LPA transiently stimulates MAPK ERK in LP_A1/edg2-expressing theca cells and suggest an alternative mechanism regulating the activation of ERK that differs from the canonical EGF-Ras-MAPK kinase pathway.

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