Lysophosphatidic Acid Signals through Mitogen-Activated Protein Kinase-Extracellular Signal Regulated Kinase in Ovarian Theca Cells Expressing the LPA1/edg2-Receptor: Involvement of a Nonclassical Pathway?

• Published in: Molecular endocrinology (Baltimore, Md.) Md.), 2003-08, Vol.17 (8), p.1593-1606
• Main Authors: Budnik, Lygia T, Brunswig-Spickenheier, Bärbel, Mukhopadhyay, Amal K
• Format: Article
• Language: English
• Subjects: 8-Bromo Cyclic Adenosine Monophosphate - pharmacology; Animals; Cattle; Cell Membrane - drug effects; Cell Membrane - metabolism; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cells, Cultured; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Epidermal Growth Factor - pharmacology; Female; Humans; Lysophospholipids - metabolism; Lysophospholipids - pharmacology; MAP Kinase Kinase 1; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - drug effects; Mitogen-Activated Protein Kinase Kinases - metabolism; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - drug effects; Mitogen-Activated Protein Kinases - metabolism; Pertussis Toxin - pharmacology; Phosphorylation; Protein Transport - drug effects; ras Proteins - antagonists & inhibitors; ras Proteins - metabolism; Receptors, G-Protein-Coupled - drug effects; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Receptors, Lysophosphatidic Acid; Signal Transduction; Tetradecanoylphorbol Acetate - pharmacology; Theca Cells - drug effects; Theca Cells - metabolism
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2002-0371

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-LPA1/edg2-type antibody showed a distinct cell surface labeling, which is reflected in the expression of (LPA1)-type LPA receptors at both mRNA and protein levels. The findings indicate that LPA transiently stimulates MAPK ERK in LPA1/edg2-expressing theca cells and suggest an alternative mechanism regulating the activation of ERK that differs from the canonical EGF-Ras-MAPK kinase pathway.