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Platelet-Derived Growth Factor Stimulates Phospholipase C-1, Extracellular Signal-Regulated Kinase, and Arachidonic Acid Release in Rat Myometrial Cells: Contribution to Cyclic 3',5'-Adenosine Monophosphate Production and Effect on Cell Proliferation¹

^a Signalisation et Régulations Cellulaires, Centre National de la Recherche Scientifique, UMR 8619, Université Paris-Sud, 91405 Orsay Cedex, France

ABSTRACT

In the present study, we examined downstream signaling events that followed exposure of cultured rat myometrial cells to platelet-derived growth factor (PDGF) and their effect on cell proliferation. PDGF-BB induced tyrosine phosphorylation of PDGF-ß receptors and increased inositol trisphosphate production via the tyrosine phosphorylation of phospholipase (PL)C-1. PDGF-BB also increased cAMP synthesis. This increase was potentiated by forskolin and reduced by indomethacin, a cyclooxygenase inhibitor, reflecting a Gs protein-mediated process via prostaglandin biosynthesis. The prostaglandin produced by PDGF was characterized as prostacyclin (PGI₂). PDGF-BB increased arachidonic acid (AA) release, which, similarly to cAMP accumulation, was abolished in the presence of AACOCF3, a cytosolic PLA₂ inhibitor, and in the absence of Ca²⁺. U-73122, a potent inhibitor of PLC activity, blocked both the production of inositol phosphates and the AA release triggered by PDGF-BB. Extracellular signal-regulated kinases (ERKs) 1 and 2 are expressed in myometrial cells, and PDGF-BB selectively activated ERK2. PD98059, an inhibitor of the ERK-activating kinase, blocked PDGF-BB-mediated ERK2 activation, AA release, and cAMP production. The results demonstrate that PDGF-BB stimulated cAMP formation through both PLC activation and ERK-dependent AA release and PGI₂ biosynthesis. PDGF-BB also increased cell proliferation and [³H]thymidine incorporation. This was abolished by PD98059, demonstrating that the ERK cascade is required for the mitogenic effect of PDGF-BB. Forskolin, which potentiated the cAMP response to PDGF-BB, attenuated both DNA synthesis and ERK activation triggered by PDGF-BB, suggesting the presence of a negative feedback regulation.

FOOTNOTES

First decision: 3 January 2001.

¹ This work was supported by grants from the Centre National de la Recherche Scientifique (UMR 8619) and by a contribution from the Association de la Recherche contre le Cancer (contract 1355).

² Correspondence: Denis Leiber, Laboratoire de Signalisation et Régulations Cellulaires, CNRS UMR 8619, Bâtiment 430, Université de Paris- Sud 91405 Orsay Cedex, France. FAX: 033 1 69 85 37 15;denis.leiber{at}erc.u-psud.fr

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