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Prostaglandin F₂ Stimulates Tyrosine Phosphorylation and Mitogen-Activated Protein Kinase in Osteoblastic MC3T3-E1 Cells via Protein Kinase C Activation

Department of Oral Anatomy, Meikai University School of Dentistry (Y.H., M.S., H.M., T.K., M.K.), Sakado, Saitama 350–02, Japan; and the Division of Endocrinology and Metabolism, University of Connecticut Health Center (L.G.R.), Farmington, Connecticut 06030

Address all correspondence and requests for reprints to: Yoshiyuki Hakeda, Ph.D., Department of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350–02, Japan. E-mail: y-hakeda{at}dent.meikai.ac.jp

PGF₂ stimulates the proliferation of clonal osteoblastic MC3T3-E1 cells via PGF₂ receptor linked to phospholipase C activation. To elucidate intracellular events elicited by this receptor, we examined the effects of PGF₂ on tyrosine phosphorylation and mitogen-activated protein kinase (MAPK) activity in MC3T3-E1 cells. PGF₂ rapidly raised the level of phosphotyrosine of cellular proteins with M_r values of 62, 68, 72, 76, 82, 125, and 150 kDa. This PGF₂-induced tyrosine phosphorylation of proteins (except for pp62) was blocked by down-regulating protein kinase C (PKC) by 12-O-tetradecanoylphorbol 13-acetate pretreatment and by GF 109203X, a potent specific PKC inhibitor. The addition of PGF₂ also transiently activated MAPK in the same range of concentrations that stimulated tyrosine phosphorylation. In addition, PGF₂ augmented the MAPK kinase kinase activity of Raf-1, whereas basal activity of MAPK/extracellular signal-regulated protein kinase kinase was less than that of Raf-1 and was little affected by PGF₂. Like the tyrosine phosphorylation, these activations of Raf-1 and MAPK activities were reduced by inhibition and down-regulation of PKC. Genistein, a potent inhibitor of tyrosine kinases, did not block the Raf-1 induced by PGF₂, indicating a tyrosine kinase-independent pathway for Raf-1 activation. However, the tyrosine kinase inhibitor partially inhibited the MAPK activity, suggesting an involvement of another Raf-1-independent kinase cascade for activation of MAPK by PGF₂. Fluprostenol, a specific agonist of PGF₂ receptor, mimicked the actions of PGF₂ consistent with a PGF₂ receptor pathway. Thus, the action of PGF₂ on osteoblastic MC3T3-E1 cells appears to involve a single receptor that uses diverse interacting signal transduction systems.

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