Parathyroid Hormone Activates Mitogen-activated Protein Kinase via a cAMP-mediated Pathway Independent of Ras

• Published in: The Journal of biological chemistry 1997-02, Vol.272 (6), p.3423-3429
• Main Authors: Verheijen, Mark H.G., Defize, Libert H.K.
• Format: Article
• Language: English
• Subjects: Animals; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; CHO Cells; Cricetinae; Cyclic AMP - metabolism; Enzyme Activation; GTP-Binding Proteins - metabolism; Parathyroid Hormone - pharmacology; Parathyroid Hormone-Related Protein; Proteins - metabolism; ras Proteins - metabolism; Rats; Receptor, Parathyroid Hormone, Type 1; Receptors, Parathyroid Hormone - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.272.6.3423

In a previous study, we demonstrated that parathyroid hormone (PTH) inhibits mitogen-activated protein (MAP) kinase activation in osteosarcoma cells via a protein kinase A-dependent pathway. Here, we show that PTH can induce a transient activation of MAP kinase as well. This was observed in both Chinese hamster ovary R15 cells stably expressing high levels of rat PTH/PTH-related peptide receptor and parietal yolk sac carcinoma cells expressing the receptor endogenously. PTH was a strong activator of adenylate cyclase and phospholipase C in Chinese hamster ovary R15 cells. PTH-induced MAP kinase activation did not depend on activation of Gi, phorbol ester-sensitive protein kinase C, elevated intracellular calcium levels, or release of Gβγ subunits. It could, however, be mimicked by addition of forskolin or 8-bromo-cAMP to these cells. Prolonged treatment with forskolin caused sustained protein kinase A activity, whereas MAP kinase activity returned to basal levels. Subsequent treatment with PTH or 8-bromo-cAMP did not result in MAP kinase activation, whereas phorbol ester- or insulin-induced MAP kinase activation was unaffected. Finally, expression of a dominant negative form of Ras (RasAsn-17), which completely blocked insulin-induced MAP kinase activation, did not affect activation by PTH or cAMP. In conclusion, PTH regulates MAP kinase activity in a cell type-specific fashion. The activation of MAP kinase by PTH is mediated by cAMP and independent of Ras.