Parathyroid hormone activates mitogen-activated protein kinase via a cAMP-mediated pathway independent of Ras

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Abstract

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 G(i), 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 (Ras(Asn-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.

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Verheijen, M. H. G., & Defize, L. H. K. (1997). Parathyroid hormone activates mitogen-activated protein kinase via a cAMP-mediated pathway independent of Ras. Journal of Biological Chemistry, 272(6), 3423–3429. https://doi.org/10.1074/jbc.272.6.3423

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