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

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 Gbetagamma 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.