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J Biol Chem, Vol. 273, Issue 31, 19809-19816, July 31, 1998

The Calcitonin Receptor Stimulates Shc Tyrosine Phosphorylation and Erk1/2 Activation
INVOLVEMENT OF G_i, PROTEIN KINASE C, AND CALCIUM

Yan Chen, Jia-Fwu Shyu, Anu Santhanagopal^¶, Daisuke Inoue, Jean-Pierre David, S. Jeffrey Dixon^¶, William C. Horne, and Roland Baron

From the  Departments of Cell Biology and Orthopedics and the Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520 and the ^¶ Department of Physiology and Division of Oral Biology, Faculty of Medicine and Dentistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada

While it is well established that adenylyl cyclase and phospholipase C- are two proximal signal effectors for the calcitonin receptor, the more distal signaling pathways are less well characterized. G protein-coupled receptors can activate Erk1/2 by G_s-, G_i-, or G_q-dependent signaling pathways, depending on the specific receptor and cell type examined. Since the calcitonin receptor can couple to all three of these G proteins, the ability of calcitonin to activate Erk1/2 was investigated. Calcitonin induced time- and concentration-dependent increases in Shc tyrosine phosphorylation, Shc-Grb2 association and Erk1/2 phosphorylation and activation in a HEK 293 cell line that stably expresses the rabbit calcitonin receptor C1a isoform. Pertussis toxin, which inactivates G_i, and calphostin C, a protein kinase C inhibitor, each partially inhibited calcitonin-induced Shc tyrosine phosphorylation, Shc-Grb2 association, and Erk1/2 phosphorylation. In contrast, neither forskolin nor H89, a protein kinase A inhibitor, had a significant effect on basal or calcitonin-stimulated Erk1/2 phosphorylation. Our results suggest that the calcitonin receptor induces Shc phosphorylation and Erk1/2 activation in HEK293 cells by parallel G_i- and PKC-dependent mechanisms. The calcitonin-induced elevation of cytosolic free Ca²⁺ was required for Erk1/2 phosphorylation, since preventing any change in cytosolic free Ca²⁺ by chelating both cytosolic and extracellular Ca²⁺ abolished the response. However, the change in Ca²⁺ that is induced by calcitonin is not sufficient to account for the calcitonin-induced Erk1/2 phosphorylation, since treatment with 100 nM ionomycin or 10 µM thapsigargin, each of which induced elevations of Ca²⁺ comparable to those induced by calcitonin, induced significantly less Erk1/2 phosphorylation than that induced by calcitonin. Erk1/2 may have important roles as downstream effectors mediating cellular responses to calcitonin stimulation.

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