Epac Activation Converts cAMP from a Proliferative into a Differentiation Signal in PC12 Cells
- 1 December 2005
- journal article
- Published by American Society for Cell Biology (ASCB) in Molecular Biology of the Cell
- Vol. 16 (12), 5639-5648
- https://doi.org/10.1091/mbc.e05-05-0432
Abstract
Elevation of the intracellular cAMP concentration ([cAMP]i) regulates metabolism, cell proliferation, and differentiation and plays roles in memory formation and neoplastic growth. cAMP mediates its effects mainly through activation of protein kinase A (PKA) as well as Epac1 and Epac2, exchange factors activating the small GTPases Rap1 and Rap2. However, how cAMP utilizes these effectors to induce distinct biological responses is unknown. We here studied the specific roles of PKA and Epac in neuroendocrine PC12 cells. In these cells, elevation of [cAMP]iactivates extracellular signal-regulated kinase (ERK) 1/2 and induces low-degree neurite outgrowth. The present study showed that specific stimulation of PKA triggered ERK1/2 activation that was considerably more transient than that observed upon simultaneous activation of both PKA and Epac. Unexpectedly, the PKA-specific cAMP analog induced cell proliferation rather than neurite outgrowth. The proliferative signaling pathway activated by the PKA-specific cAMP analog involved activation of the epidermal growth factor receptor and ERK1/2. Activation of Epac appeared to extend the duration of PKA-dependent ERK1/2 activation and converted cAMP from a proliferative into an anti-proliferative, neurite outgrowth-promoting signal. Thus, the present study showed that the outcome of cAMP signaling can depend heavily on the set of cAMP effectors activated.Keywords
This publication has 45 references indexed in Scilit:
- Enhanced activation of Akt and extracellular‐regulated kinase pathways by simultaneous occupancy of Gq‐coupled 5‐HT2A receptors and Gs‐coupled 5‐HT7A receptors in PC12 cellsJournal of Neurochemistry, 2004
- Gs Protein-coupled Receptor Agonists Induce Transactivation of the Epidermal Growth Factor Receptor in T84 CellsOnline Journal of Public Health Informatics, 2004
- Does Rap1 deserve a bad Rap?Trends in Biochemical Sciences, 2003
- Stimulation of the ERK Pathway by GTP-loaded Rap1 Requires the Concomitant Activation of Ras, Protein Kinase C, and Protein Kinase A in Neuronal CellsOnline Journal of Public Health Informatics, 2003
- Ras-dependent ERK Activation by the Human Gs-coupled Serotonin Receptors 5-HT4(b) and 5-HT7(a)Online Journal of Public Health Informatics, 2003
- Cyclic AMP Induces Transactivation of the Receptors for Epidermal Growth Factor and Nerve Growth Factor, Thereby Modulating Activation of MAP Kinase, Akt, and Neurite Outgrowth in PC12 CellsOnline Journal of Public Health Informatics, 2002
- New Signaling Pathway for Parathyroid Hormone and Cyclic AMP Action on Extracellular-regulated Kinase and Cell Proliferation in Bone CellsOnline Journal of Public Health Informatics, 2002
- Cell Type-specific Regulation of B-Raf Kinase by cAMP and 14-3-3 ProteinsOnline Journal of Public Health Informatics, 2000
- EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptorCurrent Biology, 1994
- Differentiation of PC12 cells in response to a cAMP analogue is accompanied by sustained activation of mitogen‐activated protein kinaseFEBS Letters, 1994