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Vol. 16, Issue 12, 5639-5648, December 2005

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Epac Activation Converts cAMP from a Proliferative into a Differentiation Signal in PC12 Cells

Department of Internal Medicine, University of Saarland, D-66421 Homburg/Saar, Germany

Submitted May 17, 2005; Revised September 7, 2005; Accepted September 27, 2005
Monitoring Editor: J. Silvio Gutkind

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]_i activates 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.

Abbreviations used: 2-Me-cAMP, 8-(4-methoxyphenylthio)-2'-O-methyl-adenosine-3',5'-cyclic AMP; 6-Bnz-cAMP, N⁶-benzoyladenosine-3',5'-cyclic monophosphate; [cAMP]_i, intracellular cAMP concentration; CPT-cAMP, 8-(4-chlorphenylthio)-adenosine-3',5'-cyclic monophosphate; EGF, epidermal growth factor; EGFR, EGF receptor; ERK, extracellular signal-regulated kinase; GsPCR, G_s protein-coupled receptors; HRP, horseradish peroxidase; NGF, nerve growth factor; PACAP, pituitary adenylyl cyclase-activating peptide; PKA, protein kinase A; Rap1GAP, GTPase-activating protein of Rap1.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Albrecht Piiper (inapii{at}uniklinikumsaarland.de).

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