Visit our Expo - Redox and Inflammation signaling 2012

Session II : Receptor signaling and G proteins Poster II, 29
Epac activation converts cAMP from a proliferative into a differentiation signal in PC12
cells
Simone Kiermayer, Ricardo M. Biondi, Guido Plotz, Jörg Haupenthal, Stefan Zeuzem,
and Albrecht Piiper.
Universitätsklinikum des Saarlandes, Department of Internal Medicine II, Kirrberger
Str., Building 41, 66421 Homburg/Saar, Germany. E-mail: inskie@uniklinikumsaarland.de
cAMP plays, amongst others, an important role in the regulation of cell proliferation and
differentiation. How an elevated intracellular cAMP concentration [cAMP]i induces distinct
biological responses is still unknown. Thus, we investigated the qualitative effects of an
elevated [cAMP]i using cAMP-analoga, which specifically activate the main cAMP effectors,
protein kinase A (PKA) or Epac1 and Epac2, exchange factors activating the small GTPases
Rap1 and Rap2. As a model we used neuroendocrine PC12 cells, in which elevation of
[cAMP]i activates extracellular signal-regulated kinase (ERK) 1/2 and induces low-degree
neurite outgrowth. Our studies revealed that the specific stimulation of PKA triggered
ERK1/2 activation. It 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. This proliferative signaling pathway involved
activation of the epidermal growth factor receptor and ERK1/2. Activation of Epac and its
down-stream effector Rap1 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, we found strong evidence that the outcome of cAMP
signaling can depend on the set of cAMP effectors activated.
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