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J. Biol. Chem., Vol. 279, Issue 45, 46497-46508, November 5, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/45/46497    most recent M403604200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Keiper, M. Articles by Schmidt, M. Search for Related Content PubMed PubMed Citation Articles by Keiper, M. Articles by Schmidt, M. Social Bookmarking                      What's this?

Epac- and Ca²+-controlled Activation of Ras and Extracellular Signal-regulated Kinases by G_s-coupled Receptors^*

Melanie Keiper, Matthias B. Stope, Daniel Szatkowski, Anja Böhm, Karina Tysack, Frank vom Dorp, Oliver Saur, Paschal A. Oude Weernink, Sandrine Evellin, Karl H. Jakobs, and Martina Schmidt¶

From the Institut für Pharmakologie, Universitätsklinikum Essen, 45122 Essen, Germany

We have recently reported that two typical G_s-coupled receptors, the ₂-adrenergic receptor and the receptor for prostaglandin E₁, stimulate phospholipase C- (PLC-) and increase intracellular Ca²⁺ concentration ([Ca²⁺]_i) in HEK-293 cells and N1E-115 neuroblastoma cells, respectively, by a pathway involving Epac1, a cAMP-activated and Rap-specific guanine nucleotide exchange factor (GEF), and the GTPase Rap2B. Here we have demonstrated that these G_s-coupled receptors use this pathway to activate H-Ras and the extracellular signal-regulated kinases 1 and 2 (ERK1/2). Specifically, agonist activation of the receptors resulted in activation of H-Ras and ERK1/2. The latter action was suppressed by dominant negative H-Ras, but not Rap1A. The receptor actions were independent of protein kinase A but fully mimicked by an Epac-specific cAMP analog as well as by a constitutively active Rap2B mutant. On the other hand, a cAMP-binding-deficient Epac1 mutant, the Rap GTPase-activating proteinII, and a dominant negative Rap2B mutant suppressed receptor- and Epac-mediated activation of H-Ras and ERK1/2. Finally, we have demonstrated that activation of H-Ras and ERK1/2 requires the lipase activity of PLC- and the subsequent [Ca²⁺]_i increase, suggesting that H-Ras activation is mediated by a Ca²⁺-activated GEF. In line with this hypothesis, receptor-mediated activation of H-Ras and ERK1/2 was strongly enhanced by expression of RasGRP1, a Ca²⁺-regulated Ras-GEF. Collectively, our data indicated that G_s-coupled receptors can activate H-Ras and subsequently the mitogen-activated protein kinases ERK1/2 by a Ca²⁺-activated Ras-GEF, possibly RasGRP1, mediated by cAMP-activated Epac proteins, which then lead via Rap2B and PLC- stimulation to [Ca²⁺]_i increase.

Received for publication, April 1, 2004 , and in revised form, August 12, 2004.

^* This work was supported by the Deutsche Forschungsgemeinschaft, the Interne Forschungsförderung Essen, and the Fonds der Chemischen Industrie. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to the work.

Present address: Dipartimento di Biologia Molecolare, Via Fiorentina 1, 53100 Siena, Italy.

^¶ To whom correspondence should be addressed: Institut für Pharmakologie, Universitätsklinikum Essen, Hufelandstrasse 55, 45122 Essen, Germany. Tel.: 49-201-723-3457; Fax: 49-201-723-5968; E-mail: martina.schmidt{at}uni-essen.de.

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