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J. Biol. Chem., Vol. 279, Issue 19, 20345-20355, May 7, 2004

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Glucagon Promotes cAMP-response Element-binding Protein Phosphorylation via Activation of ERK1/2 in MIN6 Cell Line and Isolated Islets of Langerhans^*

Stéphane Dalle, Christine Longuet, Safia Costes, Christophe Broca, Omar Faruque, Ghislaine Fontés, El Habib Hani, and Dominique Bataille¶

From the Unité INSERM U376, CHU Arnaud-de-Villeneuve, 34295 Montpellier Cedex 5 and UMR 5160 CNRS, Institut de Biologie-Faculté de Médecine, 34060 Montpellier Cedex 1, France

By using the MIN6 cell line and pancreatic islets, we show that in the presence of a low glucose concentration, corresponding to physiological glucagon release from cells, glucagon treatment of the cell caused a rapid, time-dependent phosphorylation and activation of p44/p42 mitogen-activated protein kinase (ERK1/2) independently from extracellular calcium influx. Inhibition of either cAMP-dependent protein kinase (PKA) or MEK completely blocked ERK1/2 activation by glucagon. However, no significant activation of several upstream activators of MEK, including Shc-p21^Ras and phosphatidylinositol 3-kinase, was observed in response to glucagon treatment. Chelation of intracellular calcium (intracellular [Ca²⁺]) reduced glucagon-mediated ERK1/2 activation. In addition, internalization of glucagon receptors through clathrin-coated pits formation is required for ERK1/2 activation. Remarkably, glucagon promotes the nuclear translocation of ERK1/2 and induces the phosphorylation of cAMP-response element-binding protein (CREB). Miniglucagon, produced from glucagon and released together with the mother hormone from the cells in low glucose situations, blocks the insulinotropic effect of glucagon, whereas it does not inhibit the glucagon-induced PKA/ERK1/2/CREB pathway. We conclude that glucagon-induced ERK1/2 activation is mediated by PKA and that an increase in [Ca²⁺]_i is required for maximal ERK activation. Our results uncover a novel mechanism by which the PKA/ERK1/2 signaling network engaged by glucagon, in situation of low glucose concentration, regulates phosphorylation of CREB, a transcription factor crucial for normal cell function and survival.

Received for publication, November 14, 2003 , and in revised form, February 18, 2004.

^* This work was supported in part by l'Association pour la Recherche sur le Cancer ARC (to S. D.), the Foundation pour la Recherche Médicale (to G. F.), the Université Montpellier-1, and the Conseil Régional du Languedoc-Roussillon. 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.

^¶ To whom correspondence should be addressed: Unité INSERM U376, CHU Arnaud-de-Villeneuve, 371, Rue du Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France. Tel.: 33-4-67-41-52-30; Fax: 33-4-67-41-52-22; E-mail: bataille{at}montp.inserm.fr.

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