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J. Biol. Chem., Vol. 279, Issue 45, 46715-46722, November 5, 2004

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Activation State of the Ras2 Protein and Glucose-induced Signaling in Saccharomyces cerevisiae^*

Sonia Colombo, Daniela Ronchetti, Johan M. Thevelein, Joris Winderickx¶, and Enzo Martegani||

From the Dipartimento di Biotecnologie e Bioscienze, Università Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy, Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, Katholieke Universiteit Leuven and Department of Molecular Microbiology, Flemish Interuniversity Institute of Biotechnology (VIB), Kasteelpark Arenberg 31, B-3001 Leuven-Heverlee, Flanders, Belgium, and ^¶Laboratorium voor Functionele Biologie, Katholieke Universiteit Leuven, Instituut voor Plantkunde en Microbiologie, Kasteelpark Arenberg 31, B-3001 Leuven-Heverlee, Flanders, Belgium

The activity of adenylate cyclase in the yeast Saccharomyces cerevisiae is controlled by two G-protein systems, the Ras proteins and the G protein Gpa2. Glucose activation of cAMP synthesis is thought to be mediated by Gpa2 and its G-protein-coupled receptor Gpr1. Using a sensitive GTP-loading assay for Ras2 we demonstrate that glucose addition also triggers a fast increase in the GTP loading state of Ras2 concomitant with the glucose-induced increase in cAMP. This increase is severely delayed in a strain lacking Cdc25, the guanine nucleotide exchange factor for Ras proteins. Deletion of the Ras-GAPs IRA2 (alone or with IRA1) or the presence of RAS2^Val19 allele causes constitutively high Ras GTP loading that no longer increases upon glucose addition. The glucose-induced increase in Ras2 GTP-loading is not dependent on Gpr1 or Gpa2. Deletion of these proteins causes higher GTP loading indicating that the two G-protein systems might directly or indirectly interact. Because deletion of GPR1 or GPA2 reduces the glucose-induced cAMP increase the observed enhancement of Ras2 GTP loading is not sufficient for full stimulation of cAMP synthesis. Glucose phosphorylation by glucokinase or the hexokinases is required for glucose-induced Ras2 GTP loading. These results indicate that glucose phosphorylation might sustain activation of cAMP synthesis by enhancing Ras2 GTP loading likely through inhibition of the Ira proteins. Strains with reduced feedback inhibition on cAMP synthesis also display elevated basal and induced Ras2 GTP loading consistent with the Ras2 protein acting as a target of the feedback-inhibition mechanism.

Received for publication, May 10, 2004 , and in revised form, August 24, 2004.

^* This work was supported by grant Fondo Agevolazioni alla Ricera, ex 60% (FAR) (to E. M.) and by grants from the Fund for Scientific Research-Flanders (to J. W. and J. M. T.). 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. Tel.: 39-02-64483533; Fax: 39-02-64483565; E-mail: Enzo.Martegani{at}unimib.it.

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