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The role of feedback control mechanisms on the establishment of oscillatory regimes in the Ras/cAMP/PKA pathway in S. cerevisiae

Daniela Besozzi1*, Paolo Cazzaniga2, Dario Pescini3, Giancarlo Mauri4, Sonia Colombo5 and Enzo Martegani5

Author Affiliations

1 Università degli Studi di Milano, Dipartimento di Informatica, Via Comelico 39, 20135 Milano, Italy

2 Università degli Studi di Bergamo, Dipartimento di Scienze della Persona, Piazzale S. Agostino 2, 24129 Bergamo, Italy

3 Università degli Studi di Milano-Bicocca, Dipartimento di Statistica, Via Bicocca degli Arcimboldi 8, 20126 Milano, Italy

4 Università degli Studi di Milano-Bicocca, Dipartimento di Informatica, Sistemistica e Comunicazione, Viale Sarca 336, 20126 Milano, Italy

5 Università degli Studi di Milano-Bicocca, Dipartimento di Biotecnologie e Bioscienze, Piazza della Scienza 2, 20126 Milano, Italy

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EURASIP Journal on Bioinformatics and Systems Biology 2012, 2012:10  doi:10.1186/1687-4153-2012-10

Published: 20 July 2012


In the yeast Saccharomyces cerevisiae, the Ras/cAMP/PKA pathway is involved in the regulation of cell growth and proliferation in response to nutritional sensing and stress conditions. The pathway is tightly regulated by multiple feedback loops, exerted by the protein kinase A (PKA) on a few pivotal components of the pathway. In this article, we investigate the dynamics of the second messenger cAMP by performing stochastic simulations and parameter sweep analysis of a mechanistic model of the Ras/cAMP/PKA pathway, to determine the effects that the modulation of these feedback mechanisms has on the establishment of stable oscillatory regimes. In particular, we start by studying the role of phosphodiesterases, the enzymes that catalyze the degradation of cAMP, which represent the major negative feedback in this pathway. Then, we show the results on cAMP oscillations when perturbing the amount of protein Cdc25 coupled with the alteration of the intracellular ratio of the guanine nucleotides (GTP/GDP), which are known to regulate the switch of the GTPase Ras protein. This multi-level regulation of the amplitude and frequency of oscillations in the Ras/cAMP/PKA pathway might act as a fine tuning mechanism for the downstream targets of PKA, as also recently evidenced by some experimental investigations on the nucleocytoplasmic shuttling of the transcription factor Msn2 in yeast cells.