title: Simulation of the Ras/cAMP/PKA pathway in budding yeast highlights the establishment of stable oscillatory states.
abstract: In the yeast Saccharomyces cerevisiae, the Ras/cAMP/PKA pathway plays a major role in the regulation of metabolism, stress resistance and cell cycle progression. We extend here a mechanistic model of the Ras/cAMP/PKA pathway that we previously defined by describing the molecular interactions and post-translational modifications of proteins, and perform a computational analysis to investigate the dynamical behaviors of the components of this pathway, regulated by different control mechanisms. We carry out stochastic simulations to consider, in particular, the effect of the negative feedback loops on the activity of both Ira2 (a Ras-GAP) and Cdc25 (a Ras-GEF) proteins. Our results show that stable oscillatory regimes for the dynamics of cAMP can be obtained only through the activation of these feedback mechanisms, and when the amount of Cdc25 is within a specific range. In addition, we highlight that the levels of guanine nucleotides pools are able to regulate the pathway, by influencing the transition between stable steady states and oscillatory regimes.
authors: Università degli Studi di Milano-Bicocca, Dipartimento di Statistica, Milano, Italy. dario.pescini@unimib.it
authors: Dario
authors: D
authors: Pescini
authors: Paolo
authors: P
authors: Cazzaniga
authors: Daniela
authors: D
authors: Besozzi
authors: Giancarlo
authors: G
authors: Mauri
authors: Loredana
authors: L
authors: Amigoni
authors: Sonia
authors: S
authors: Colombo
authors: Enzo
authors: E
authors: Martegani
mesh_terms: D001683:Biological Clocks; D002453:Cell Cycle; D003198:Computer Simulation; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D025461:Feedback, Physiological; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D006150:Guanine Nucleotides / Q000378:metabolism; D008954:Models, Biological; D012441:Saccharomyces cerevisiae / Q000378:metabolism / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D015398:Signal Transduction; D020666:ras-GRF1 / Q000378:metabolism*
chemical_list: C542351:CDC25 protein, S cerevisiae; D020690:GTPase-Activating Proteins; D006150:Guanine Nucleotides; C064960:IRA2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D020666:ras-GRF1; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases