Simulation of the Ras/cAMP/PKA pathway in budding yeast highlights the establishment of stable oscillatory states

Pescini, Dario; Cazzaniga, Paolo; Besozzi, Daniela; Mauri, Giancarlo; Amigoni, Loredana; Colombo, Sonia; Martegani, Enzo

doi:10.1016/j.biotechadv.2011.06.014

Cited by 27 publications

(50 citation statements)

References 33 publications

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“…The mechanistic model of the Ras/cAMP/PKA pathway that we previously presented in [16,17] was developed according to the stochastic formulation of chemical kinetics [25], defined by specifying the set of molecular species occurring in the pathway and the set of biochemical reactions, together with their related stochastic constants (see Table 1). In particular, the model describes the major interactions between the pivotal components of the Ras/cAMP/PKA pathway, as well as the negative feedback mechanisms which are able to regulate the intracellular levels of cAMP.…”

Section: Methodsmentioning

confidence: 99%

“…The complete network of the interactions between all molecular species, as well as the SBML version of the model, are available for free download at the BioSimWare website (http://biosimware.disco.unimib.it). A “generalized mass-action based” [27] version of this mechanistic model was derived, in order to compare the outcome of stochastic and deterministic approaches, as also discussed in [17]. …”

Section: Methodsmentioning

confidence: 99%

“…The frequency of oscillations of cAMP can then be easily calculated by dividing the number of maxima (minima) by the length of the chosen time interval. We refer to [17] for additional details on this method.…”

Section: Methodsmentioning

confidence: 99%

“…Then, we continue the investigation initiated in [17] and study the role played by the guanine nucleotide concentrations, which control the exchange activity of Cdc25. Through the investigation of the simultaneous modulation of the amount of Cdc25 and of the intracellular ratio of guanine nucleotides, we show here that a decrease in the ratio GTP/GDP—which mimics a reduced nutritional condition in yeast cells—is able to control the transition between stable steady states and oscillations, independently from the amount of Cdc25.…”

Section: Introductionmentioning

confidence: 96%

“…To understand the role of the negative feedback controls, in [16,17] we defined and analyzed a stochastic model of the Ras/cAMP/PKA pathway. In particular, we focused our attention on the mechanisms that allow the emergence of oscillatory regimes, since recent experiments evidenced in vivo the presence of continuous oscillations related to this pathway under specific stress conditions [18,19].…”

Section: Introductionmentioning

confidence: 99%

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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

Besozzi

Cazzaniga

Pescini

et al. 2012

J Bioinform Sys Biology

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Besozzi

Cazzaniga

Pescini

et al. 2012

J Bioinform Sys Biology

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A mathematical model captures the role of adenyl cyclase Cyr1 and guanidine exchange factor Ira2 in creating a growth‐to‐hyphal bistable switch in Candida albicans

Sriram

2022

FEBS Open Bio

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Recent biochemical experiments have indicated that in Candida albicans , a commensal fungal pathogen, the Ras signaling pathway plays a significant role in the yeast‐to‐hyphal transition; specifically, two enzymes in this pathway, Adenyl Cyclase Cyr1 and GTPase activating protein Ira2, facilitate this transition, in the presence of energy sensor ATP. However, the precise mechanism by which protein interactions between Ira2 and Cyr1 and the energy sensor ATP result in the yeast‐to‐hyphal transition and create a switch‐like process are unknown. We propose a new set of biochemical reaction steps that captures all the essential interactions between Ira2, Cyr1, and ATP in the Ras pathway. With the help of chemical reaction network theory, we demonstrate that this set of biochemical reaction steps results in bistability. Further, bifurcation analysis of the differential equations based on this set of reaction steps supports the existence of a bistable switch, and this switch may act as a checkpoint mechanism for the promotion of growth‐to‐hyphal transition in C. albicans .

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Fuzzy Logic for Knowledge‐Driven and Data‐Driven Modeling in Biomedical Sciences

Cazzaniga,

Spolaor,

Fuchs

et al. 2024

Big Data Analysis and Artificial Intelligence for Medical Sciences

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Simulation of the Ras/cAMP/PKA pathway in budding yeast highlights the establishment of stable oscillatory states

Cited by 27 publications

References 33 publications

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

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

A mathematical model captures the role of adenyl cyclase Cyr1 and guanidine exchange factor Ira2 in creating a growth‐to‐hyphal bistable switch in Candida albicans

Fuzzy Logic for Knowledge‐Driven and Data‐Driven Modeling in Biomedical Sciences

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