Abstract
BackgroundCyclic adenosine monophosphate (cAMP) has a key signaling role in all eukaryotic organisms. In Saccharomyces cerevisiae, it is the second messenger in the Ras/PKA pathway which regulates nutrient sensing, stress responses, growth, cell cycle progression, morphogenesis, and cell wall biosynthesis. A stochastic model of the pathway has been reported.ResultsWe have created deterministic mathematical models of the PKA module of the pathway, as well as the complete cAMP pathway. First, a simplified conceptual model was created which reproduced the dynamics of changes in cAMP levels in response to glucose addition in wild-type as well as cAMP phosphodiesterase deletion mutants. This model was used to investigate the role of the regulatory Krh proteins that had not been included previously. The Krh-containing conceptual model reproduced very well the experimental evidence supporting the role of Krh as a direct inhibitor of PKA. These results were used to develop the Complete cAMP Model. Upon simulation it illustrated several important features of the yeast cAMP pathway: Pde1p is more important than is Pde2p for controlling the cAMP levels following glucose pulses; the proportion of active PKA is not directly proportional to the cAMP level, allowing PKA to exert negative feedback; negative feedback mechanisms include activating Pde1p and deactivating Ras2 via phosphorylation of Cdc25. The Complete cAMP model is easier to simulate, and although significantly simpler than the existing stochastic one, it recreates cAMP levels and patterns of changes in cAMP levels observed experimentally in vivo in response to glucose addition in wild-type as well as representative mutant strains such as pde1Δ, pde2Δ, cyr1Δ, and others. The complete model is made available in SBML format.ConclusionWe suggest that the lower number of reactions and parameters makes these models suitable for integrating them with models of metabolism or of the cell cycle in S. cerevisiae. Similar models could be also useful for studies in the human pathogen Candida albicans as well as other less well-characterized fungal species.
Highlights
Cyclic adenosine monophosphate has a key signaling role in all eukaryotic organisms
The models were later exported in Systems Biology Markup Language (SBML) format [36], which allowed the models to be exchanged between programs
The Cyclic adenosine monophosphate (cAMP) level can range from 0.015 mM in glucose starved cells, to approximately 0.05 mM [38]
Summary
Cyclic adenosine monophosphate (cAMP) has a key signaling role in all eukaryotic organisms. In Saccharomyces cerevisiae, it is the second messenger in the Ras/PKA pathway which regulates nutrient sensing, stress responses, growth, cell cycle progression, morphogenesis, and cell wall biosynthesis. In eukaryotes cAMP activates Protein Kinase A (PKA), the target kinase of the cAMP-mediated signal transduction pathway. In the widely used model baker's yeast Saccharomyces cerevisiae, this pathway regulates a variety of cellular processes, including metabolism [1], response to stress [2,3] and progression through the cell cycle [4,5]. Cyclic AMP is synthesized by adenylate cyclase (Cyr1p), which in turn is regulated by Gpa2p [7] and Ras2p [8], both of which are G proteins. The level of intracellular GTP is believed to influence the level of GTPbound Ras2p [14], and the GTP level increases following a pulse of glucose [13], the mechanism behind this increase is not fully understood
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