Abstract
Background The cyclic AMP-Protein Kinase A (cAMP-PKA) pathway is an evolutionarily conserved signal transduction mechanism that regulates cellular growth and differentiation in animals and fungi. We present a mathematical model that recapitulates the short-term and long-term dynamics of this pathway in the budding yeast, Saccharomyces cerevisiae. Our model is aimed at recapitulating the dynamics of cAMP signaling for wild-type cells as well as single (pde1Δ and pde2Δ) and double (pde1Δpde2Δ) phosphodiesterase mutants.Results Our model focuses on PKA-mediated negative feedback on the activity of phosphodiesterases and the Ras branch of the cAMP-PKA pathway. We show that both of these types of negative feedback are required to reproduce the wild-type signaling behavior that occurs on both short and long time scales, as well as the the observed responses of phosphodiesterase mutants. A novel feature of our model is that, for a wide range of parameters, it predicts that intracellular cAMP concentrations should exhibit decaying oscillatory dynamics in their approach to steady state following glucose stimulation. Experimental measurements of cAMP levels in two genetic backgrounds of S. cerevisiae confirmed the presence of decaying cAMP oscillations as predicted by the model.Conclusions Our model of the cAMP-PKA pathway provides new insights into how yeast respond to alterations in their nutrient environment. Because the model has both predictive and explanatory power it will serve as a foundation for future mathematical and experimental studies of this important signaling network.
Highlights
Background The cyclic AMPProtein Kinase A pathway is an evolutionarily conserved signal transduction mechanism that regulates cellular growth and differentiation in animals and fungi
Our model of the cyclic adenosine monophosphate (cAMP)-Protein Kinase A (PKA) pathway provides new insights into how yeast respond to alterations in their nutrient environment
We show that the simplified version of the model, given by Equations (4a)–(4d), can adequately replicate the short-term dynamics of cAMP, reported by
Summary
Background The cyclic AMPProtein Kinase A (cAMP-PKA) pathway is an evolutionarily conserved signal transduction mechanism that regulates cellular growth and differentiation in animals and fungi. The cyclic adenosine monophosphate (cAMP) – Protein Kinase A (PKA) pathway plays a central role in mediating diverse biological responses such as growth, development, and cell differentiation [1,2]. A small GTP-binding protein, in its GTP-bound (active) state stimulates adenylate cyclase, causing a rapid increase in intracellular cAMP levels (Figure 1, top right) [11]. In parallel to Ras, a second G-protein pathway, involving the proteins Gpr, Gpa, and Rgs, responds to extracellular levels of glucose and increases adenylate cyclase activity (Figure 1, top left). PKA is a holoenzyme that includes both regulatory (Bcy1) and catalytic subunits (Tpk, Tpk and Tpk3) [27,28]. cAMP binding to the regulatory subunits leads to the release of the catalytic PKA subunits ([29]; Figure 1, bottom) which are free to interact with downstream targets such as metabolic enzymes, transcription factors and other kinases [30,31,32,33]
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