Abstract
The yeast pheromone response pathway is a canonical three-step mitogen activated protein kinase (MAPK) cascade which requires a scaffold protein for proper signal transduction. Recent experimental studies into the role the scaffold plays in modulating the character of the transduced signal, show that the presence of the scaffold increases the biphasic nature of the signal response. This runs contrary to prior theoretical investigations into how scaffolds function. We describe a mathematical model of the yeast MAPK cascade specifically designed to capture the experimental conditions and results of these empirical studies. We demonstrate how the system can exhibit either graded or ultrasensitive (biphasic) response dynamics based on the binding kinetics of enzymes to the scaffold. At the basis of our theory is an analytical result that weak interactions make the response biphasic while tight interactions lead to a graded response. We then show via an analysis of the kinetic binding rate constants how the results of experimental manipulations, modeled as changes to certain of these binding constants, lead to predictions of pathway output consistent with experimental observations. We demonstrate how the results of these experimental manipulations are consistent within the framework of our theoretical treatment of this scaffold-dependent MAPK cascades, and how future efforts in this style of systems biology can be used to interpret the results of other signal transduction observations.
Highlights
The yeast pheromone response system is one of the first signal transduction systems to be identified and studied in detail [1,2,3]
This model is tailored to several experimental results from the recent literature, and we demonstrate how the apparent conflict can be resolved by examining how the kinetic binding parameters influence the signal response output
The first model is a revisit of the original mitogen activated protein kinase (MAPK) model first discussed by Ferrel, while the second is a simplified system describing the influence of the Ste5 scaffold on the MAPK pathway
Summary
The yeast pheromone response system is one of the first signal transduction systems to be identified and studied in detail [1,2,3]. While Ste has no catalytic activity of its own, its function is necessary for successful response to the pheromone signal Scaffolds such as Ste have been a subject of extensive theoretical and empirical investigations, much of the work focusing on how the scaffold controls the output response of its pathway [6,7,8,9]. Past theoretical investigations into scaffold-free MAPK systems demonstrate a tendency towards a biphasic response, while systems involving a scaffold show in theory a strong and robust graded response, which is contrary to the recent experimental findings To address this discrepancy between theory and experimental results, we devise a new model of the yeast pheromone response system. We offer several hypotheses, based on our results, which explain how experimental perturbations to this pathway reported in the literature lead to non-obvious changes to the biphasic nature of the transduced signal
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