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Signal response sensitivity in the yeast mitogen-activated protein kinase cascade.

Thalhauser CJ, Komarova NL - PLoS ONE (2010)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Mathematics, University of California Irvine, Irvine, California, United States of America.

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.

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Dependence of ultrasensitive output response on cytosolic phosphorylation of scaffolds.Plots of Hill coefficient as a function of  are shown for cytosolic rate control parameter  = 0 (circles), 0.1 (squares) and 1 (diamonds).
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pone-0011568-g008: Dependence of ultrasensitive output response on cytosolic phosphorylation of scaffolds.Plots of Hill coefficient as a function of are shown for cytosolic rate control parameter  = 0 (circles), 0.1 (squares) and 1 (diamonds).

Mentions: We have already observed that loss of the requirement for signal-induced membrane binding prior to full scaffold activation leads to a decrease in the ultrasensitive nature of the signal response. We now look to determine whether it is the scaffold alignment or initial enzymatic activation of Ste11 which is responsible for the majority of the ultrasensitive behavior. We perform a numerical experiment in which any scaffold, whether bound to the membrane or free in the cytoplasm, can undergo the enzymatic activation step. The relative level of cytosolic scaffold phosphorylation is controlled by the parameter ;  = 0 implies the scaffold must be bound to the membrane for activation, while means that cytosolic scaffold is targeted at the same rate as membrane bound scaffold. The results of this experiment are presented in figure 8. In this experiment, we observe a very minor decrease in ultrasensitive response from the scaffold even in the case where the cytosolic scaffold is as strong a phosphorylation target as is the membrane bound scaffold.


Signal response sensitivity in the yeast mitogen-activated protein kinase cascade.

Thalhauser CJ, Komarova NL - PLoS ONE (2010)

Dependence of ultrasensitive output response on cytosolic phosphorylation of scaffolds.Plots of Hill coefficient as a function of  are shown for cytosolic rate control parameter  = 0 (circles), 0.1 (squares) and 1 (diamonds).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2909145&req=5

pone-0011568-g008: Dependence of ultrasensitive output response on cytosolic phosphorylation of scaffolds.Plots of Hill coefficient as a function of are shown for cytosolic rate control parameter  = 0 (circles), 0.1 (squares) and 1 (diamonds).
Mentions: We have already observed that loss of the requirement for signal-induced membrane binding prior to full scaffold activation leads to a decrease in the ultrasensitive nature of the signal response. We now look to determine whether it is the scaffold alignment or initial enzymatic activation of Ste11 which is responsible for the majority of the ultrasensitive behavior. We perform a numerical experiment in which any scaffold, whether bound to the membrane or free in the cytoplasm, can undergo the enzymatic activation step. The relative level of cytosolic scaffold phosphorylation is controlled by the parameter ;  = 0 implies the scaffold must be bound to the membrane for activation, while means that cytosolic scaffold is targeted at the same rate as membrane bound scaffold. The results of this experiment are presented in figure 8. In this experiment, we observe a very minor decrease in ultrasensitive response from the scaffold even in the case where the cytosolic scaffold is as strong a phosphorylation target as is the membrane bound scaffold.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Mathematics, University of California Irvine, Irvine, California, United States of America.

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.

Show MeSH
Related in: MedlinePlus