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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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Abrogation of Fus3-scaffold interaction can lead to loss of ultrasensitive Fus3 response.Wild-type (solid, , total activated scaffold) and Fus3-less (dashed, , free active Fus3) scaffold system responses are plotted for .
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pone-0011568-g011: Abrogation of Fus3-scaffold interaction can lead to loss of ultrasensitive Fus3 response.Wild-type (solid, , total activated scaffold) and Fus3-less (dashed, , free active Fus3) scaffold system responses are plotted for .

Mentions: To test the plausibility of this hypothesis, we modify our model to ablate the fus3 binding site. We assume instead that fus3 is present in the cytoplasm and interacts via standard Michaelis-Menton kinetics with activated, scaffold-associated ste7. We then simulate the model under two conditions: first, without modification with a slow rate; second, with fus3 activation occurring off-scaffold, but with the scaffold having a much faster selective activation rate. For our hypothesis to be plausible, we must be able to observe a lower Hill coefficient in the second system than in the first. The results of this simulation are plotted in figure 11. We clearly observe a proof-of-concept, in that a system in which the scaffold is unable to bind Fus3 but can align ste11 and ste7 much more quickly, is in fact capable of generating a more graded response. Beyond proof of concept, it is also important to note that our hypothesis here predicts that Fus3 should reach its response maximum faster in the scenario in which it does not bind to the scaffold, due to a significantly decreased time to ste7 activation. It has been observed that in wild type systems, scaffold-associated Fus3 is considerably slower to reach its activity maximum than scaffold-free Kss1, and in the experiment in which Fus3 cannot bind to the scaffold, its activation kinetics mirror much more closely the faster Kss1 rates [12].


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

Thalhauser CJ, Komarova NL - PLoS ONE (2010)

Abrogation of Fus3-scaffold interaction can lead to loss of ultrasensitive Fus3 response.Wild-type (solid, , total activated scaffold) and Fus3-less (dashed, , free active Fus3) scaffold system responses are plotted for .
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2909145&req=5

pone-0011568-g011: Abrogation of Fus3-scaffold interaction can lead to loss of ultrasensitive Fus3 response.Wild-type (solid, , total activated scaffold) and Fus3-less (dashed, , free active Fus3) scaffold system responses are plotted for .
Mentions: To test the plausibility of this hypothesis, we modify our model to ablate the fus3 binding site. We assume instead that fus3 is present in the cytoplasm and interacts via standard Michaelis-Menton kinetics with activated, scaffold-associated ste7. We then simulate the model under two conditions: first, without modification with a slow rate; second, with fus3 activation occurring off-scaffold, but with the scaffold having a much faster selective activation rate. For our hypothesis to be plausible, we must be able to observe a lower Hill coefficient in the second system than in the first. The results of this simulation are plotted in figure 11. We clearly observe a proof-of-concept, in that a system in which the scaffold is unable to bind Fus3 but can align ste11 and ste7 much more quickly, is in fact capable of generating a more graded response. Beyond proof of concept, it is also important to note that our hypothesis here predicts that Fus3 should reach its response maximum faster in the scenario in which it does not bind to the scaffold, due to a significantly decreased time to ste7 activation. It has been observed that in wild type systems, scaffold-associated Fus3 is considerably slower to reach its activity maximum than scaffold-free Kss1, and in the experiment in which Fus3 cannot bind to the scaffold, its activation kinetics mirror much more closely the faster Kss1 rates [12].

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