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Dose-to-duration encoding and signaling beyond saturation in intracellular signaling networks.

Behar M, Hao N, Dohlman HG, Elston TC - PLoS Comput. Biol. (2008)

Bottom Line: We demonstrate that modulation of signal duration increases the range of stimulus concentrations for which dose-dependent responses are possible; this increased dynamic range produces the counterintuitive result of "signaling beyond saturation" in which dose-dependent responses are still possible after apparent saturation of the receptors.The ability of signaling pathways to convert stimulus strength into signal duration results directly from the nonlinear nature of these systems and emphasizes the importance of considering the dynamic properties of signaling pathways when characterizing their behavior.Understanding how signaling pathways encode and transmit quantitative information about the external environment will not only deepen our understanding of these systems but also provide insight into how to reestablish proper function of pathways that have become dysregulated by disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, United States of America.

ABSTRACT
The cellular response elicited by an environmental cue typically varies with the strength of the stimulus. For example, in the yeast Saccharomyces cerevisiae, the concentration of mating pheromone determines whether cells undergo vegetative growth, chemotropic growth, or mating. This implies that the signaling pathways responsible for detecting the stimulus and initiating a response must transmit quantitative information about the intensity of the signal. Our previous experimental results suggest that yeast encode pheromone concentration as the duration of the transmitted signal. Here we use mathematical modeling to analyze possible biochemical mechanisms for performing this "dose-to-duration" conversion. We demonstrate that modulation of signal duration increases the range of stimulus concentrations for which dose-dependent responses are possible; this increased dynamic range produces the counterintuitive result of "signaling beyond saturation" in which dose-dependent responses are still possible after apparent saturation of the receptors. We propose a mechanism for dose-to-duration encoding in the yeast pheromone pathway that is consistent with current experimental observations. Most previous investigations of information processing by signaling pathways have focused on amplitude encoding without considering temporal aspects of signal transduction. Here we demonstrate that dose-to-duration encoding provides cells with an alternative mechanism for processing and transmitting quantitative information about their surrounding environment. The ability of signaling pathways to convert stimulus strength into signal duration results directly from the nonlinear nature of these systems and emphasizes the importance of considering the dynamic properties of signaling pathways when characterizing their behavior. Understanding how signaling pathways encode and transmit quantitative information about the external environment will not only deepen our understanding of these systems but also provide insight into how to reestablish proper function of pathways that have become dysregulated by disease.

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A model for dose-to-duration encoding in the pheromone response pathway.(A) Receptor affinity is feedback-regulated by species X. The signal is converted into a square pulse by the intermediate kinase MK (e.g., Ste20, Ste11, or Ste7), which also activates the MAP kinases Fus3 and Kss1. (B) Time courses of signal activity at different stages of the pathway: receptor occupancy (top left) and [MK*] (top right), and Fus3 and Kss1 activity (bottom left and right, respectively).
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pcbi-1000197-g007: A model for dose-to-duration encoding in the pheromone response pathway.(A) Receptor affinity is feedback-regulated by species X. The signal is converted into a square pulse by the intermediate kinase MK (e.g., Ste20, Ste11, or Ste7), which also activates the MAP kinases Fus3 and Kss1. (B) Time courses of signal activity at different stages of the pathway: receptor occupancy (top left) and [MK*] (top right), and Fus3 and Kss1 activity (bottom left and right, respectively).

Mentions: With the above considerations in mind, we developed a mathematical model to investigate the scenario in which the negative feedback loop acts on the receptor. Figure 7A shows a schematic diagram of the system and the shape of the propagated signal at each level of the pathway. The model is described by Equations 3–5 and 7–9 of the Methods. As discussed in the previous section, because the negative feedback acts on the receptor, it is necessary to incorporate an intermediate step (MK in Figure 7) to transform the propagated signal into a square-pulse. Any of the upstream kinases (Ste20, Ste11 or Ste7) are capable of performing this transformation. Figure 7B shows the predicted upstream activation profile (compare with Figure 6C) and the MAP kinase activation profiles produced by the models compared with the experimental results. If we again disregard the second increase in Kss1 activity at high pheromone concentrations, the correspondence between the model results and experimental data is striking, especially considering the simplicity of the model. We note that this agreement does not prove the validity of the model, but demonstrates that the mechanisms discussed above are consistent with the experimental data. The model also provides an important guide for future experimental work.


Dose-to-duration encoding and signaling beyond saturation in intracellular signaling networks.

Behar M, Hao N, Dohlman HG, Elston TC - PLoS Comput. Biol. (2008)

A model for dose-to-duration encoding in the pheromone response pathway.(A) Receptor affinity is feedback-regulated by species X. The signal is converted into a square pulse by the intermediate kinase MK (e.g., Ste20, Ste11, or Ste7), which also activates the MAP kinases Fus3 and Kss1. (B) Time courses of signal activity at different stages of the pathway: receptor occupancy (top left) and [MK*] (top right), and Fus3 and Kss1 activity (bottom left and right, respectively).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2543107&req=5

pcbi-1000197-g007: A model for dose-to-duration encoding in the pheromone response pathway.(A) Receptor affinity is feedback-regulated by species X. The signal is converted into a square pulse by the intermediate kinase MK (e.g., Ste20, Ste11, or Ste7), which also activates the MAP kinases Fus3 and Kss1. (B) Time courses of signal activity at different stages of the pathway: receptor occupancy (top left) and [MK*] (top right), and Fus3 and Kss1 activity (bottom left and right, respectively).
Mentions: With the above considerations in mind, we developed a mathematical model to investigate the scenario in which the negative feedback loop acts on the receptor. Figure 7A shows a schematic diagram of the system and the shape of the propagated signal at each level of the pathway. The model is described by Equations 3–5 and 7–9 of the Methods. As discussed in the previous section, because the negative feedback acts on the receptor, it is necessary to incorporate an intermediate step (MK in Figure 7) to transform the propagated signal into a square-pulse. Any of the upstream kinases (Ste20, Ste11 or Ste7) are capable of performing this transformation. Figure 7B shows the predicted upstream activation profile (compare with Figure 6C) and the MAP kinase activation profiles produced by the models compared with the experimental results. If we again disregard the second increase in Kss1 activity at high pheromone concentrations, the correspondence between the model results and experimental data is striking, especially considering the simplicity of the model. We note that this agreement does not prove the validity of the model, but demonstrates that the mechanisms discussed above are consistent with the experimental data. The model also provides an important guide for future experimental work.

Bottom Line: We demonstrate that modulation of signal duration increases the range of stimulus concentrations for which dose-dependent responses are possible; this increased dynamic range produces the counterintuitive result of "signaling beyond saturation" in which dose-dependent responses are still possible after apparent saturation of the receptors.The ability of signaling pathways to convert stimulus strength into signal duration results directly from the nonlinear nature of these systems and emphasizes the importance of considering the dynamic properties of signaling pathways when characterizing their behavior.Understanding how signaling pathways encode and transmit quantitative information about the external environment will not only deepen our understanding of these systems but also provide insight into how to reestablish proper function of pathways that have become dysregulated by disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, United States of America.

ABSTRACT
The cellular response elicited by an environmental cue typically varies with the strength of the stimulus. For example, in the yeast Saccharomyces cerevisiae, the concentration of mating pheromone determines whether cells undergo vegetative growth, chemotropic growth, or mating. This implies that the signaling pathways responsible for detecting the stimulus and initiating a response must transmit quantitative information about the intensity of the signal. Our previous experimental results suggest that yeast encode pheromone concentration as the duration of the transmitted signal. Here we use mathematical modeling to analyze possible biochemical mechanisms for performing this "dose-to-duration" conversion. We demonstrate that modulation of signal duration increases the range of stimulus concentrations for which dose-dependent responses are possible; this increased dynamic range produces the counterintuitive result of "signaling beyond saturation" in which dose-dependent responses are still possible after apparent saturation of the receptors. We propose a mechanism for dose-to-duration encoding in the yeast pheromone pathway that is consistent with current experimental observations. Most previous investigations of information processing by signaling pathways have focused on amplitude encoding without considering temporal aspects of signal transduction. Here we demonstrate that dose-to-duration encoding provides cells with an alternative mechanism for processing and transmitting quantitative information about their surrounding environment. The ability of signaling pathways to convert stimulus strength into signal duration results directly from the nonlinear nature of these systems and emphasizes the importance of considering the dynamic properties of signaling pathways when characterizing their behavior. Understanding how signaling pathways encode and transmit quantitative information about the external environment will not only deepen our understanding of these systems but also provide insight into how to reestablish proper function of pathways that have become dysregulated by disease.

Show MeSH
Related in: MedlinePlus