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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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Pathway architectures that convert stimulus dose to signal duration.(A) Feed-forward and (B) negative feedback encoding modules (KK: Kinase-Kinase, K: Kinase, X: Phosphatase). Shown are cases of negative regulation operating by inhibiting activation (left diagrams) or promoting deactivation (right diagrams).
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pcbi-1000197-g003: Pathway architectures that convert stimulus dose to signal duration.(A) Feed-forward and (B) negative feedback encoding modules (KK: Kinase-Kinase, K: Kinase, X: Phosphatase). Shown are cases of negative regulation operating by inhibiting activation (left diagrams) or promoting deactivation (right diagrams).

Mentions: In this section we discuss mechanisms that can achieve dose-to-duration encoding. As previously mentioned, we are focusing on cases involving a sustained input, and therefore need to consider systems capable of adaptation or desensitization. In order to work as a dose-to-duration transducer, the duration of the output has to increase with the concentration of the stimulus. As we illustrate below, this is not a general property of adaptive systems. Figure 3 shows a number of architectures capable of performing the dose-to-duration transformation. The two pathway architectures depicted in Figure 3A consist of incoherent feed-forward loops [13] in which the upstream stimulus activates both a positive and negative regulator of the signaling protein K. For the system to show transient activity, negative regulation must occur on a slower time scale than the activation rate of K. As shown in the figure, this can be achieved if the negative regulation is mediated by an intermediate species X. This species can operate either by inhibiting activation of K by KK or by promoting deactivation of K. This type of architecture occurs in ERK signaling networks in which agonists, such as epidermal growth factor, causes transient extracellular signal-regulated kinase (ERK) activation by triggering rapid Ras activation followed by slow recruitment of its negative regulator, Ras GTP-ase regulating protein (Ras-GAP), to the membrane [14].


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

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

Pathway architectures that convert stimulus dose to signal duration.(A) Feed-forward and (B) negative feedback encoding modules (KK: Kinase-Kinase, K: Kinase, X: Phosphatase). Shown are cases of negative regulation operating by inhibiting activation (left diagrams) or promoting deactivation (right diagrams).
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000197-g003: Pathway architectures that convert stimulus dose to signal duration.(A) Feed-forward and (B) negative feedback encoding modules (KK: Kinase-Kinase, K: Kinase, X: Phosphatase). Shown are cases of negative regulation operating by inhibiting activation (left diagrams) or promoting deactivation (right diagrams).
Mentions: In this section we discuss mechanisms that can achieve dose-to-duration encoding. As previously mentioned, we are focusing on cases involving a sustained input, and therefore need to consider systems capable of adaptation or desensitization. In order to work as a dose-to-duration transducer, the duration of the output has to increase with the concentration of the stimulus. As we illustrate below, this is not a general property of adaptive systems. Figure 3 shows a number of architectures capable of performing the dose-to-duration transformation. The two pathway architectures depicted in Figure 3A consist of incoherent feed-forward loops [13] in which the upstream stimulus activates both a positive and negative regulator of the signaling protein K. For the system to show transient activity, negative regulation must occur on a slower time scale than the activation rate of K. As shown in the figure, this can be achieved if the negative regulation is mediated by an intermediate species X. This species can operate either by inhibiting activation of K by KK or by promoting deactivation of K. This type of architecture occurs in ERK signaling networks in which agonists, such as epidermal growth factor, causes transient extracellular signal-regulated kinase (ERK) activation by triggering rapid Ras activation followed by slow recruitment of its negative regulator, Ras GTP-ase regulating protein (Ras-GAP), to the membrane [14].

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