Dose-to-duration encoding and signaling beyond saturation in intracellular signaling networks.
Dose-to-duration encoding and signaling beyond saturation in intracellular signaling networks.
复制标题
在细胞内信号网络中，剂量到延伸的编码和信号超出饱和度。
DOI：
10.1371/journal.pcbi.1000197
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发表时间：
2008-10
影响因子：
4.3
通讯作者：
Elston, Timothy C.
中科院分区：
文献类型：
--
作者：
Behar, Marcelo;Hao, Nan;Dohlman, Henrik G.;Elston, Timothy C.
由环境线索引起的细胞反应通常随刺激的强度而变化。例如，在酿酒酵母中，交配信息素的浓度决定了细胞是进行营养生长、趋化生长还是交配。这意味着负责检测刺激和启动反应的信号通路必须传递有关信号强度的定量信息。我们之前的实验结果表明，酵母编码信息素浓度作为传输信号的持续时间。在这里，我们使用数学模型来分析执行这种“剂量到持续时间”转换的可能的生化机制。我们证明了信号持续时间的调制增加了刺激浓度的范围，其中剂量依赖性反应是可能的；这种增加的动态范围产生了违反直觉的“信号超过饱和”的结果，在这种情况下，在受体明显饱和后，剂量依赖性反应仍然是可能的。我们提出了酵母信息素途径中剂量-持续时间编码的机制，这与目前的实验观察结果一致。以前大多数关于信号通路信息处理的研究都集中在振幅编码上，而没有考虑信号转导的时间方面。在这里，我们证明了剂量-持续时间编码为细胞提供了另一种机制来处理和传递有关其周围环境的定量信息。信号通路将刺激强度转化为信号持续时间的能力直接来自于这些系统的非线性性质，并强调了在表征信号通路行为时考虑其动态特性的重要性。了解信号通路如何编码和传递有关外部环境的定量信息不仅将加深我们对这些系统的理解，而且还将为如何重建因疾病而失调的通路的适当功能提供见解。细胞必须能够探测到周围环境的变化并作出反应。通常情况下，环境信号，如激素或生长因子，被膜受体接收，进而激活细胞内信号通路。然后，这些通路将有关刺激的信息传递给引发适当反应所需的细胞成分。在许多情况下，反应的性质取决于刺激的剂量。因此，除了传递定性信息（例如，刺激的存在或不存在）外，信号通路还必须传递有关刺激强度的定量信息。在这里，我们介绍“剂量-持续时间”编码作为传递此类信息的有效策略。我们证明，通过提供一种克服饱和效应的机制，信号持续时间的调制增加了可能产生剂量依赖性反应的刺激浓度范围。这种增加的动态范围产生了违反直觉的“信号超过饱和”的结果，在这种情况下，在受体明显饱和后，剂量依赖性反应仍然是可能的。最后，我们证明了剂量-持续时间编码在酵母交配反应途径中使用，并提出了一个简单的机制，可以解释当前的实验观察结果。
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. Cells must be able to detect and respond to changes in their surroundings. Often environmental cues, such as hormones or growth factors, are received by membrane receptors that in turn activate intracellular signaling pathways. These pathways then transmit information about the stimulus to the cellular components required to elicit an appropriate response. In many cases, the nature of the response depends on the dose of the stimulus. Thus, in addition to relaying qualitative information (e.g., the presence or absence of a stimulus), signaling pathways must also transmit quantitative information about the intensity of the stimulus. Here we introduce “dose-to-duration” encoding as an effective strategy for relaying such information. We demonstrate that by providing a mechanism for overcoming saturation effects, 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. Finally, we demonstrate that dose-to-duration encoding is used in the yeast mating response pathway and presents a simple mechanism that can account for current experimental observations.
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影响因子：
16
作者：
Hao, Nan;Nayak, Sujata;Dohlman, Henrik G.
通讯作者：
Dohlman, Henrik G.
影响因子：
4.8
作者：
Hao, N;Yildirim, N;Dohlman, HG
通讯作者：
Dohlman, HG
影响因子：
3.4
作者：
Behar, Marcelo;Hao, Nan;Elston, Timothy C.
通讯作者：
Elston, Timothy C.
DOI：
10.1073/pnas.0703894104
发表时间：
2007-10-09
影响因子：
11.1
作者：
Behar, Marcelo;Dohlman, Henrik G.;Elston, Timothy C.
通讯作者：
Elston, Timothy C.
影响因子：
--
作者：
Esch, R. Keith;Wang, Yuqi;Errede, Beverly
通讯作者：
Errede, Beverly