Operating regimes of signaling cycles: statics, dynamics, and noise filtering.
Operating regimes of signaling cycles: statics, dynamics, and noise filtering.
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DOI：
10.1371/journal.pcbi.0030246
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发表时间：
2007-12
影响因子：
4.3
通讯作者：
Mirny LA
中科院分区：
文献类型：
--
作者：
Gomez-Uribe C;Verghese GC;Mirny LA
信号通路的普遍组成部分是共价修饰循环（例如 MAPK 级联中的磷酸化和去磷酸化）。我们的论文探讨了这种简单的生化电路可以完成的信息处理和过滤。信号循环因在某种稳态状态下表现出高度 S 形（超灵敏）输入输出特性而闻名。在这里，我们系统地研究了循环的稳态行为及其对时变刺激的响应。我们证明了该循环实际上可以在四种不同的状态下运行，每种状态都有其特定的输入输出特征。这些结果是使用总准稳态近似获得的，该近似比通常用于酶反应的 Michaelis-Menten 近似更有效。我们引用的实验数据表明信号循环在新机制之一中运行的可能性。然后我们考虑循环的动态行为，迄今为止这一点相对被忽视了。我们证明了循环的内在架构使它们在所有四种状态下都充当可调低通滤波器，滤除信号和环境线索中的高频波动或噪声。此外，截止频率可以通过单元来调整。数值模拟表明，即使对于大幅度的噪声，我们的分析结果也很好。我们认为，噪声过滤和可调性使信号循环成为更复杂的细胞信号传导途径的通用组成部分。细胞受到不断变化的环境和随时间变化的刺激。在细胞表面感应到的信号通过信号通路在细胞内传输。这些通路可以以多种方式转换信号并执行一些初步的信息处理。信号通路的一个普遍组成部分是一个简单的生化循环，涉及酶-底物对的共价修饰。我们的论文致力于全面描述这个简单循环的静态和动态行为，这是理解此类循环互连行为的重要第一步。众所周知，信号周期可以起到静态开关的作用，稳态输出是输入的“超灵敏”函数，即输入仅发生很小的变化就从低值变为高值。我们证明，实际上存在四种主要的静态和动态操作状态（超灵敏是静态状态之一）。每个制度都有自己的投入产出特征。尽管这四种机制具有独特的特征，但它们都通过滤除输入中的高频波动或噪声来响应时变刺激，同时传递低频信息承载变化。细胞可以选择机制并调整特定信号通路中各个周期的噪声过滤特征。这种可调性使信号循环成为复杂细胞信号传导途径的通用组成部分。
A ubiquitous building block of signaling pathways is a cycle of covalent modification (e.g., phosphorylation and dephosphorylation in MAPK cascades). Our paper explores the kind of information processing and filtering that can be accomplished by this simple biochemical circuit. Signaling cycles are particularly known for exhibiting a highly sigmoidal (ultrasensitive) input–output characteristic in a certain steady-state regime. Here, we systematically study the cycle's steady-state behavior and its response to time-varying stimuli. We demonstrate that the cycle can actually operate in four different regimes, each with its specific input–output characteristics. These results are obtained using the total quasi–steady-state approximation, which is more generally valid than the typically used Michaelis-Menten approximation for enzymatic reactions. We invoke experimental data that suggest the possibility of signaling cycles operating in one of the new regimes. We then consider the cycle's dynamic behavior, which has so far been relatively neglected. We demonstrate that the intrinsic architecture of the cycles makes them act—in all four regimes—as tunable low-pass filters, filtering out high-frequency fluctuations or noise in signals and environmental cues. Moreover, the cutoff frequency can be adjusted by the cell. Numerical simulations show that our analytical results hold well even for noise of large amplitude. We suggest that noise filtering and tunability make signaling cycles versatile components of more elaborate cell-signaling pathways. A cell is subjected to constantly changing environments and time-varying stimuli. Signals sensed at the cell surface are transmitted inside the cell by signaling pathways. Such pathways can transform signals in diverse ways and perform some preliminary information processing. A ubiquitous building block of signaling pathways is a simple biochemical cycle involving covalent modification of an enzyme–substrate pair. Our paper is devoted to fully characterizing the static and dynamic behavior of this simple cycle, an essential first step in understanding the behavior of interconnections of such cycles. It is known that a signaling cycle can function as a static switch, with the steady-state output being an “ultrasensitive” function of the input, i.e., changing from a low to high value for only a small change in the input. We show that there are in fact precisely four major regimes of static and dynamic operation (with ultrasensitive being one of the static regimes). Each regime has its own input–output characteristics. Despite the distinctive features of these four regimes, they all respond to time-varying stimuli by filtering out high-frequency fluctuations or noise in their inputs, while passing through the lower-frequency information-bearing variations. A cell can select the regime and tune the noise-filtering characteristics of the individual cycles in a specific signaling pathway. This tunability makes signaling cycles versatile components of elaborate cell-signaling pathways.
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影响因子：
16
作者：
Heinrich, R;Neel, BG;Rapoport, TA
通讯作者：
Rapoport, TA
影响因子：
5.4
作者：
Blüthgen, N;Bruggeman, FJ;Kholodenko, BN
通讯作者：
Kholodenko, BN
影响因子：
2
作者：
Bruggeman, FJ;Westerhoff, HV;Kholodenko, BN
通讯作者：
Kholodenko, BN
影响因子：
64.8
作者：
Hartwell, LH;Hopfield, JJ;Murray, AW
通讯作者：
Murray, AW
影响因子：
13.8
作者：
Ferrell, JE
通讯作者：
Ferrell, JE