Mathematical and computational analysis of adaptation via feedback inhibition in signal transduction pathways
Mathematical and computational analysis of adaptation via feedback inhibition in signal transduction pathways
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DOI：
10.1529/biophysj.107.107516
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发表时间：
2007-08-01
影响因子：
3.4
通讯作者：
Elston, Timothy C.
中科院分区：
文献类型：
--
作者：
Behar, Marcelo;Hao, Nan;Elston, Timothy C.
我们对细胞内信号系统中短期适应的反馈调节机制进行了系统的分析。一旦接收到外部提示，这些系统就会产生一种短暂的反应，即使刺激持续存在，这种反应也会迅速恢复到基础水平。能够短期适应的信号传导途径存在于多种系统中，如酵母的高渗透压响应、网骨藻中的梯度感应和脊椎动物中的细胞因子响应。使用数学分析和计算实验，我们比较不同的反馈架构的响应幅度和持续时间，适应能力，并响应可变的刺激水平。我们的分析揭示了这些系统的三个重要特征：1），多步信号级联通过与信号放大不同的效应提高对低剂量的敏感性; 2），一些反馈架构充当将刺激强度转换为响应持续时间的信号换能器;和3），反馈失活充当瞬时和持续响应之间的剂量依赖性开关。最后，我们提出了每一种形式的反馈调节，可以帮助他们的识别特征。
We perform a systematic analysis of mechanisms of feedback regulation that underlie short-term adaptation in intracellular signaling systems. Upon receiving an external cue, these systems generate a transient response that quickly returns to basal levels even if the stimulus persists. Signaling pathways capable of short- term adaptation are found in systems as diverse as the high osmolarity response of yeast, gradient sensing in Dictyostelium, and the cytokine response in vertebrates. Using mathematical analysis and computational experiments, we compare different feedback architectures in terms of response amplitude and duration, ability to adapt, and response to variable stimulus levels. Our analysis reveals three important features of these systems: 1), multiple step signaling cascades improve sensitivity to low doses by an effect distinct from signal amplification; 2), some feedback architectures act as signal transducers converting stimulus strength into response duration; and 3), feedback deactivation acts as a dose-dependent switch between transient and sustained responses. Finally, we present characteristic features for each form of feedback regulation that can aid in their identification.