Resistance to signal activation governs design features of the MAP kinase signaling module
Resistance to signal activation governs design features of the MAP kinase signaling module
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DOI：
10.1002/bit.10836
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发表时间：
2004-02-05
影响因子：
3.8
通讯作者：
Asthagiri, AR
中科院分区：
文献类型：
--
作者：
Chapman, S;Asthagiri, AR
鉴于其对许多细胞功能的广泛影响，重新设计丝裂原活化蛋白（MAP）激酶信号传导模块将为工程细胞行为提供强有力的手段。早期的挑战包括识别与生物功能最相关的定量模块特征，并开发简单的设计规则来可预测地修改这些特征。这项计算研究描绘了如何功能，如信号放大，输入效力，输出的动态范围可以通过操纵主模块组件进行调整。重要的是，该模型构建确定了对信号激活的抗性的度量，该度量定量预测了激酶和磷酸酶表达中的广泛扰动的模块特征和设计权衡。它的预测效用扩展到动态特性，如信号寿命，这往往决定MAP激酶对细胞功能的影响。综上所述，我们认为通过调节抗性来可预测地改变MAP激酶信号传导不仅是一种可行的工程策略，而且也是一种被自然系统利用的策略，以允许每个MAP激酶以上下文依赖的方式发挥多效性效应。外部刺激不仅激活激酶，而且改变磷酸酶的表达和活性，从而重新配置单个模块，用于定量不同的信号传导模式，例如瞬时与持续动力学，每种模式对细胞功能都有独特的影响。(C)2004 Wiley Periodicals，Inc.
Given its broad influence over numerous cell functions, redesigning the mitogen-activated protein (MAP) kinase signaling module would offer a powerful means to engineer cell behavior. Early challenges include identifying quantitative module features most relevant to biological function and developing simple design rules to predictably modify these features. This computational study delineates how features such as signal amplification, input potency, and dynamic range of output may be tuned by manipulating chief module components. Importantly, the model construction identifies a metric of resistance to signal activation that quantitatively predicts module features and design trade-offs for broad perturbations in kinase and phosphatase expression. Its predictive utility extends to dynamic properties such as signal lifetime, which often dictates MAP kinase effect on cell function. Taken together, we propose that predictably altering MAP kinase signaling by tuning resistance is not only a feasible engineering strategy, but also one exploited by natural systems to allow each MAP kinase to exert pleiotropic effects in a context-dependent manner. External stimuli not only activate kinases, but also alter phosphatase expression and activity, thereby reconfiguring a single module for quantitatively distinct modes of signaling such as transient vs. sustained dynamics, each with unique effects on cell function. (C) 2004 Wiley Periodicals, Inc.