Regulation of signal duration and the statistical dynamics of kinase activation by scaffold proteins.
Regulation of signal duration and the statistical dynamics of kinase activation by scaffold proteins.
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DOI：
10.1371/journal.pcbi.1000099
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发表时间：
2008-06-27
影响因子：
4.3
通讯作者：
Chakraborty AK
中科院分区：
文献类型：
--
作者：
Locasale JW;Chakraborty AK
引导多种激酶组装成空间定位的信号传导复合物的支架蛋白通常对于维持适当的生物反应是必不可少的。虽然支架被广泛认为对信号传播的动力学有显着的影响，但这些后果的机制还没有得到很好的理解。在这里，蒙特卡罗模拟模型激酶级联被用来调查的时间特性的信号级联可以通过支架蛋白的存在下的影响。具体来说，我们研究了空间定位激酶组件的支架上的信号动力学的影响。模拟表明，支架对细胞信号传导动力学的主要影响是控制蛋白激酶的激活如何随时间分布。支架可以通过允许激酶在广泛的时间范围内被激活来影响激酶激活的时间，从而允许在早期和晚期进行信号传导。导致最佳信号幅度的支架浓度也导致激酶被激活的时间的最宽分布。这些计算提供了对一种机制的深入了解，该机制描述了在支架介导的蛋白激酶级联反应中信号的持续时间可能如何被调节。我们的研究结果说明了另一个复杂的控制特性，出现从空间定位组件的激酶级联支架蛋白的物理效应的广泛阵列。信号转导是细胞通讯的科学。细胞检测来自环境的信号，并利用它们来决定是否或何时增殖。所有健康的细胞都需要严格调节信号转导，异常的信号转导导致无数疾病，如癌症和糖尿病。例如，在哺乳动物等高等生物体中，导致细胞增殖的信号转导通常由支架蛋白引导。支架蛋白通过为参与细胞信号传导的多种蛋白质提供进行有效信号传输的平台来指导这些蛋白质的组装。尽管人们普遍认为支架对信号转导的方式具有显着的影响，但这些后果背后的机制还没有得到很好的理解。因此，我们使用了一种计算方法，该方法模拟了在支架存在下包含一组蛋白质的模型信号转导模块的行为。这些模拟揭示了支架如何动态调节细胞信号传导时间的机制。支架允许在适当的时间在细胞内传递受控水平的信号。我们的研究结果支持了这样的可能性：这些由支架调节的信号动态会影响许多医学上重要的细胞内过程中的细胞决策。
Scaffolding proteins that direct the assembly of multiple kinases into a spatially localized signaling complex are often essential for the maintenance of an appropriate biological response. Although scaffolds are widely believed to have dramatic effects on the dynamics of signal propagation, the mechanisms that underlie these consequences are not well understood. Here, Monte Carlo simulations of a model kinase cascade are used to investigate how the temporal characteristics of signaling cascades can be influenced by the presence of scaffold proteins. Specifically, we examine the effects of spatially localizing kinase components on a scaffold on signaling dynamics. The simulations indicate that a major effect that scaffolds exert on the dynamics of cell signaling is to control how the activation of protein kinases is distributed over time. Scaffolds can influence the timing of kinase activation by allowing for kinases to become activated over a broad range of times, thus allowing for signaling at both early and late times. Scaffold concentrations that result in optimal signal amplitude also result in the broadest distributions of times over which kinases are activated. These calculations provide insights into one mechanism that describes how the duration of a signal can potentially be regulated in a scaffold mediated protein kinase cascade. Our results illustrate another complexity in the broad array of control properties that emerge from the physical effects of spatially localizing components of kinase cascades on scaffold proteins. Signal transduction is the science of cellular communication. Cells detect signals from their environment and use them to make decisions such as whether or when to proliferate. Tight regulation of signal transduction is required for all healthy cells, and aberrant signaling leads to countless diseases such as cancer and diabetes. For example, in higher organisms such as mammals, signal transduction that leads to cell proliferation is often guided by a scaffold protein. Scaffolding proteins direct the assembly of multiple proteins involved in cell signaling by providing a platform for these proteins to carry out efficient signal transmission. Although scaffolds are widely believed to have dramatic effects on how signal transduction is carried out, the mechanisms that underlie these consequences are not well understood. Therefore, we used a computational approach that simulates the behavior of a model signal transduction module comprising a set of proteins in the presence of a scaffold. The simulations reveal mechanisms for how scaffolds can dynamically regulate the timing of cell signaling. Scaffolds allow for controlled levels of signal that are delivered inside the cell at appropriate times. Our findings support the possibility that these signaling dynamics regulated by scaffolds affect cell decision-making in many medically important intracellular processes.
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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：
64.8
作者：
Daniels, Mark A.;Teixeiro, Emma;Palmer, Ed
通讯作者：
Palmer, Ed
影响因子：
56.9
作者：
Bashor, Caleb J.;Helman, Noah C.;Lim, Wendell A.
通讯作者：
Lim, Wendell A.
影响因子：
64.8
作者：
Dodge-Kafka, KL;Soughayer, J;Scott, JD
通讯作者：
Scott, JD
影响因子：
4.4
作者：
Locasale, Jason W.
通讯作者：
Locasale, Jason W.