Physical modulation of intracellular signaling processes by locational regulation
Physical modulation of intracellular signaling processes by locational regulation
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DOI：
10.1016/s0006-3495(97)78846-5
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发表时间：
1997-05-01
影响因子：
3.4
通讯作者：
Lauffenburger, DA
中科院分区：
文献类型：
--
作者：
Haugh, JM;Lauffenburger, DA
最近在信号转导领域的观察表明，蛋白质在细胞内的位置与在溶液中测量的蛋白质活性对于激活其下游通路一样重要。细胞的物理组织可以对控制最终感知信号的化学反应网络提供额外的控制层。使用细胞质和质膜作为相关的区室区别，我们分析了重新定位对与膜相关靶标的关联率的影响。我们根据可测量参数（例如可用目标的数量、分子扩散率和固有反应速率常数）将这种效应量化为增强因子 E。然后，我们采用两个简单但相关的示例模型来说明重新定位如何影响信号转导途径的动态。研究了这些模型的时间分布和相位行为。我们还将信号转导的实验可观察方面（例如峰值激活和刺激和响应的相对时间尺度）与我们模型中的重定位机制的定量方面联系起来。在我们的示例方案中，当关联率增强因子 E 低至 10 时，信号对中的胞质物质几乎完全重新定位才能产生有意义的模型途径激活；当 E 为 100 或更大时，只有一小部分蛋白质必须重新定位。
Recent observations in the field of signal transduction suggest that where a protein is located within a cell can be as important as its activity measured in solution for activation of its downstream pathway, The physical organization of the cell can provide an additional layer of control upon the chemical reaction networks that govern ultimately perceived signals. Using the cytosol and plasma membrane as relevant compartmental distinctions, we analyze the effect of relocation on the rate of association with a membrane-associated target. We quantify this effect as an enhancement factor E in terms of measurable parameters such as the number of available targets, molecular diffusivities, and intrinsic reaction rate constants. We then employ two simple yet relevant example models to illustrate how relocation can affect the dynamics of signal transduction pathways. The temporal profiles and phase behavior of these models are investigated. We also relate experimentally observable aspects of signal transduction such as peak activation and the relative time scales of stimulus and response to quantitative aspects of the relocation mechanisms in our models. In our example schemes, nearly complete relocation of the cytosolic species in the signaling pair is required to generate meaningful activation of the model pathways when the association rate enhancement factor E is as low as 10; when E is 100 or greater, only a small fraction of the protein must be relocated.