Lukas Thomas J
Department of Molecular Pharmacology and Drug Discovery Program, Northwestern University, Chicago, Illinois 60611, USA.
Biophys J. 2004 Sep;87(3):1406-16. doi: 10.1529/biophysj.103.035253.
The postgenomic era is providing a wealth of information about the genes involved in many cellular processes. However, the ability to apply this information to understanding cellular signal transduction is limited by the lack of tools that quantitatively describe cellular signaling processes. The objective of the current studies is to provide a framework for modeling cellular signaling processes beginning at a plasma membrane receptor and ending with a measurable endpoint in the signaling process. Agonist-induced Ca(2+) mobilization coupled to down stream phosphorylation events was modeled using knowledge of in vitro and in vivo process parameters. The simulation process includes several modules that describe cellular processes involving receptor activation phosphoinositide metabolism, Ca(2+)-release, and activation of a calmodulin-dependent protein kinase. A Virtual Cell-based simulation was formulated using available literature data and compared to new and existing experimental results. The model provides a new approach to facilitate hypothesis-driven investigation and experimental design based upon simulation results. These investigations may be directed at the timing of multiple phosphorylation/dephosphorylation events affecting key enzymatic activities in the signaling pathway.
后基因组时代正在提供大量关于参与许多细胞过程的基因的信息。然而，由于缺乏定量描述细胞信号转导过程的工具，将这些信息应用于理解细胞信号转导的能力受到限制。当前研究的目的是提供一个框架，用于对细胞信号转导过程进行建模，该过程从质膜受体开始，到信号转导过程中一个可测量的终点结束。利用体外和体内过程参数的知识，对与下游磷酸化事件相关的激动剂诱导的Ca(2+)动员进行了建模。模拟过程包括几个模块，这些模块描述了涉及受体激活、磷酸肌醇代谢、Ca(2+)释放以及钙调蛋白依赖性蛋白激酶激活的细胞过程。使用现有文献数据构建了基于虚拟细胞的模拟，并与新的和现有的实验结果进行了比较。该模型提供了一种新方法，以促进基于模拟结果的假设驱动研究和实验设计。这些研究可能针对影响信号通路中关键酶活性的多个磷酸化/去磷酸化事件的时间。
