Spatio-temporal modeling of signaling protein recruitment to EGFR
Spatio-temporal modeling of signaling protein recruitment to EGFR
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DOI：
10.1186/1752-0509-4-57
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发表时间：
2010-05-06
影响因子：
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通讯作者：
Wilson, Bridget S.
中科院分区：
文献类型：
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作者：
Hsieh, Ming-yu;Yang, Shujie;Wilson, Bridget S.
背景：用随机模拟器研究了EGFR信号在单分子三维细节上的启动。该模型考虑了以前未被探索的对受体-适配器偶联的贡献，例如受体聚集以及受体和结合伙伴的扩散特性。基于代理和基于规则的方法考虑了组合的复杂性、与多个磷酸化位点相关的问题以及同时结合接头的可能性。结果：该模型用于模拟四种不同的信号分子(Grb2、PLC Gamma 1、Stat5、Shc)到磷酸化的EGFR尾部的招募，规则基于空间约束的粗粒度预测。部分参数来自定量免疫印迹、免疫沉淀和电子显微镜数据。结果表明，受体聚集增加了个体适配器对激活的EGFR的保留效率，如果受体过度表达造成拥挤，这种效应就会被推翻。多个蛋白质的同时对接高度依赖于受体-接头的稳定性，与聚集性无关。结论：总的来说，我们认为受体密度、反应动力学和膜空间组织都有助于提高信号转导效率，并影响致癌过程。
Background: A stochastic simulator was implemented to study EGFR signal initiation in 3D with single molecule detail. The model considers previously unexplored contributions to receptor-adaptor coupling, such as receptor clustering and diffusive properties of both receptors and binding partners. The agent-based and rule-based approach permits consideration of combinatorial complexity, a problem associated with multiple phosphorylation sites and the potential for simultaneous binding of adaptors.Results: The model was used to simulate recruitment of four different signaling molecules (Grb2, PLC gamma 1, Stat5, Shc) to the phosphorylated EGFR tail, with rules based on coarse-grained prediction of spatial constraints. Parameters were derived in part from quantitative immunoblotting, immunoprecipitation and electron microscopy data. Results demonstrate that receptor clustering increases the efficiency of individual adaptor retainment on activated EGFR, an effect that is overridden if crowding is imposed by receptor overexpression. Simultaneous docking of multiple proteins is highly dependent on receptor-adaptor stability and independent of clustering.Conclusions: Overall, we propose that receptor density, reaction kinetics and membrane spatial organization all contribute to signaling efficiency and influence the carcinogenesis process.