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首页> 外文期刊>Molecular BioSystems >Molecular Systems Biology Of Erbb1 Signaling: Bridging The Gap Through Multiscale Modeling And High-performance Computing
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Molecular Systems Biology Of Erbb1 Signaling: Bridging The Gap Through Multiscale Modeling And High-performance Computing

机译：Erbb1信号传导的分子系统生物学：通过多尺度建模和高性能计算弥合差距

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摘要

The complexity in intracellular signaling mechanisms relevant for the conquest of many diseases resides at different levels of organization with scales ranging from the subatomic realm relevant to catalytic functions of enzymes to the mesoscopic realm relevant to the cooperative association of molecular assemblies and membrane processes. Consequently, the challenge of representing and quantifying functional or dysfunctional modules within the networks remains due to the current limitations in our understanding of mesoscopic biology, i.e., how the components assemble into functional molecular ensembles. A multiscale approach is necessary to treat a hierarchy of interactions ranging from molecular (nm, ns) to signaling (μm, ms) length and time scales, which necessitates the development and application of specialized modeling tools. Complementary to multiscale experimentation (encompassing structural biology, mechanistic enzymology, cell biology, and single molecule studies) multiscale modeling offers a powerful and quantitative alternative for the study of functional intracellular signaling modules. Here, we describe the application of a multiscale approach to signaling mediated by the ErbB1 receptor which constitutes a network hub for the cell's proliferative, migratory, and survival programs. Through our multiscale model, we mechanistically describe how point-mutations in the ErbBI receptor can profoundly alter signaling characteristics leading to the onset of oncogenic transformations. Specifically, we describe how the point mutations induce cascading fragility mechanisms at the molecular scale as well as at the scale of the signaling network to preferentially activate the survival factor Akt. We provide a quantitative explanation for how the hallmark of preferential Akt activation in cell-lines harboring the constitutively active mutant ErbBI receptors causes these cell-lines to be addicted to ErbBI-mediated generation of survival signals. Consequently, inhibition of ErbBI activity leads to a remarkable therapeutic response in the addicted cell lines.
机译：与征服许多疾病有关的细胞内信号传导机制的复杂性在于组织的不同层次，其规模范围从与酶的催化功能有关的亚原子领域到与分子组装和膜过程的协同结合有关的介观领域。因此，由于目前我们对介观生物学的理解，即各组分如何组装成功能性分子集合，目前存在局限性，因此在网络中表示和量化功能或功能失调的模块仍然存在挑战。必须使用多尺度方法来处理从分子（nm，ns）到信号传递（μm，ms）长度和时间尺度的相互作用层次，这需要开发和应用专门的建模工具。与多尺度实验（包括结构生物学，机制酶学，细胞生物学和单分子研究）互补，多尺度建模为功能性细胞内信号传导模块的研究提供了强大而定量的选择。在这里，我们描述了多尺度方法在由ErbB1受体介导的信号转导中的应用，ErbB1受体构成了细胞增殖，迁移和存活程序的网络中心。通过我们的多尺度模型，我们机械地描述了ErbBI受体中的点突变如何能够深刻改变信号传导特征，从而导致致癌性转化的发生。具体而言，我们描述了点突变如何在分子规模以及信号网络规模上诱导级联的脆性机制，从而优先激活存活因子Akt。我们提供了定量解释，说明在具有组成型活性突变型ErbBI受体的细胞系中优先Akt激活的标志如何导致这些细胞系沉迷于ErbBI介导的存活信号的产生。因此，抑制ErbBI活性导致在上瘾的细胞系中产生显着的治疗反应。

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