Molecular systems biology of ErbB1 signaling: bridging the gap through multiscale modeling and high-performance computing.
Molecular systems biology of ErbB1 signaling: bridging the gap through multiscale modeling and high-performance computing.
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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。
DOI：
10.1039/b803806f
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发表时间：
2008-12
影响因子：
--
通讯作者：
Radhakrishnan R
中科院分区：
文献类型：
--
作者：
Shih AJ;Purvis J;Radhakrishnan R
与征服许多疾病相关的细胞内信号传导机制的复杂性存在于不同的组织水平上，其规模从与酶的催化功能相关的亚原子领域到与分子组装和膜过程的合作关联相关的介观领域。因此，表示和量化网络内功能或功能障碍模块的挑战仍然是由于我们对介观生物学的理解的当前限制，即，这些成分是如何组装成功能性分子集合体的。一个多尺度的方法是必要的，以处理从分子（nm，ns）到信号（μm，ms）的长度和时间尺度的相互作用的层次结构，这需要专门的建模工具的开发和应用。作为多尺度实验（包括结构生物学、机械酶学、细胞生物学和单分子研究）的补充，多尺度建模为功能性细胞内信号模块的研究提供了一种强大的定量选择。在这里，我们描述了一个多尺度的方法，由ErbB1受体介导的信号传导的应用程序，构成了一个网络枢纽细胞的增殖，迁移和生存计划。通过我们的多尺度模型，我们机械地描述了ErbB1受体的点突变如何深刻地改变信号特征，导致致癌转化的发生。具体而言，我们描述了点突变如何诱导级联脆弱性机制在分子尺度上，以及在规模的信号网络，优先激活生存因子Akt。我们提供了一个定量的解释，如何在细胞系中的组成型活性突变体ErbB1受体的标志性的Akt优先激活导致这些细胞系沉迷于ErbB1介导的生存信号的产生。因此，ErbB1活性的抑制导致成瘾细胞系中显著的治疗反应。
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 ErbB1 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 ErbB1 receptors causes these cell-lines to be addicted to ErbB1-mediated generation of survival signals. Consequently, inhibition of ErbB1 activity leads to a remarkable therapeutic response in the addicted cell lines.
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影响因子：
158.5
作者：
Lynch, TJ;Bell, DW;Haber, DA
通讯作者：
Haber, DA
影响因子：
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作者：
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11.2
作者：
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Settleman, Jeffrey
影响因子：
3.8
作者：
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通讯作者：
Radhakrishnan, Ravi
影响因子：
11.5
作者：
Lee, JW;Soung, YH;Lee, SH
通讯作者：
Lee, SH