Shih Andrew J, Purvis Jeremy, Radhakrishnan Ravi
Department of Bioengineering, University of Pennsylvania, 210 S 33rd Street, 240 Skirkanich Hall, Philadelphia, PA 19104, USA.
Mol Biosyst. 2008 Dec;4(12):1151-9. doi: 10.1039/b803806f. Epub 2008 Sep 12.
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 (microm, 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.
与攻克多种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层次，其尺度范围从与酶催化功能相关的亚原子领域到与分子组装和膜过程的协同关联相关的介观领域。因此，由于我们目前对介观生物学的理解存在局限性，即组件如何组装成功能性分子集合体，在网络中表示和量化功能或功能失调模块的挑战依然存在。需要一种多尺度方法来处理从分子（纳米，纳秒）到信号传导（微米，毫秒）长度和时间尺度的相互作用层次结构，这就需要开发和应用专门的建模工具。作为多尺度实验（包括结构生物学、机理酶学、细胞生物学和单分子研究）的补充，多尺度建模为研究功能性细胞内信号传导模块提供了一种强大且定量的替代方法。在此，我们描述了一种多尺度方法在由ErbB1受体介导的信号传导中的应用，该受体构成了细胞增殖、迁移和存活程序的网络枢纽。通过我们的多尺度模型，我们从机理上描述了ErbB1受体中的点突变如何深刻改变信号传导特征，从而导致致癌转化的发生。具体而言，我们描述了点突变如何在分子尺度以及信号网络尺度上诱导级联脆弱机制，以优先激活存活因子Akt。我们提供了一个定量解释，说明在携带组成型活性突变体ErbB1受体的细胞系中，优先激活Akt的特征如何导致这些细胞系对ErbB1介导的存活信号产生成瘾性。因此，抑制ErbB1活性会在成瘾的细胞系中引发显著的治疗反应。
