Amit Ido, Wides Ron, Yarden Yosef
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
Mol Syst Biol. 2007;3:151. doi: 10.1038/msb4100195. Epub 2007 Dec 4.
Robust biological signaling networks evolved, through gene duplications, from simple, relatively fragile cascades. Architectural features such as layered configuration, branching and modularity, as well as functional characteristics (e.g., feedback control circuits), enable fail-safe performance in the face of internal and external perturbations. These universal features are exemplified here using the receptor tyrosine kinase (RTK) family. The RTK module is richly mutated and overexpressed in human malignancies, and pharmaceutical interception of its signaling effectively retards growth of specific tumors. Therapy-induced interception of RTK-signaling pathways and the common evolvement of drug resistance are respectively considered here as manifestations of fragility and plasticity of robust networks. The systems perspective we present views pathologies as hijackers of biological robustness and offers ways for identifying fragile hubs, as well as strategies to overcome drug resistance.
强大的生物信号网络通过基因复制，从简单、相对脆弱的级联反应进化而来。诸如分层配置、分支和模块化等结构特征，以及功能特性（如反馈控制回路），使得在面对内部和外部干扰时能够实现故障安全性能。这里以受体酪氨酸激酶（RTK）家族为例来说明这些普遍特征。RTK模块在人类恶性肿瘤中发生大量突变并过度表达，对其信号进行药物阻断可有效延缓特定肿瘤的生长。本文分别将治疗诱导的RTK信号通路阻断和耐药性的共同演变视为强大网络的脆弱性和可塑性的表现。我们提出的系统观点将病理学视为生物稳健性的劫持者，并提供了识别脆弱节点的方法以及克服耐药性的策略。
