Biological Systems Architecture Group, Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford OX3 9DS, United Kingdom.
FEBS Lett. 2012 Aug 14;586(17):2740-50. doi: 10.1016/j.febslet.2012.04.029. Epub 2012 Apr 25.
The molecular architectures of intracellular signaling networks are largely unknown. Understanding their design principles and mechanisms of processing information is essential to grasp the molecular basis of virtually all biological processes. This is particularly challenging for human pathologies like cancers, as essentially each tumor is a unique disease with vastly deranged signaling networks. However, even in normal cells we know almost nothing. A few 'signalosomes', like the COP9 and the TCR signaling complexes have been described, but detailed structural information on their architectures is largely lacking. Similarly, many growth factor receptors, for example EGF receptor, insulin receptor and c-Met, signal via huge protein complexes built on large platform proteins (Gab, Irs/Dok, p130Cas[BCAR1], Frs families etc.), which are structurally not well understood. Subsequent higher order processing events remain even more enigmatic. We discuss here methods that can be employed to study signaling architectures, and the importance of too often neglected features like macromolecular crowding, intrinsic disorder in proteins and the sophisticated cellular infrastructures, which need to be carefully considered in order to develop a more mature understanding of cellular signal processing.
细胞内信号转导网络的分子架构在很大程度上是未知的。了解它们的设计原则和信息处理机制对于掌握几乎所有生物过程的分子基础至关重要。这对于癌症等人类疾病尤其具有挑战性，因为基本上每个肿瘤都是一种具有严重紊乱信号网络的独特疾病。然而，即使在正常细胞中，我们也几乎一无所知。已经描述了一些“信号小体”，如 COP9 和 TCR 信号复合物，但它们的结构信息在很大程度上仍然缺乏。同样，许多生长因子受体，例如表皮生长因子受体、胰岛素受体和 c-Met，通过构建在大型平台蛋白（Gab、Irs/Dok、p130Cas[BCAR1]、Frs 家族等）上的巨大蛋白质复合物进行信号转导，这些复合物的结构尚不清楚。随后的更高阶处理事件仍然更加神秘。我们在这里讨论可用于研究信号转导架构的方法，以及经常被忽视的特征的重要性，如大分子拥挤、蛋白质的固有无序性和复杂的细胞基础设施，为了更成熟地理解细胞信号处理，需要仔细考虑这些特征。
