Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRASG13D) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRASG13D (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.

中文翻译：

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表达KRASG13D转化水平的结直肠癌细胞中EGFR网络的广泛重新布线。

蛋白质-蛋白质相互作用网络（PPIN）可以组织基本的生物学过程，但是致癌突变如何影响这些相互作用及其在网络级别的功能却鲜为人知。在这里，我们分析了常见的致癌性KRAS突变（KRASG13D）如何影响大肠癌（CRC）细胞中PPIN结构和表皮生长因子受体（EGFR）网络的功能。映射> 6000 PPI显示该网络在表达KRASG13D（mtKRAS）转化水平的细胞中广泛重排。驱动PPIN重新布线的因素是多因素的，包括蛋白质表达和磷酸化的变化。数学建模还表明，低亲和力和高亲和力KRAS相互作用子的结合动力学有助于重新布线。PPIN重新接线会大大改变蛋白质复合物的组成，信号流，转录调控和细胞表型。这些变化已通过针对性的全局实验分析得到验证。重要的是，在最广泛重新连接的PPIN节点中的遗传改变在CRC中经常发生，并且预后不良的患者预后。