Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.
Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland; Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Belfield, Ireland; School of Medicine and Medical Science, University College Dublin, Belfield, Ireland.
Cell Rep. 2019 Mar 12;26(11):3100-3115.e7. doi: 10.1016/j.celrep.2019.02.038.
Modern omics technologies allow us to obtain global information on different types of biological networks. However, integrating these different types of analyses into a coherent framework for a comprehensive biological interpretation remains challenging. Here, we present a conceptual framework that integrates protein interaction, phosphoproteomics, and transcriptomics data. Applying this method to analyze HRAS signaling from different subcellular compartments shows that spatially defined networks contribute specific functions to HRAS signaling. Changes in HRAS protein interactions at different sites lead to different kinase activation patterns that differentially regulate gene transcription. HRAS-mediated signaling is the strongest from the cell membrane, but it regulates the largest number of genes from the endoplasmic reticulum. The integrated networks provide a topologically and functionally resolved view of HRAS signaling. They reveal distinct HRAS functions including the control of cell migration from the endoplasmic reticulum and TP53-dependent cell survival when signaling from the Golgi apparatus.
现代组学技术使我们能够获得不同类型生物网络的全局信息。然而，将这些不同类型的分析整合到一个连贯的框架中进行全面的生物学解释仍然具有挑战性。在这里，我们提出了一个概念框架，将蛋白质相互作用、磷酸化蛋白质组学和转录组学数据整合在一起。将这种方法应用于分析来自不同亚细胞区室的 HRAS 信号，表明空间定义的网络为 HRAS 信号提供特定的功能。不同部位的 HRAS 蛋白相互作用的变化导致不同的激酶激活模式，从而差异调节基因转录。HRAS 介导的信号从细胞膜最强，但它从内质网调节最多数量的基因。整合的网络提供了 HRAS 信号的拓扑和功能解析视图。它们揭示了不同的 HRAS 功能，包括从内质网控制细胞迁移和从高尔基体发出信号时 TP53 依赖性细胞存活。
