An Integrated Global Analysis of Compartmentalized HRAS Signaling

Abstract

Summary: 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. : Santra et al. develop MiNETi (Mixed Network Integration) to integrate multi-omics data. Applying MiNETi to analyze the interactome, phosphoproteome, and transcriptome regulated by HRAS signaling from different subcellular compartments shows that HRAS controls phosphorylation-dependent signaling mainly from the cell membrane but regulates a large number of genes from endomembranes. Keywords: RAS, subcellular compartmentalization, signal transduction data integration, network biology, proteomics, transcriptomics, cell migration, TP53, apoptosis