An Integrated Global Analysis of Compartmentalized HRAS Signaling

Tapesh Santra, Ana Herrero, Javier Rodriguez, Alex von Kriegsheim, Luis F. Iglesias-Martinez, Thomas Schwarzl, Des Higgins, Thin-Thin Aye, Albert J.R. Heck, Fernando Calvo, Lorena Agudo-Ibáñez, Piero Crespo, David Matallanas, Walter Kolch

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)3100-3115.e7
Number of pages23
JournalCell Reports
Volume26
Issue number11
DOIs
Publication statusPublished - 12 Mar 2019

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