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Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS G13D
Author(s)
Date Issued
2020-01-24
Date Available
2021-01-25T07:46:42Z
Abstract
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.
Sponsorship
European Commission Horizon 2020
European Commission - Seventh Framework Programme (FP7)
European Research Council
Science Foundation Ireland
Teagasc
Other Sponsorship
Canada Research Chair Program
Krembil Foundation
Ontario Research Fund
Natural Sciences Research Council
Canada Foundation for Innovation
IBM
EMBL Australia
Canadian Cancer Society Research Institute
Genome Canada via Ontario Genomics
Ontario Research fund
Consortium Québécois sur la Découverte du Médicament
Brain Canada
CQDM Explore
OCE
Tistou & Charlotte Kerstan Stiftung
Type of Material
Journal Article
Publisher
Springer
Journal
Nature Communications
Volume
11
Copyright (Published Version)
2020 the Authors
Language
English
Status of Item
Peer reviewed
ISSN
2041-1723
This item is made available under a Creative Commons License
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Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D.pdf
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3.78 MB
Format
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