Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS G13D

Title: Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS G13D
Authors: Kennedy, Susan A.Jarboui, Mohamed-AliSrihari, SriganeshRaso, CinziaCharitou, TheodosiaHerrera-Montavez, CarlosKrstic, AleksandarMatallanas, DavidKiel, ChristinaRauch, NoraRukhlenko, Oleksii S.Kholodenko, Boris N.Iglesias-Martinez, Luis F.Ryan, Colm J.Pilkington, RuthKolch, Walteret al.
Permanent link: http://hdl.handle.net/10197/11873
Date: 24-Jan-2020
Online since: 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.
Funding Details: European Commission Horizon 2020
European Commission - Seventh Framework Programme (FP7)
European Research Council
Science Foundation Ireland
Funding Details: Canada Research Chair Program
Krembil Foundation
Ontario Research Fund
Natural Sciences Research Council
Canada Foundation for Innovation
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
Tistou & Charlotte Kerstan Stiftung
Type of material: Journal Article
Publisher: Springer
Journal: Nature Communications
Volume: 11
Copyright (published version): 2020 the Authors
Keywords: Colorectal neoplasmsNeoplastic cell transformationPrognosisSurvival analysisPhosphorylationMutationProto-oncogene proteins p21(ras)bcl-Associated death proteinProtein interaction mapsErbB receptors
Language: en
Status of Item: Peer reviewed
ISSN: 2041-1723
This item is made available under a Creative Commons License: https://creativecommons.org/licenses/by/3.0/ie/
Appears in Collections:Conway Institute Research Collection
Computer Science Research Collection
SBI Research Collection
Medicine Research Collection

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