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Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D

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dc.contributor.author Kennedy, Susan A.
dc.contributor.author Kiel, Christina
dc.contributor.author Serrano Pubull, Luis, 1982-
dc.contributor.author Kolch, Walter
dc.date.accessioned 2020-04-21T10:03:16Z
dc.date.available 2020-04-21T10:03:16Z
dc.date.issued 2020
dc.identifier.citation Kennedy SA, Jarboui MA, Srihari S, Raso C, Bryan K, Dernayka L et al. Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D. Nat Commun. 2020 Jan 24; 11(1): 499. DOI: 10.1038/s41467-019-14224-9
dc.identifier.issn 2041-1723
dc.identifier.uri http://hdl.handle.net/10230/44294
dc.description.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.
dc.description.sponsorship This work was supported by European Union FP7 Grant No. 278568 “PRIMES” and Science Foundation Ireland Investigator Program Grant 14/IA/2395 to W.K. B.K. is supported by SmartNanoTox (Grant no. 686098), NanoCommons (Grant no. 731032), O.R. by MSCA-IF-2016 SAMNets (Grant no. 750688). D.M. is supported by Science Foundation Ireland Career Development award 15-CDA-3495. I.J. is supported by the Canada Research Chair Program (CRC #225404), Krembil Foundation, Ontario Research Fund (GL2-01-030 and #34876), Natural Sciences Research Council (NSERC #203475), Canada Foundation for Innovation (CFI #225404, #30865), and IBM. O.S. is supported by ERC investigator Award ColonCan 311301 and CRUK. I.S. is supported by the Canadian Cancer Society Research Institute (#703889), Genome Canada via Ontario Genomics (#9427 & #9428), Ontario Research fund (ORF/ DIG-501411 & RE08-009), Consortium Québécois sur la Découverte du Médicament (CQDM Quantum Leap) & Brain Canada (Quantum Leap), and CQDM Explore and OCE (#23929). T.C. was supported by a Teagasc Walsh Fellowship
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Nature Research
dc.rights © Susan A. Kennedy et al. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.other Cèl·lules -- Transformació
dc.subject.other Còlon -- Càncer
dc.subject.other Mutació (Biologia)
dc.subject.other Proteïnes
dc.title Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1038/s41467-019-14224-9
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/278568
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/311301
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/731032
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/750688
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/686098
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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