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

Kennedy, S. A. et al. (2020) Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D. Nature Communications, 11, 499. (doi: 10.1038/s41467-019-14224-9) (PMID:31980649) (PMCID:PMC6981206)

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.

• Item Type: Articles
• Additional Information: 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. D.J.L. is supported by EMBL Australia. 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. MU and KB are supported by the Tistou & Charlotte Kerstan Stiftung. We thank Prof M. Uhlen for discussions and critical review of the HKE3 and HCT116 genome analysis. PRIMESDB (primesdb.eu) is supported by use of the NeCTAR Research Cloud and by eResearch SA. The NeCTAR Research Cloud is a collaborative Australian research platform supported by the National Collaborative Research Infrastructure Strategy.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cammareri, Dr Patrizia and Sansom, Professor Owen
• Authors: Kennedy, S. A., Jarboui, M.-A., Srihari, S., Raso, C., Bryan, K., Dernayka, L., Charitou, T., Bernal-Llinares, M., Herrera-Montavez, C., Krstic, A., Matallanas, D., Kotlyar, M., Jurisica, I., Curak, J., Wong, V., Stagljar, I., LeBihan, T., Imrie, L., Pillai, P., Lynn, M. A., Fasterius, E., Al-Khalili Szigyarto, C., Breen, J., Kiel, C., Serrano, L., Rauch, N., Rukhlenko, O., Kholodenko, B. N., Iglesias-Martinez, L. F., Ryan, C. J., Pilkington, R., Cammareri, P., Sansom, O., Shave, S., Auer, M., Horn, N., Klose, F., Ueffing, M., Boldt, K., Lynn, D. J., and Kolch, W.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Nature Communications 11: 499
• Publisher Policy: Reproduced under a Creative Commons License