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Nat Commun. 2020 Jan 24;11(1):499. doi: 10.1038/s41467-019-14224-9.

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

Author information

1
Systems Biology Ireland, University College Dublin, Dublin, Ireland.
2
Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
3
Werner Siemens Imaging Center, University of Tübingen, Tübingen, Germany.
4
EMBL Australia Group, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia.
5
QIMR-Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
6
Krembil Research Institute, University Health Network, Toronto, Canada.
7
Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, Canada.
8
Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovak Republic.
9
Donnelly Centre, University of Toronto, Toronto, Canada.
10
Department of Biochemistry, University of Toronto, Toronto, Canada.
11
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
12
Mediterranean Institute for Life Sciences, Split, Croatia.
13
Synthetic and Systems Biology, University of Edinburgh, Edinburgh, UK.
14
School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden.
15
Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden.
16
School of Biological Sciences, University of Adelaide Bioinformatics Hub, Adelaide, SA, Australia.
17
Computational & Systems Biology Program, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
18
Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain.
19
Conway Institute, University College Dublin, Dublin, Ireland.
20
Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
21
School of Computer Science, University College Dublin, Dublin, Ireland.
22
Cancer Research UK Beatson Institute, Glasgow, UK.
23
Institute of Cancer Studies, Glasgow University, Glasgow, UK.
24
School of Biological Sciences and School of Biomedical Sciences, University of Edinburgh, Edinburgh, UK.
25
Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany. karsten.boldt@uni-tuebingen.de.
26
EMBL Australia Group, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia. david.lynn@sahmri.com.
27
College of Medicine and Public Health, Flinders University, Bedford Park, SA, 5042, Australia. david.lynn@sahmri.com.
28
Systems Biology Ireland, University College Dublin, Dublin, Ireland. walter.kolch@ucd.ie.
29
Conway Institute, University College Dublin, Dublin, Ireland. walter.kolch@ucd.ie.
30
School of Medicine, University College Dublin, Dublin, Ireland. walter.kolch@ucd.ie.

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.

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