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

Susan A. Kennedy, Mohamed-Ali Jarboui, Sriganesh Srihari, Cinzia Raso, Kenneth Bryan, Layal Dernayka, Theodosia Charitou, Manuel Bernal-Llinares, Carlos Herrera-Montavez, Aleksandar Krstic, David Matallanas, Max Kotlyar, Igor Jurisica, Jasna Curak, Victoria Wong, Igor Stagljar, Thierry LeBihan, Lisa Imrie, Priyanka Pillai, Miriam A. Lynn, Erik Fasterius, Cristina Al-Khalili Szigyarto, James Breen, Christina Kiel, Luis Serrano, Nora Rauch, Oleksii Rukhlenko, Boris N. Kholodenko, Luis F. Iglesias-Martinez, Colm J. Ryan, Ruth Pilkington, Patrizia Cammareri, Owen Sansom, Steven Shave, Manfred Auer, Nicola Horn, Franziska Klose, Marius Ueffing, Karsten Boldt (), David J. Lynn () and Walter Kolch ()
Additional contact information
Susan A. Kennedy: University College Dublin
Mohamed-Ali Jarboui: University of Tübingen
Sriganesh Srihari: South Australian Health and Medical Research Institute
Cinzia Raso: University College Dublin
Kenneth Bryan: South Australian Health and Medical Research Institute
Layal Dernayka: University of Tübingen
Theodosia Charitou: University College Dublin
Manuel Bernal-Llinares: South Australian Health and Medical Research Institute
Carlos Herrera-Montavez: University College Dublin
Aleksandar Krstic: University College Dublin
David Matallanas: University College Dublin
Max Kotlyar: University Health Network
Igor Jurisica: University Health Network
Jasna Curak: University of Toronto
Victoria Wong: University of Toronto
Igor Stagljar: University of Toronto
Thierry LeBihan: University of Edinburgh
Lisa Imrie: University of Edinburgh
Priyanka Pillai: South Australian Health and Medical Research Institute
Miriam A. Lynn: South Australian Health and Medical Research Institute
Erik Fasterius: KTH Royal Institute of Technology
Cristina Al-Khalili Szigyarto: KTH Royal Institute of Technology
James Breen: University of Adelaide Bioinformatics Hub
Christina Kiel: University College Dublin
Luis Serrano: Barcelona Institute of Science and Technology
Nora Rauch: University College Dublin
Oleksii Rukhlenko: University College Dublin
Boris N. Kholodenko: University College Dublin
Luis F. Iglesias-Martinez: University College Dublin
Colm J. Ryan: University College Dublin
Ruth Pilkington: University College Dublin
Patrizia Cammareri: Cancer Research UK Beatson Institute
Owen Sansom: Cancer Research UK Beatson Institute
Steven Shave: University of Edinburgh
Manfred Auer: University of Edinburgh
Nicola Horn: University of Tübingen
Franziska Klose: University of Tübingen
Marius Ueffing: University of Tübingen
Karsten Boldt: University of Tübingen
David J. Lynn: South Australian Health and Medical Research Institute
Walter Kolch: University College Dublin

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14224-9

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