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

Author

Listed:
  • Susan A. Kennedy

    (University College Dublin)

  • Mohamed-Ali Jarboui

    (University of Tübingen
    University of Tübingen)

  • Sriganesh Srihari

    (South Australian Health and Medical Research Institute
    QIMR-Berghofer 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
    South Australian Health and Medical Research Institute)

  • 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
    University of Toronto
    Slovak Academy of Sciences)

  • Jasna Curak

    (University of Toronto
    University of Toronto
    University of Toronto)

  • Victoria Wong

    (University of Toronto
    University of Toronto
    University of Toronto)

  • Igor Stagljar

    (University of Toronto
    University of Toronto
    University of Toronto
    Mediterranean Institute for Life Sciences)

  • 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
    KTH Royal Institute of Technology)

  • James Breen

    (University of Adelaide Bioinformatics Hub
    South Australian Health and Medical Research Institute)

  • Christina Kiel

    (University College Dublin
    Barcelona Institute of Science and Technology
    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
    University College Dublin
    Yale University School of Medicine)

  • Luis F. Iglesias-Martinez

    (University College Dublin)

  • Colm J. Ryan

    (University College Dublin
    University College Dublin)

  • Ruth Pilkington

    (University College Dublin)

  • Patrizia Cammareri

    (Cancer Research UK Beatson Institute)

  • Owen Sansom

    (Cancer Research UK Beatson Institute
    Glasgow University)

  • 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
    Flinders University)

  • Walter Kolch

    (University College Dublin
    University College Dublin
    University College Dublin)

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.

Suggested Citation

  • Susan A. Kennedy & Mohamed-Ali Jarboui & Sriganesh Srihari & Cinzia Raso & Kenneth Bryan & Layal Dernayka & Theodosia Charitou & Manuel Bernal-Llinares & Carlos Herrera-Montavez & Aleksandar Krstic & , 2020. "Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14224-9
    DOI: 10.1038/s41467-019-14224-9
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