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Quantitative analysis reveals how EGFR activation and downregulation are coupled in normal but not in cancer cells

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  • Fabrizio Capuani

    (IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
    Present address: Dipartimento di Fisica, Sapienza Università di Roma, Piazzale A. Moro 5, 00185, Rome, Italy)

  • Alexia Conte

    (IFOM, Fondazione Istituto FIRC di Oncologia Molecolare)

  • Elisabetta Argenzio

    (IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
    Present address: The Netherlands Cancer Institute, Amsterdam, The Netherlands)

  • Luca Marchetti

    (The Microsoft Research—University of Trento Centre for Computational and Systems Biology (COSBI))

  • Corrado Priami

    (The Microsoft Research—University of Trento Centre for Computational and Systems Biology (COSBI)
    Università di Trento)

  • Simona Polo

    (IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
    Università degli Studi di Milano)

  • Pier Paolo Di Fiore

    (IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
    Università degli Studi di Milano
    Istituto Europeo di Oncologia)

  • Sara Sigismund

    (IFOM, Fondazione Istituto FIRC di Oncologia Molecolare)

  • Andrea Ciliberto

    (IFOM, Fondazione Istituto FIRC di Oncologia Molecolare)

Abstract

Ubiquitination of the epidermal growth factor receptor (EGFR) that occurs when Cbl and Grb2 bind to three phosphotyrosine residues (pY1045, pY1068 and pY1086) on the receptor displays a sharp threshold effect as a function of EGF concentration. Here we use a simple modelling approach together with experiments to show that the establishment of the threshold requires both the multiplicity of binding sites and cooperative binding of Cbl and Grb2 to the EGFR. While the threshold is remarkably robust, a more sophisticated model predicted that it could be modulated as a function of EGFR levels on the cell surface. We confirmed experimentally that the system has evolved to perform optimally at physiological levels of EGFR. As a consequence, this system displays an intrinsic weakness that causes—at the supraphysiological levels of receptor and/or ligand associated with cancer—uncoupling of the mechanisms leading to signalling through phosphorylation and attenuation through ubiquitination.

Suggested Citation

  • Fabrizio Capuani & Alexia Conte & Elisabetta Argenzio & Luca Marchetti & Corrado Priami & Simona Polo & Pier Paolo Di Fiore & Sara Sigismund & Andrea Ciliberto, 2015. "Quantitative analysis reveals how EGFR activation and downregulation are coupled in normal but not in cancer cells," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8999
    DOI: 10.1038/ncomms8999
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    Cited by:

    1. Cemal Erdem & Arnab Mutsuddy & Ethan M. Bensman & William B. Dodd & Michael M. Saint-Antoine & Mehdi Bouhaddou & Robert C. Blake & Sean M. Gross & Laura M. Heiser & F. Alex Feltus & Marc R. Birtwistle, 2022. "A scalable, open-source implementation of a large-scale mechanistic model for single cell proliferation and death signaling," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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