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

Fabrizio Capuani, Alexia Conte, Elisabetta Argenzio, Luca Marchetti, Corrado Priami, Simona Polo, Pier Paolo Di Fiore, Sara Sigismund, Andrea Ciliberto

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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.

Original languageEnglish
Article number7999
JournalNature Communications
Volume6
DOIs
Publication statusPublished - Aug 12 2015

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Capuani, F., Conte, A., Argenzio, E., Marchetti, L., Priami, C., Polo, S., Di Fiore, P. P., Sigismund, S., & Ciliberto, A. (2015). Quantitative analysis reveals how EGFR activation and downregulation are coupled in normal but not in cancer cells. Nature Communications, 6, [7999]. https://doi.org/10.1038/ncomms8999