Capuani2015 - Binding of Cbl and Grb2 to EGFR (Early Activation Model - EAM)

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  • Quantitative analysis reveals how EGFR activation and downregulation are coupled in normal but not in cancer cells.
  • Capuani F, Conte A, Argenzio E, Marchetti L, Priami C, Polo S, Di Fiore PP, Sigismund S, Ciliberto A
  • Nature communications , 8/ 2015 , Volume 6 , pages: 7999
  • IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, Milan 20139, Italy.
  • 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.
Fabrizio Capuani

Metadata information

BioModels Database MODEL1505190000
BioModels Database BIOMD0000000595
PubMed 26264748
Taxonomy Homo sapiens
Human Disease Ontology cancer
Brenda Tissue Ontology HeLa cell
Curation status
  • Model originally submitted by : Fabrizio Capuani
  • Submitted: 19-May-2015 13:47:02
  • Last Modified: 19-Apr-2016 22:55:15
  • Version: 2 public model Download this version
    • Submitted on: 19-Apr-2016 22:55:15
    • Submitted by: Fabrizio Capuani
    • With comment: Current version of Capuani2015 - Binding of Cbl and Grb2 to EGFR (Early Activation Model - EAM)
  • Version: 1 public model Download this version
    • Submitted on: 19-May-2015 13:47:02
    • Submitted by: Fabrizio Capuani
    • With comment: Original import of Early Activation Model
Curator's comment:
(added: 11 Mar 2016, 09:15:20, updated: 11 Mar 2016, 09:15:20)
Figure 6b in the paper. Parameter scan over EGF (L in model) and plot the values of UbNorm and TyrNorm after 120 seconds of simulation. The model units for EGF (L) are nM (nano Molar), while to compare to experiments we converted them in ng/ml (the conversion factor is 0,17, i.e. 17 nM = 100 ng/ml).