Capuani2015 - Binding of Cbl and Gbr2 to EGFR (Multisite Phosphorylation Model - MPM)

View the 2016-09 Model of the Month entry for this model

Model Identifier
BIOMD0000000594
Short description
Fabrizio Capuani, Alexia Conte, Elisabetta Argenzio, Luca Marchetti, Corrado Priami, Simona Polo, Pier Paolo Di Fiore, Sara Sigismund & Andrea Ciliberto. Quantitative analysis reveals how EGFR activation and downregulation are coupled in normal but not in cancer cells. Nature Communications 6 (2015).

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.
Format
SBML (L2V4)
Related Publication
  • Quantitative analysis reveals how EGFR activation and downregulation are coupled in normal but not in cancer cells. Click here to expand
  • Fabrizio Capuani, Alexia Conte, Elisabetta Argenzio, Luca Marchetti, Corrado Priami, Simona Polo, Pier Paolo Di Fiore, Sara Sigismund, Andrea Ciliberto
  • Nature communications , 8/ 2015 , Volume 6 , pages: 7999 , PubMed ID: 26264748
  • 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.
Contributors
Submitter of the first revision: Fabrizio Capuani
Submitter of this revision: Lucian Smith
Curator: Lucian Smith
Modeller: Fabrizio Capuani

Metadata information

is (2 statements)
BioModels Database BIOMD0000000594
BioModels Database MODEL1505190001

isDescribedBy (1 statement)
PubMed 26264748

hasTaxon (1 statement)
Taxonomy Homo sapiens

isVersionOf (1 statement)
hasProperty (2 statements)
Human Disease Ontology cancer
Mathematical Modelling Ontology Ordinary differential equation model

occursIn (1 statement)
Brenda Tissue Ontology HeLa cell

Curation status
Curated
Modelling approach(es)
ordinary differential equation model

Connected external resources