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

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Related Publication
  • 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 , 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.
Fabrizio Capuani

Metadata information

BioModels Database MODEL1505190001
BioModels Database BIOMD0000000594
PubMed 26264748
Taxonomy Homo sapiens
Human Disease Ontology cancer
Brenda Tissue Ontology HeLa cell

Curation status

Name Description Size Actions

Model files

BIOMD0000000594_url.xml SBML L2V4 representation of Capuani2015 - Binding of Cbl and Gbr2 to EGFR (Multisite Phosphorylation Model - MPM) 137.36 KB Preview | Download

Additional files

BIOMD0000000594.vcml Auto-generated VCML file 158.52 KB Preview | Download
BIOMD0000000594-biopax2.owl Auto-generated BioPAX (Level 2) 150.29 KB Preview | Download
BIOMD0000000594-biopax3.owl Auto-generated BioPAX (Level 3) 272.50 KB Preview | Download
BIOMD0000000594.xpp Auto-generated XPP file 23.83 KB Preview | Download
BIOMD0000000594.png Auto-generated Reaction graph (PNG) 6.61 MB Preview | Download
BIOMD0000000594_urn.xml Auto-generated SBML file with URNs 137.17 KB Preview | Download
BIOMD0000000594.sci Auto-generated Scilab file 16.61 KB Preview | Download
BIOMD0000000594.m Auto-generated Octave file 30.09 KB Preview | Download
BIOMD0000000594.svg Auto-generated Reaction graph (SVG) 378.01 KB Preview | Download
BIOMD0000000594.pdf Auto-generated PDF file 735.25 KB Preview | Download

  • Model originally submitted by : Fabrizio Capuani
  • Submitted: 19-May-2015 20:46:44
  • Last Modified: 19-Apr-2016 22:55:48
  • Version: 2 public model Download this version
    • Submitted on: 19-Apr-2016 22:55:48
    • Submitted by: Fabrizio Capuani
    • With comment: Current version of Capuani2015 - Binding of Cbl and Gbr2 to EGFR (Multisite Phosphorylation Model - MPM)
  • Version: 1 public model Download this version
    • Submitted on: 19-May-2015 20:46:44
    • Submitted by: Fabrizio Capuani
    • With comment: Original import of Multisite Phosphorylation Model plus Binding

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

: Variable used inside SBML models

Species Initial Concentration/Amount
EGFR 11CU 0.0 mol
EGFR 11LU 0.0 mol
EGFR 12CU 0.0 mol
EGFR 12LU 0.0 mol
EGFR 12UG 0.0 mol
Reactions Rate Parameters
EGFR_11CU => EGFR_12CU; EGFR_11CU kkin68*EGFR_11CU kkin68 = NaN
EGFR_11LU => Grb2 + EGFR_11CU; EGFR_11LU kucg*EGFR_11LU kucg = 0.309271
Grb2 + EGFR_11CU => EGFR_11CG; Grb2, EGFR_11CU kb68*Grb2*EGFR_11CU kb68 = NaN
EGFR_10LU => EGFR_11LU; EGFR_10LU 2*kkin68*EGFR_10LU kkin68 = NaN
EGFR_11LU => EGFR_12LU; EGFR_11LU kkin68*EGFR_11LU kkin68 = NaN
EGFR_12CU => Cbl + EGFR_12UU; EGFR_12CU ku45*EGFR_12CU ku45 = 0.001011
Grb2 + EGFR_12CU => EGFR_12LU; Grb2, EGFR_12CU kbcg*Grb2*EGFR_12CU kbcg = NaN
EGFR_12LU => Grb2 + EGFR_12CU; EGFR_12LU kucg*EGFR_12LU kucg = 0.309271
EGFR_12CG => Grb2 + EGFR_12CU; EGFR_12CG ku68*EGFR_12CG ku68 = NaN
EGFR_12LU => EGFR_11LU; EGFR_12LU 2*kptp68*EGFR_12LU kptp68 = NaN
Grb2 + EGFR_12LU => EGFR_12LG; Grb2, EGFR_12LU 2*kb68*Grb2*EGFR_12LU kb68 = NaN
EGFR_12UG => EGFR_02UG; EGFR_12UG kptp*EGFR_12UG kptp = 0.016
EGFR_12UG => EGFR_11UG; EGFR_12UG kptp68*EGFR_12UG kptp68 = NaN
Curator's comment:
(added: 11 Mar 2016, 09:07:21, updated: 11 Mar 2016, 09:07:21)
Figure 4a (left) in the paper. Parameter scan over EGF (lTot in model) and plot the values of UbNorm and TyrNorm after 120 seconds of simulation. The model units for EGF (lTot) 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).