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

View the 2016-09 Model of the Month entry for this model
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Model Identifier
BIOMD0000000594
Short description
Format
SBML (L2V4)
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.
Contributors
Fabrizio Capuani

Metadata information

is
BioModels Database MODEL1505190001
BioModels Database BIOMD0000000594
isDescribedBy
PubMed 26264748
hasTaxon
Taxonomy Homo sapiens
hasProperty
Human Disease Ontology cancer
occursIn
Brenda Tissue Ontology HeLa cell

Curation status
Curated

Tags
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_urn.xml Auto-generated SBML file with URNs 137.17 KB Preview | Download
BIOMD0000000594.m Auto-generated Octave file 30.09 KB Preview | Download
BIOMD0000000594.xpp Auto-generated XPP file 23.83 KB Preview | Download
BIOMD0000000594.sci Auto-generated Scilab file 16.61 KB Preview | Download
BIOMD0000000594.svg Auto-generated Reaction graph (SVG) 378.01 KB Preview | Download
BIOMD0000000594-biopax3.owl Auto-generated BioPAX (Level 3) 272.50 KB Preview | Download
BIOMD0000000594-biopax2.owl Auto-generated BioPAX (Level 2) 150.29 KB Preview | Download
BIOMD0000000594.png Auto-generated Reaction graph (PNG) 6.61 MB Preview | Download
BIOMD0000000594.vcml Auto-generated VCML file 158.52 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
Revisions
  • 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
Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
TyrNorm 0.0146119024667186 mol
EGFR 00UU

Epidermal growth factor receptor
0.833 mol
EGFR 10UU 0.0 mol
EGFR 10CU 0.0 mol
EGFR 10LU 0.0 mol
EGFR 01UG 0.0 mol
Reactions
Reactions Rate Parameters
PYMax = 2.279493223
(EGFR_10UU) => (EGFR_00UU)

([EGFR_10UU]) => ([Epidermal growth factor receptor])
kptp*EGFR_10UU

kptp*[EGFR_10UU]
kptp = 0.016
(EGFR_00UU) => (EGFR_10UU)

([Epidermal growth factor receptor]) => ([EGFR_10UU])
kkin*EGFR_00UU

kkin*[Epidermal growth factor receptor]
kkin = NaN
(EGFR_00UU) => (EGFR_01UU)

([Epidermal growth factor receptor]) => ([EGFR_01UU])
2*kkin68*EGFR_00UU

2*kkin68*[Epidermal growth factor receptor]
kkin68 = NaN
(EGFR_11UU) => (EGFR_10UU)

([EGFR_11UU]) => ([EGFR_10UU])
kptp68*EGFR_11UU

kptp68*[EGFR_11UU]
kptp68 = NaN
(EGFR_10UU) => (EGFR_11UU)

([EGFR_10UU]) => ([EGFR_11UU])
2*kkin68*EGFR_10UU

2*kkin68*[EGFR_10UU]
kkin68 = NaN
(EGFR_10CU) => (Cbl + EGFR_10UU)

([EGFR_10CU]) => ([E3 ubiquitin-protein ligase CBL] + [EGFR_10UU])
ku45*EGFR_10CU

ku45*[EGFR_10CU]
ku45 = 0.001011
(EGFR_10LU) => (EGFR_11LU)

([EGFR_10LU]) => ([EGFR_11LU])
2*kkin68*EGFR_10LU

2*kkin68*[EGFR_10LU]
kkin68 = NaN
(EGFR_10LU) => (CG + EGFR_10UU)

([EGFR_10LU]) => ([E3 ubiquitin-protein ligase CBL; Growth factor receptor-bound protein 2] + [EGFR_10UU])
ku45*EGFR_10LU

ku45*[EGFR_10LU]
ku45 = 0.001011
(EGFR_10LU) => (Grb2 + EGFR_10CU)

([EGFR_10LU]) => ([Growth factor receptor-bound protein 2] + [EGFR_10CU])
kucg*EGFR_10LU

kucg*[EGFR_10LU]
kucg = 0.309271
(EGFR_11UG) => (EGFR_01UG)

([EGFR_11UG]) => ([EGFR_01UG])
kptp*EGFR_11UG

kptp*[EGFR_11UG]
kptp = 0.016
(EGFR_01UG) => (EGFR_02UG)

([EGFR_01UG]) => ([EGFR_02UG])
kkin68*EGFR_01UG

kkin68*[EGFR_01UG]
kkin68 = NaN
(EGFR_01UG) => (Grb2 + EGFR_01UU)

([EGFR_01UG]) => ([Growth factor receptor-bound protein 2] + [EGFR_01UU])
ku68*EGFR_01UG

ku68*[EGFR_01UG]
ku68 = NaN
(EGFR_01UL) => (Cbl + EGFR_01UG)

([EGFR_01UL]) => ([E3 ubiquitin-protein ligase CBL] + [EGFR_01UG])
kucg*EGFR_01UL

kucg*[EGFR_01UL]
kucg = 0.309271
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).