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BIOMD0000000399 - Jenkinson2011_EGF_MAPK

 

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Reference Publication
Publication ID: 21548948
Jenkinson G, Goutsias J.
Thermodynamically consistent model calibration in chemical kinetics.
BMC Syst Biol 2011; 5: 64
Whitaker Biomedical Engineering Institute, The Johns Hopkins University, Baltimore, MD 21218, USA. goutsias@jhu.edu  [more]
Model
Original Model: BIOMD0000000399.xml.origin
Submitter: Garrett Jenkinson
Submission ID: MODEL1105060003
Submission Date: 06 May 2011 19:16:29 UTC
Last Modification Date: 12 Feb 2014 11:27:00 UTC
Creation Date: 03 Nov 2011 14:33:48 UTC
Encoders:  Vijayalakshmi Chelliah
   Garrett Jenkinson
set #1
bqbiol:isVersionOf Reactome REACT_9417.3
Gene Ontology epidermal growth factor receptor signaling pathway
bqbiol:occursIn Taxonomy Homo sapiens
bqbiol:hasVersion Gene Ontology MAPK cascade
Gene Ontology Ras protein signal transduction
set #2
bqmodel:isDerivedFrom BioModels Database Schoeberl2002_EGF_MAPK
Notes

This is a model described in the article:
Thermodynamically Consistent Model Calibration in Chemical Kinetics.
Garrett Jenkinson and John Goutsias, BMC Systems Biology 2011 May 6;5(1):64.; PMID: 21548948 .

ABSTRACT:
BACKGROUND:
The dynamics of biochemical reaction systems are constrained by the fundamental laws of thermodynamics, which impose well-defined relationships among the reaction rate constants characterizing these systems. Constructing biochemical reaction systems from experimental observations often leads to parameter values that do not satisfy the necessary thermodynamic constraints. This can result in models that are not physically realizable and may lead to inaccurate, or even erroneous, descriptions of cellular function.
RESULTS:
We introduce a thermodynamically consistent model calibration (TCMC) method that can be effectively used to provide thermodynamically feasible values for the parameters of an open biochemical reaction system. The proposed method formulates the model calibration problem as a constrained optimization problem that takes thermodynamic constraints (and, if desired, additional non-thermodynamic constraints) into account. By calculating thermodynamically feasible values for the kinetic parameters of a well-known model of the EGF/ERK signaling cascade, we demonstrate the qualitative and quantitative significance of imposing thermodynamic constraints on these parameters and the effectiveness of our method for accomplishing this important task. MATLAB software, using the Systems Biology Toolbox 2.1, can be accessed from www.cis.jhu.edu/~goutsias/CSS lab/software.html. An SBML file containing the thermodynamically feasible EGF/ERK signaling cascade model can be found in the BioModels database.
CONCLUSIONS:
TCMC is a simple and flexible method for obtaining physically plausible values for the kinetic parameters of open biochemical reaction systems. It can be effectively used to recalculate a thermodynamically consistent set of parameter values for existing thermodynamically infeasible biochemical reaction models of cellular function as well as to estimate thermodynamically feasible values for the parameters of new models. Furthermore, TCMC can provide dimensionality reduction, better estimation performance, and lower computational complexity, and can help to alleviate the problem of data overfitting.

This model is a thermodynamically feasible version of a previous model in the BioModels database, BIOMD0000000019 , described in Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors. Schoeberl et al (2002), PMID: 11923843 .
The only difference between the present model and the model listed under BIOMD0000000019 are the values of the parameters.

This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2012 The BioModels.net Team.
For more information see the terms of use .
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Model
Publication ID: 21548948 Submission Date: 06 May 2011 19:16:29 UTC Last Modification Date: 12 Feb 2014 11:27:00 UTC Creation Date: 03 Nov 2011 14:33:48 UTC
Mathematical expressions
Reactions
v1 v2 v3 v4
v5 v6 v7 v8
v9 v10 v11 v12
v13 v14 v15 v16
v17 v18 v19 v20
v21 v22 v23 v24
v25 v26 v27 v28
v29 v30 v31 v32
v33 v34 v35 v36
v37 v38 v39 v40
v41 v42 v43 v44
v45 v46 v47 v48
v49 v50 v51 v52
v53 v54 v55 v56
v57 v58 v59 v60
v61 v62 v63 v64
v65 v66 v67 v68
v69 v70 v71 v72
v73 v74 v75 v76
v77 v78 v79 v80
v81 v82 v83 v84
v85 v86 v87 v88
v89 v90 v91 v92
v93 v94 v95 v96
v97 v98 v99 v100
v101 v102 v103 v104
v105 v106 v107 v108
v109 v110 v111 v112
v113 v114 v115 v116
v117 v118 v119 v120
v121 v122 v123 v124
v125      
Rules
Assignment Rule (variable: t_Ras_GTP) Assignment Rule (variable: t_MEK_PP) Assignment Rule (variable: t_ERK_PP) Assignment Rule (variable: t_Raf*)
Assignment Rule (variable: t_SHC_P_t) Assignment Rule (variable: t_EGF_EGFR*) Assignment Rule (variable: C_internalization) Assignment Rule (variable: k5)
Physical entities
Compartments Species
extracellular volume EGF EGFR  
cytoplasm EGF-EGFR EGF-EGFR^2 EGF-EGFR*^2
EGFRi EGF-EGFR*^2-GAP-Grb2-Prot EGF-EGFRi*^2
Proti EGF-EGFRi EGF-EGFRi^2
Prot GAP EGFi
EGF-EGFRi*^2-GAP EGF-EGFRi*^2-GAP-Grb2 EGF-EGFRi*^2-GAP-Grb2-Sos
EGF-EGFRi*^2-GAP-Grb2-Sos-Ras-GDP EGF-EGFRi*^2-GAP-Grb2-Sos-Ras-GTP Grb2
EGF-EGFR*^2-GAP-Grb2 Sos EGF-EGFR*^2-GAP-Grb2-Sos
Ras-GDP EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GDP Ras-GTP
EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GTP Grb2-Sos Shc
EGF-EGFR*^2-GAP-Shc EGF-EGFR*^2-GAP-Shc* EGF-EGFR*^2-GAP-Shc*-Grb2
EGF-EGFR*^2-GAP-Shc*-Grb2-Sos EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GDP EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GTP
Shc*-Grb2-Sos Shc*-Grb2 Shc*
Raf Raf-Ras-GTP Ras-GTP*
Phosphotase1 Raf* Raf*-P'ase
MEK MEK-Raf* MEK-P
MEK-P-Raf* MEK-PP MEK-PP-P'ase2
Phosphatase2 MEK-P-P'ase2 ERK
ERK-MEK-PP ERK-P ERK-P-MEK-PP
ERK-PP Phosphotase3 ERK-PP-P'ase3
ERK-P-P'ase3 EGF-EGFRi*^2-GAP-Shc EGF-EGFRi*^2-GAP-Shc*
EGF-EGFRi*^2-GAP-Shc*-Grb2 EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos-Ras-GDP
EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos-Ras-GTP Rasi-GTP Rafi-Rasi-GTP
Rasi-GTP* Rafi* Rafi*-P'ase
MEKi-Rafi* MEKi-P MEKi-P-Rafi*
MEKi-PP MEKi-PP-P'ase2i MEKi-P-P'ase2i
ERKi-MEKi-PP ERKi-P ERKi-P-MEKi-PP
ERKi-PP ERKi-PP-P'ase3i ERKi-P-P'ase3i
EGFRideg EGF-EGFRi*^2deg EGF-EGFR*^2-GAP-Grb2-Sos-Prot
EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GDP-Prot EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GTP-Prot EGF-EGFR*^2-GAP-Shc*-Grb2-Prot
EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Prot EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GDP-Prot EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GTP-Prot
t_Raf* t_Ras_GTP t_MEK_PP
t_ERK_PP t_SHC_P_t t_EGF_EGFR*
endosomal volume EGFideg EGF-EGFR*^2-GAP  
Global parameters
k1 kr1 kr2 k2
k3 kr3 k4 kr4
k5 k6 kr6 k7
k8 kr8 k10 kr10
kr11 k11 kr12 k12
k13 k14 kr14 k15
kr16 k16 kr17 k17
kr18 k18 kr19 k19
kr20 k20 k21 kr21
k22 kr22 k23 kr23
k24 kr24 kr25 k25
k28 kr28 k29 kr29
kr32 k32 k33 kr33
k34 kr34 k35 kr35
Vm36 Km36 k37 kr37
k40 kr40 kr41 k41
k42 kr42 k43 kr44
k44 k45 k47 kr48
k48 k49 kr50 k50
k52 kr52 k53 k55
kr56 k56 k57 kr58
k58 k59 k60 k61
C_internalization total_Receptors    
Reactions (125)
 
 v1 [EGF] + [EGFR] ↔ [EGF-EGFR];  
 
 v2 2.0 × [EGF-EGFR] ↔ [EGF-EGFR^2];  
 
 v3 [EGF-EGFR^2] ↔ [EGF-EGFR*^2];  
 
 v4 [EGF-EGFR*^2-GAP-Grb2] + [Prot] ↔ [EGF-EGFR*^2-GAP-Grb2-Prot];  
 
 v5 [EGF-EGFR*^2-GAP-Grb2-Prot] ↔ [EGF-EGFRi*^2-GAP-Grb2] + [Proti];  
 
 v6 [EGFR] ↔ [EGFRi];  
 
 v7 [EGF-EGFR*^2] → [EGF-EGFRi*^2];  
 
 v8 [EGF-EGFR*^2] + [GAP] ↔ [EGF-EGFR*^2-GAP];  
 
 v9 [EGF-EGFR*^2-GAP-Grb2] → [EGF-EGFRi*^2-GAP-Grb2];  
 
 v10 [EGFRi] + [EGFi] ↔ [EGF-EGFRi];  
 
 v11 2.0 × [EGF-EGFRi] ↔ [EGF-EGFRi^2];  
 
 v12 [EGF-EGFRi^2] ↔ [EGF-EGFRi*^2];  
 
 v13  → [EGFR];  
 
 v14 [EGF-EGFRi*^2] + [GAP] ↔ [EGF-EGFRi*^2-GAP];  
 
 v15 [Proti] → [Prot];  
 
 v16 [Grb2] + [EGF-EGFR*^2-GAP] ↔ [EGF-EGFR*^2-GAP-Grb2];  
 
 v17 [Sos] + [EGF-EGFR*^2-GAP-Grb2] ↔ [EGF-EGFR*^2-GAP-Grb2-Sos];  
 
 v18 [Ras-GDP] + [EGF-EGFR*^2-GAP-Grb2-Sos] ↔ [EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GDP];  
 
 v19 [EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GDP] ↔ [Ras-GTP] + [EGF-EGFR*^2-GAP-Grb2-Sos];  
 
 v20 [EGF-EGFR*^2-GAP-Grb2-Sos] + [Ras-GTP*] ↔ [EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GTP];  
 
 v21 [EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GTP] ↔ [EGF-EGFR*^2-GAP-Grb2-Sos] + [Ras-GDP];  
 
 v22 [Shc] + [EGF-EGFR*^2-GAP] ↔ [EGF-EGFR*^2-GAP-Shc];  
 
 v23 [EGF-EGFR*^2-GAP-Shc] ↔ [EGF-EGFR*^2-GAP-Shc*];  
 
 v24 [Grb2] + [EGF-EGFR*^2-GAP-Shc*] ↔ [EGF-EGFR*^2-GAP-Shc*-Grb2];  
 
 v25 [Sos] + [EGF-EGFR*^2-GAP-Shc*-Grb2] ↔ [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos];  
 
 v26 [Ras-GDP] + [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos] ↔ [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GDP];  
 
 v27 [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GDP] ↔ [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos] + [Ras-GTP];  
 
 v28 [Ras-GTP] + [Raf] ↔ [Raf-Ras-GTP];  
 
 v29 [Raf-Ras-GTP] ↔ [Ras-GTP*] + [Raf*];  
 
 v30 [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos] + [Ras-GTP*] ↔ [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GTP];  
 
 v31 [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GTP] ↔ [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos] + [Ras-GDP];  
 
 v32 [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos] ↔ [EGF-EGFR*^2-GAP] + [Shc*-Grb2-Sos];  
 
 v33 [Shc*-Grb2-Sos] ↔ [Shc*] + [Grb2-Sos];  
 
 v34 [EGF-EGFR*^2-GAP-Grb2-Sos] ↔ [EGF-EGFR*^2-GAP] + [Grb2-Sos];  
 
 v35 [Grb2-Sos] ↔ [Sos] + [Grb2];  
 
 v36 [Shc*] → [Shc];  
 
 v37 [EGF-EGFR*^2-GAP-Shc*] ↔ [EGF-EGFR*^2-GAP] + [Shc*];  
 
 v38 [Grb2] + [Shc*] ↔ [Shc*-Grb2];  
 
 v39 [EGF-EGFR*^2-GAP-Shc*-Grb2] ↔ [EGF-EGFR*^2-GAP] + [Shc*-Grb2];  
 
 v40 [Sos] + [Shc*-Grb2] ↔ [Shc*-Grb2-Sos];  
 
 v41 [Grb2-Sos] + [EGF-EGFR*^2-GAP-Shc*] ↔ [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos];  
 
 v42 [Phosphotase1] + [Raf*] ↔ [Raf*-P'ase];  
 
 v43 [Raf*-P'ase] ↔ [Raf] + [Phosphotase1];  
 
 v44 [MEK] + [Raf*] ↔ [MEK-Raf*];  
 
 v45 [MEK-Raf*] ↔ [MEK-P] + [Raf*];  
 
 v46 [MEK-P] + [Raf*] ↔ [MEK-P-Raf*];  
 
 v47 [MEK-P-Raf*] ↔ [MEK-PP] + [Raf*];  
 
 v48 [MEK-PP] + [Phosphatase2] ↔ [MEK-PP-P'ase2];  
 
 v49 [MEK-PP-P'ase2] ↔ [MEK-P] + [Phosphatase2];  
 
 v50 [Phosphatase2] + [MEK-P] ↔ [MEK-P-P'ase2];  
 
 v51 [MEK-P-P'ase2] ↔ [MEK] + [Phosphatase2];  
 
 v52 [ERK] + [MEK-PP] ↔ [ERK-MEK-PP];  
 
 v53 [ERK-MEK-PP] ↔ [MEK-PP] + [ERK-P];  
 
 v54 [MEK-PP] + [ERK-P] ↔ [ERK-P-MEK-PP];  
 
 v55 [ERK-P-MEK-PP] ↔ [ERK-PP] + [MEK-PP];  
 
 v56 [ERK-PP] + [Phosphotase3] ↔ [ERK-PP-P'ase3];  
 
 v57 [ERK-PP-P'ase3] ↔ [ERK-P] + [Phosphotase3];  
 
 v58 [Phosphotase3] + [ERK-P] ↔ [ERK-P-P'ase3];  
 
 v59 [ERK-P-P'ase3] ↔ [ERK] + [Phosphotase3];  
 
 v60 [EGFRi] → [EGFRideg];  
 
 v61 [EGFi] → [EGFideg];  
 
 v62 [EGF-EGFRi*^2] → [EGF-EGFRi*^2deg];  
 
 v63 [EGF-EGFRi*^2-GAP] + [Grb2] ↔ [EGF-EGFRi*^2-GAP-Grb2];  
 
 v64 [Sos] + [EGF-EGFRi*^2-GAP-Grb2] ↔ [EGF-EGFRi*^2-GAP-Grb2-Sos];  
 
 v65 [Ras-GDP] + [EGF-EGFRi*^2-GAP-Grb2-Sos] ↔ [EGF-EGFRi*^2-GAP-Grb2-Sos-Ras-GDP];  
 
 v66 [EGF-EGFRi*^2-GAP-Grb2-Sos-Ras-GDP] ↔ [Rasi-GTP] + [EGF-EGFRi*^2-GAP-Grb2-Sos];  
 
 v67 [Rasi-GTP*] + [EGF-EGFRi*^2-GAP-Grb2-Sos] ↔ [EGF-EGFRi*^2-GAP-Grb2-Sos-Ras-GTP];  
 
 v68 [EGF-EGFRi*^2-GAP-Grb2-Sos-Ras-GTP] ↔ [EGF-EGFRi*^2-GAP-Grb2-Sos] + [Ras-GDP];  
 
 v69 [Shc] + [EGF-EGFRi*^2-GAP] ↔ [EGF-EGFRi*^2-GAP-Shc];  
 
 v70 [EGF-EGFRi*^2-GAP-Shc] ↔ [EGF-EGFRi*^2-GAP-Shc*];  
 
 v71 [Grb2] + [EGF-EGFRi*^2-GAP-Shc*] ↔ [EGF-EGFRi*^2-GAP-Shc*-Grb2];  
 
 v72 [Sos] + [EGF-EGFRi*^2-GAP-Shc*-Grb2] ↔ [EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos];  
 
 v73 [Ras-GDP] + [EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos] ↔ [EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos-Ras-GDP];  
 
 v74 [EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos-Ras-GDP] ↔ [EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos] + [Rasi-GTP];  
 
 v75 [Rasi-GTP] + [Raf] ↔ [Rafi-Rasi-GTP];  
 
 v76 [Rafi-Rasi-GTP] ↔ [Rasi-GTP*] + [Rafi*];  
 
 v77 [Rasi-GTP*] + [EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos] ↔ [EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos-Ras-GTP];  
 
 v78 [EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos-Ras-GTP] ↔ [EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos] + [Ras-GDP];  
 
 v79 [EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos] ↔ [EGF-EGFRi*^2-GAP] + [Shc*-Grb2-Sos];  
 
 v80 [EGF-EGFRi*^2-GAP-Grb2-Sos] ↔ [EGF-EGFRi*^2-GAP] + [Grb2-Sos];  
 
 v81 [EGF-EGFRi*^2-GAP-Shc*] ↔ [EGF-EGFRi*^2-GAP] + [Shc*];  
 
 v82 [EGF-EGFRi*^2-GAP-Shc*-Grb2] ↔ [EGF-EGFRi*^2-GAP] + [Shc*-Grb2];  
 
 v83 [Grb2-Sos] + [EGF-EGFRi*^2-GAP-Shc*] ↔ [EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos];  
 
 v84 [Phosphotase1] + [Rafi*] ↔ [Rafi*-P'ase];  
 
 v85 [Rafi*-P'ase] ↔ [Raf] + [Phosphotase1];  
 
 v86 [MEK] + [Rafi*] ↔ [MEKi-Rafi*];  
 
 v87 [MEKi-Rafi*] ↔ [MEKi-P] + [Rafi*];  
 
 v88 [Rafi*] + [MEKi-P] ↔ [MEKi-P-Rafi*];  
 
 v89 [MEKi-P-Rafi*] ↔ [Rafi*] + [MEKi-PP];  
 
 v90 [MEKi-PP] + [Phosphatase2] ↔ [MEKi-PP-P'ase2i];  
 
 v91 [MEKi-PP-P'ase2i] ↔ [MEKi-P] + [Phosphatase2];  
 
 v92 [Phosphatase2] + [MEKi-P] ↔ [MEKi-P-P'ase2i];  
 
 v93 [MEKi-P-P'ase2i] ↔ [MEK] + [Phosphatase2];  
 
 v94 [ERK] + [MEKi-PP] ↔ [ERKi-MEKi-PP];  
 
 v95 [ERKi-MEKi-PP] ↔ [ERKi-P] + [MEKi-PP];  
 
 v96 [MEKi-PP] + [ERKi-P] ↔ [ERKi-P-MEKi-PP];  
 
 v97 [ERKi-P-MEKi-PP] ↔ [ERKi-PP] + [MEKi-PP];  
 
 v98 [ERKi-PP] + [Phosphotase3] ↔ [ERKi-PP-P'ase3i];  
 
 v99 [ERKi-PP-P'ase3i] ↔ [ERKi-P] + [Phosphotase3];  
 
 v100 [Phosphotase3] + [ERKi-P] ↔ [ERKi-P-P'ase3i];  
 
 v101 [ERKi-P-P'ase3i] ↔ [ERK] + [Phosphotase3];  
 
 v102 [EGF-EGFR*^2-GAP] ↔ [EGF-EGFRi*^2-GAP];  
 
 v103 [EGF-EGFR*^2-GAP-Shc] ↔ [EGF-EGFRi*^2-GAP-Shc];  
 
 v104 [EGF-EGFR*^2-GAP-Shc*] ↔ [EGF-EGFRi*^2-GAP-Shc*];  
 
 v105 [EGF-EGFR*^2-GAP-Grb2-Sos] ↔ [EGF-EGFRi*^2-GAP-Grb2-Sos];  
 
 v106 [EGF-EGFR*^2-GAP-Grb2-Sos] + [Prot] ↔ [EGF-EGFR*^2-GAP-Grb2-Sos-Prot];  
 
 v107 [EGF-EGFR*^2-GAP-Grb2-Sos-Prot] ↔ [Proti] + [EGF-EGFRi*^2-GAP-Grb2-Sos];  
 
 v108 [EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GDP] ↔ [EGF-EGFRi*^2-GAP-Grb2-Sos-Ras-GDP];  
 
 v109 [EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GDP] + [Prot] ↔ [EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GDP-Prot];  
 
 v110 [EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GDP-Prot] ↔ [Proti] + [EGF-EGFRi*^2-GAP-Grb2-Sos-Ras-GDP];  
 
 v111 [EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GTP] ↔ [EGF-EGFRi*^2-GAP-Grb2-Sos-Ras-GTP];  
 
 v112 [EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GTP] + [Prot] ↔ [EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GTP-Prot];  
 
 v113 [EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GTP-Prot] ↔ [Proti] + [EGF-EGFRi*^2-GAP-Grb2-Sos-Ras-GTP];  
 
 v114 [EGF-EGFR*^2-GAP-Shc*-Grb2] ↔ [EGF-EGFRi*^2-GAP-Shc*-Grb2];  
 
 v115 [EGF-EGFR*^2-GAP-Shc*-Grb2] + [Prot] ↔ [EGF-EGFR*^2-GAP-Shc*-Grb2-Prot];  
 
 v116 [EGF-EGFR*^2-GAP-Shc*-Grb2-Prot] ↔ [Proti] + [EGF-EGFRi*^2-GAP-Shc*-Grb2];  
 
 v117 [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos] ↔ [EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos];  
 
 v118 [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos] + [Prot] ↔ [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Prot];  
 
 v119 [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Prot] ↔ [Proti] + [EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos];  
 
 v120 [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GDP] ↔ [EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos-Ras-GDP];  
 
 v121 [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GDP] + [Prot] ↔ [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GDP-Prot];  
 
 v122 [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GDP-Prot] ↔ [Proti] + [EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos-Ras-GDP];  
 
 v123 [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GTP] ↔ [EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos-Ras-GTP];  
 
 v124 [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GTP] + [Prot] ↔ [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GTP-Prot];  
 
 v125 [EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GTP-Prot] ↔ [EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos-Ras-GTP] + [Proti];  
 
Rules (8)
 
 Assignment Rule (name: Ras_GTP) t_Ras_GTP = x42+x28+x70+x69
 
 Assignment Rule (name: MEK_PP) t_MEK_PP = x51+x77
 
 Assignment Rule (name: ERK_PP) t_ERK_PP = x59+x83
 
 Assignment Rule (name: Raf_act) t_Raf* = x45+x46+x48+x50+x72+x73+x74+x76
 
 Assignment Rule (name: SHC_P_t) t_SHC_P_t = x33+x34+x35+x36+x37+x38+x39+x40+x91+x92+x93+x94+x64+x65+x66+x67+x68
 
 Assignment Rule (name: EGF_EGFR_act) t_EGF_EGFR* = x5+x7+x15+x23+x25+x27+x29+x32+x33+x34+x35+x36+x37+x88+x89+x90+x91+x92+x93+x94+x8+x11+x17+x18+x19+x20+x21+x63+x64+x65+x66+x67+x68
 
 Assignment Rule (name: C) C_internalization = RT/(kr1/(k1*x1)+1)
 
 Assignment Rule (name: k5) k5 = piecewise(1.55, C < 3100, 0.2, C > 100000, C*(-1.35E-5)+1.55)
 
 extracellular volume Spatial dimensions: 3.0  Compartment size: 1.0
 
 EGF
Compartment: extracellular volume
Initial amount: 4962.0
 
 EGFR
Compartment: extracellular volume
Initial amount: 50000.0
 
 cytoplasm Spatial dimensions: 3.0  Compartment size: 1.0
 
 EGF-EGFR
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFR^2
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFR*^2
Compartment: cytoplasm
Initial amount: 0.0
 
 EGFRi
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFR*^2-GAP-Grb2-Prot
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFRi*^2
Compartment: cytoplasm
Initial amount: 0.0
 
 Proti
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFRi
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFRi^2
Compartment: cytoplasm
Initial amount: 0.0
 
 Prot
Compartment: cytoplasm
Initial amount: 81000.0
 
 GAP
Compartment: cytoplasm
Initial amount: 12000.0
 
 EGFi
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFRi*^2-GAP
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFRi*^2-GAP-Grb2
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFRi*^2-GAP-Grb2-Sos
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFRi*^2-GAP-Grb2-Sos-Ras-GDP
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFRi*^2-GAP-Grb2-Sos-Ras-GTP
Compartment: cytoplasm
Initial amount: 0.0
 
 Grb2
Compartment: cytoplasm
Initial amount: 11000.0
 
 EGF-EGFR*^2-GAP-Grb2
Compartment: cytoplasm
Initial amount: 0.0
 
 Sos
Compartment: cytoplasm
Initial amount: 26300.0
 
 EGF-EGFR*^2-GAP-Grb2-Sos
Compartment: cytoplasm
Initial amount: 0.0
 
 Ras-GDP
Compartment: cytoplasm
Initial amount: 72000.0
 
 EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GDP
Compartment: cytoplasm
Initial amount: 0.0
 
 Ras-GTP
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GTP
Compartment: cytoplasm
Initial amount: 0.0
 
 Grb2-Sos
Compartment: cytoplasm
Initial amount: 40000.0
 
 Shc
Compartment: cytoplasm
Initial amount: 101000.0
 
 EGF-EGFR*^2-GAP-Shc
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFR*^2-GAP-Shc*
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFR*^2-GAP-Shc*-Grb2
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFR*^2-GAP-Shc*-Grb2-Sos
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GDP
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GTP
Compartment: cytoplasm
Initial amount: 0.0
 
 Shc*-Grb2-Sos
Compartment: cytoplasm
Initial amount: 0.0
 
 Shc*-Grb2
Compartment: cytoplasm
Initial amount: 0.0
 
 Shc*
Compartment: cytoplasm
Initial amount: 0.0
 
 Raf
Compartment: cytoplasm
Initial amount: 40000.0
 
 Raf-Ras-GTP
Compartment: cytoplasm
Initial amount: 0.0
 
 Ras-GTP*
Compartment: cytoplasm
Initial amount: 0.0
 
 Phosphotase1
Compartment: cytoplasm
Initial amount: 40000.0
 
 Raf*
Compartment: cytoplasm
Initial amount: 0.0
 
 Raf*-P'ase
Compartment: cytoplasm
Initial amount: 0.0
 
 MEK
Compartment: cytoplasm
Initial amount: 2.2E7
 
 MEK-Raf*
Compartment: cytoplasm
Initial amount: 0.0
 
 MEK-P
Compartment: cytoplasm
Initial amount: 0.0
 
 MEK-P-Raf*
Compartment: cytoplasm
Initial amount: 0.0
 
 MEK-PP
Compartment: cytoplasm
Initial amount: 0.0
 
 MEK-PP-P'ase2
Compartment: cytoplasm
Initial amount: 0.0
 
 Phosphatase2
Compartment: cytoplasm
Initial amount: 40000.0
 
 MEK-P-P'ase2
Compartment: cytoplasm
Initial amount: 0.0
 
 ERK
Compartment: cytoplasm
Initial amount: 2.1E7
 
 ERK-MEK-PP
Compartment: cytoplasm
Initial amount: 0.0
 
 ERK-P
Compartment: cytoplasm
Initial amount: 0.0
 
 ERK-P-MEK-PP
Compartment: cytoplasm
Initial amount: 0.0
 
 ERK-PP
Compartment: cytoplasm
Initial amount: 0.0
 
 Phosphotase3
Compartment: cytoplasm
Initial amount: 1.0E7
 
 ERK-PP-P'ase3
Compartment: cytoplasm
Initial amount: 0.0
 
 ERK-P-P'ase3
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFRi*^2-GAP-Shc
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFRi*^2-GAP-Shc*
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFRi*^2-GAP-Shc*-Grb2
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos-Ras-GDP
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFRi*^2-GAP-Shc*-Grb2-Sos-Ras-GTP
Compartment: cytoplasm
Initial amount: 0.0
 
 Rasi-GTP
Compartment: cytoplasm
Initial amount: 0.0
 
 Rafi-Rasi-GTP
Compartment: cytoplasm
Initial amount: 0.0
 
 Rasi-GTP*
Compartment: cytoplasm
Initial amount: 0.0
 
 Rafi*
Compartment: cytoplasm
Initial amount: 0.0
 
 Rafi*-P'ase
Compartment: cytoplasm
Initial amount: 0.0
 
 MEKi-Rafi*
Compartment: cytoplasm
Initial amount: 0.0
 
 MEKi-P
Compartment: cytoplasm
Initial amount: 0.0
 
 MEKi-P-Rafi*
Compartment: cytoplasm
Initial amount: 0.0
 
 MEKi-PP
Compartment: cytoplasm
Initial amount: 0.0
 
 MEKi-PP-P'ase2i
Compartment: cytoplasm
Initial amount: 0.0
 
 MEKi-P-P'ase2i
Compartment: cytoplasm
Initial amount: 0.0
 
 ERKi-MEKi-PP
Compartment: cytoplasm
Initial amount: 0.0
 
 ERKi-P
Compartment: cytoplasm
Initial amount: 0.0
 
 ERKi-P-MEKi-PP
Compartment: cytoplasm
Initial amount: 0.0
 
 ERKi-PP
Compartment: cytoplasm
Initial amount: 0.0
 
 ERKi-PP-P'ase3i
Compartment: cytoplasm
Initial amount: 0.0
 
 ERKi-P-P'ase3i
Compartment: cytoplasm
Initial amount: 0.0
 
   EGFRideg
Compartment: cytoplasm
Initial amount: 0.0
 
   EGF-EGFRi*^2deg
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFR*^2-GAP-Grb2-Sos-Prot
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GDP-Prot
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFR*^2-GAP-Grb2-Sos-Ras-GTP-Prot
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFR*^2-GAP-Shc*-Grb2-Prot
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Prot
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GDP-Prot
Compartment: cytoplasm
Initial amount: 0.0
 
 EGF-EGFR*^2-GAP-Shc*-Grb2-Sos-Ras-GTP-Prot
Compartment: cytoplasm
Initial amount: 0.0
 
   t_Raf*
Compartment: cytoplasm
Initial amount: 0.0
 
   t_Ras_GTP
Compartment: cytoplasm
Initial amount: 0.0
 
   t_MEK_PP
Compartment: cytoplasm
Initial amount: 0.0
 
   t_ERK_PP
Compartment: cytoplasm
Initial amount: 0.0
 
   t_SHC_P_t
Compartment: cytoplasm
Initial amount: 0.0
 
   t_EGF_EGFR*
Compartment: cytoplasm
Initial amount: 0.0
 
 endosomal volume Spatial dimensions: 3.0  Compartment size: 4.3E-6
 
   EGFideg
Compartment: endosomal volume
Initial amount: 0.0
 
 EGF-EGFR*^2-GAP
Compartment: endosomal volume
Initial amount: 0.0
 
Global Parameters (90)
 
   k1
Value: 0.002372521   (Units: peritempermin)
Constant
 
   kr1
Value: 0.1146248   (Units: permin)
Constant
 
   kr2
Value: 0.5100538   (Units: permin)
Constant
 
   k2
Value: 4.80156E-4   (Units: peritempermin)
Constant
 
   k3
Value: 31.71871   (Units: permin)
Constant
 
   kr3
Value: 2.220991   (Units: permin)
Constant
 
   k4
Value: 3.047285E-5   (Units: peritempermin)
Constant
 
   kr4
Value: 0.1230832   (Units: permin)
Constant
 
   k5
Value: NaN   (Units: permin)
 
   k6
Value: 4.123214E-4   (Units: permin)
Constant
 
   kr6
Value: 0.294324   (Units: permin)
Constant
 
   k7
Value: 0.003011324   (Units: permin)
Constant
 
   k8
Value: 5.174108E-4   (Units: peritempermin)
Constant
 
   kr8
Value: 0.9058936   (Units: permin)
Constant
 
   k10
Value: 3803.728   (Units: peritempermin)
Constant
 
   kr10
Value: 171.6947   (Units: permin)
Constant
 
   kr11
Value: 0.5100538   (Units: permin)
Constant
 
   k11
Value: 4.80156E-4   (Units: peritempermin)
Constant
 
   kr12
Value: 2.220991   (Units: permin)
Constant
 
   k12
Value: 31.71871   (Units: permin)
Constant
 
   k13
Value: 0.4545611   (Units: itemspermin)
Constant
 
   k14
Value: 6.370566E-7   (Units: peritempermin)
Constant
 
   kr14
Value: 196.6479   (Units: permin)
Constant
 
   k15
Value: 46468.78   (Units: permin)
Constant
 
   kr16
Value: 0.4509308   (Units: permin)
Constant
 
   k16
Value: 4.021305E-4   (Units: peritempermin)
Constant
 
   kr17
Value: 2.524092   (Units: permin)
Constant
 
   k17
Value: 3.099213E-4   (Units: peritempermin)
Constant
 
   kr18
Value: 11.1361   (Units: permin)
Constant
 
   k18
Value: 0.004463938   (Units: peritempermin)
Constant
 
   kr19
Value: 5.84737E-6   (Units: peritempermin)
Constant
 
   k19
Value: 349.772   (Units: permin)
Constant
 
   kr20
Value: 12.816   (Units: permin)
Constant
 
   k20
Value: 5.17656E-5   (Units: peritempermin)
Constant
 
   k21
Value: 0.4722901   (Units: permin)
Constant
 
   kr21
Value: 1.714441E-5   (Units: peritempermin)
Constant
 
   k22
Value: 1.445554E-4   (Units: peritempermin)
Constant
 
   kr22
Value: 0.6220457   (Units: permin)
Constant
 
   k23
Value: 420.3359   (Units: permin)
Constant
 
   kr23
Value: 17.39321   (Units: permin)
Constant
 
   k24
Value: 0.007178843   (Units: peritempermin)
Constant
 
   kr24
Value: 563.2135   (Units: permin)
Constant
 
   kr25
Value: 1.218132   (Units: permin)
Constant
 
   k25
Value: 6.871213E-4   (Units: peritempermin)
Constant
 
   k28
Value: 9.826084E-6   (Units: peritempermin)
Constant
 
   kr28
Value: 0.9683624   (Units: permin)
Constant
 
   k29
Value: 931.1092   (Units: permin)
Constant
 
   kr29
Value: 1.096614E-4   (Units: peritempermin)
Constant
 
   kr32
Value: 5.54527E-5   (Units: peritempermin)
Constant
 
   k32
Value: 14.19908   (Units: permin)
Constant
 
   k33
Value: 10.96212   (Units: permin)
Constant
 
   kr33
Value: 1.788597E-5   (Units: peritempermin)
Constant
 
   k34
Value: 0.2467995   (Units: permin)
Constant
 
   kr34
Value: 1.283286E-4   (Units: peritempermin)
Constant
 
   k35
Value: 1.836058   (Units: permin)
Constant
 
   kr35
Value: 3.866434E-4   (Units: peritempermin)
Constant
 
   Vm36
Value: 615.0325   (Units: itemspermin)
Constant
 
   Km36
Value: 7.719778E14   (Units: items)
Constant
 
   k37
Value: 29.34687   (Units: permin)
Constant
 
   kr37
Value: 5.477036E-6   (Units: peritempermin)
Constant
 
   k40
Value: 7.409959E-5   (Units: peritempermin)
Constant
 
   kr40
Value: 2.748877   (Units: permin)
Constant
 
   kr41
Value: 44.60169   (Units: permin)
Constant
 
   k41
Value: 0.001522817   (Units: peritempermin)
Constant
 
   k42
Value: 0.009688174   (Units: peritempermin)
Constant
 
   kr42
Value: 1.870396   (Units: permin)
Constant
 
   k43
Value: 51.60945   (Units: permin)
Constant
 
   kr44
Value: 0.5985189   (Units: permin)
Constant
 
   k44
Value: 0.001406622   (Units: peritempermin)
Constant
 
   k45
Value: 6340.081   (Units: permin)
Constant
 
   k47
Value: 1632.425   (Units: permin)
Constant
 
   kr48
Value: 1489.015   (Units: permin)
Constant
 
   k48
Value: 6.874119E-4   (Units: peritempermin)
Constant
 
   k49
Value: 10.73099   (Units: permin)
Constant
 
   kr50
Value: 9.954943   (Units: permin)
Constant
 
   k50
Value: 5.464454E-4   (Units: peritempermin)
Constant
 
   k52
Value: 0.003826571   (Units: peritempermin)
Constant
 
   kr52
Value: 19.85279   (Units: permin)
Constant
 
   k53
Value: 62181.84   (Units: permin)
Constant
 
   k55
Value: 1120.398   (Units: permin)
Constant
 
   kr56
Value: 1.229629   (Units: permin)
Constant
 
   k56
Value: 0.004700229   (Units: peritempermin)
Constant
 
   k57
Value: 19.75184   (Units: permin)
Constant
 
   kr58
Value: 0.1138168   (Units: permin)
Constant
 
   k58
Value: 1.714511E-4   (Units: peritempermin)
Constant
 
   k59
Value: 6.409354   (Units: permin)
Constant
 
   k60
Value: 0.08693199   (Units: permin)
Constant
 
   k61
Value: 0.006499143   (Units: permin)
Constant
 
   C_internalization
Value: NaN
 
   total_Receptors
Value: 50000.0   (Units: items)
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000399

Curator's comment: (updated: 03 Nov 2011 14:33:22 GMT)

Figure 1 and S1 of the reference publication has been reproduced here. The inconsistency between the y-axis measure of the curation figure and that of the paper is due to the units. In the papers, ERK_PP concentration dynamics is measured in mol/m3 and as the number of molecules. The plot shows the dynamics of ERK_PP for different values of EGF ranging from 0.0625ng/mL to 50ng/mL. In the model, EGF is presented as the number of molecules. EGF=5962molecules correspond to 50ng/mL, 596.2molecules correspond to 5ng/mL, 49.62 correspond to .5ng/mL, 12.405molecules correspond to 0.125ng/mL and 6.2025molecules correspond to 0.0625ng/mL.
The simulated was done using Copasi v4.7 (Build 34).

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