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BIOMD0000000019 - Schoeberl2002 - EGF MAPK

 

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Reference Publication
Publication ID: 11923843
Schoeberl B, Eichler-Jonsson C, Gilles ED, Müller G.
Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors.
Nat. Biotechnol. 2002 Apr; 20(4): 370-375
Max Planck Institute for Dynamics of Complex Technical Systems, Leipziger Str. 44, D-39120 Magdeburg, Germany.  [more]
Model
Original Model: BIOMD0000000019.origin
Submitter: Nicolas Le Novère
Submission ID: MODEL6617455076
Submission Date: 13 Sep 2005 13:19:14 UTC
Last Modification Date: 08 Apr 2016 14:31:50 UTC
Creation Date: 15 Aug 2005 06:36:38 UTC
Encoders:  Nicolas Le Novère
   Rainer Machne
   Lukas Endler
   Ken Lau
   Birgit Schoeberl
set #1
bqbiol:hasVersion Gene Ontology MAPK cascade
Gene Ontology Ras protein signal transduction
set #2
bqbiol:isVersionOf Reactome REACT_9417.3
Gene Ontology epidermal growth factor receptor signaling pathway
set #3
bqbiol:occursIn Taxonomy Homo sapiens
Notes
Schoeberl2002 - EGF MAPK

Computational model that offers an integrated quantitative, dynamic, and topological representation of intracellular signal networks, based on known components of epidermal growth factor (EGF) receptor signal pathways.

The initial model was constructed by Ken Lau from the MATLAB source code.

This model is described in the article:

Schoeberl B, Eichler-Jonsson C, Gilles ED, Müller G
Nat. Biotechnol. 2002 Apr; 20(4): 370-375

Abstract:

We present a computational model that offers an integrated quantitative, dynamic, and topological representation of intracellular signal networks, based on known components of epidermal growth factor (EGF) receptor signal pathways. The model provides insight into signal-response relationships between the binding of EGF to its receptor at the cell surface and the activation of downstream proteins in the signaling cascade. It shows that EGF-induced responses are remarkably stable over a 100-fold range of ligand concentration and that the critical parameter in determining signal efficacy is the initial velocity of receptor activation. The predictions of the model agree well with experimental analysis of the effect of EGF on two downstream responses, phosphorylation of ERK-1/2 and expression of the target gene, c-fos.

This model does not exactly reproduce the results given in the original publication. It has, though, the same reaction graph and gives very similar time courses for the conditions depicted in the article.

Several corrections were applied to the parameters described in the paper's supplementary materials. Some parameter names were replaced by the corresponding identical ones: k(r)26 by k(r)18, k(r)27 by k(r)19, k(r)30 by k(r)20, k(r)38 by k(r)24, k(r)39 by k(r)37, k(r)46 by k(r)44, k51 by k49, k(r)54 by k(r)52 and k62 by k62. In particular the parameter values described in the column "remark" of supplementary table 1 override the values explicitely written in the numerical columns:

name in suppl. value used in model value used remarks
kr16 0.055 0.275
k30 7.9e6 2.1e6 as k20
kr30 0.3 0.4 as kr24
k38 3e7 1e7 as k20
kr38 0.055 0.55 as kr24
k52 1.1e5 5.34e7

k5 was used for v116, v119, v122 and v125 in addition of v107, v110 and v113 as listed in the legend of supplementary figure 2. k5 is calculated using th eformula from the matlab file not given in the supplements.

All rate constants were rescaled to minutes (k[min] = 60*k[sec]) and all second order rate constants additionally to molecules/cell with a cell volume of 1 picolitre (k[molecs/cell] = k[M]/(Vc*Na), with Vc=1e-12 l and Na = 6e23).

The association constant of internalized EGF was rescaled to molecules/endosome using an endosomal volume of 4.3 al (= 4.3*10 -18 litre).

The extracellular EGF concentration was converted to molecules per picolitre with a MW of 6045 Da.

[ng/ml] [numb/pl]
50 4962
0.5 49.6
0.125 12.4

With the initial conditions given in the paper, the results could not be reproduced at all. Therefore the initial conditions used in the MATLAB file were adopted for SHC (1.01 * 10 5 instead of 1.01 * 10 6 ) and Ras_GDP. (7.2 * 10 4 instead of 1.14 * 10 7 )

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 11923843 Submission Date: 13 Sep 2005 13:19:14 UTC Last Modification Date: 08 Apr 2016 14:31:50 UTC Creation Date: 15 Aug 2005 06:36:38 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: 0.0030   (Units: peritempermin)
Constant
 
   kr1
Value: 0.228   (Units: permin)
Constant
 
   kr2
Value: 6.0   (Units: permin)
Constant
 
   k2
Value: 0.0010   (Units: peritempermin)
Constant
 
   k3
Value: 60.0   (Units: permin)
Constant
 
   kr3
Value: 0.6   (Units: permin)
Constant
 
   k4
Value: 1.038E-5   (Units: peritempermin)
Constant
 
   kr4
Value: 0.0996   (Units: permin)
Constant
 
   k5
Value: NaN   (Units: permin)
 
   k6
Value: 0.0030   (Units: permin)
Constant
 
   kr6
Value: 0.3   (Units: permin)
Constant
 
   k7
Value: 0.0030   (Units: permin)
Constant
 
   k8
Value: 1.0E-4   (Units: peritempermin)
Constant
 
   kr8
Value: 12.0   (Units: permin)
Constant
 
   k10
Value: 3.25581   (Units: peritempermin)
Constant
 
   kr10
Value: 0.66   (Units: permin)
Constant
 
   kr11
Value: 6.0   (Units: permin)
Constant
 
   k11
Value: 0.0010   (Units: peritempermin)
Constant
 
   kr12
Value: 0.6   (Units: permin)
Constant
 
   k12
Value: 60.0   (Units: permin)
Constant
 
   k13
Value: 130.2   (Units: itemspermin)
Constant
 
   k14
Value: 1.0E-4   (Units: peritempermin)
Constant
 
   kr14
Value: 12.0   (Units: permin)
Constant
 
   k15
Value: 600000.0   (Units: permin)
Constant
 
   kr16
Value: 16.5   (Units: permin)
Constant
 
   k16
Value: 0.0010   (Units: peritempermin)
Constant
 
   kr17
Value: 3.6   (Units: permin)
Constant
 
   k17
Value: 0.0010   (Units: peritempermin)
Constant
 
   kr18
Value: 78.0   (Units: permin)
Constant
 
   k18
Value: 0.0015   (Units: peritempermin)
Constant
 
   kr19
Value: 1.0E-5   (Units: peritempermin)
Constant
 
   k19
Value: 30.0   (Units: permin)
Constant
 
   kr20
Value: 24.0   (Units: permin)
Constant
 
   k20
Value: 2.1E-4   (Units: peritempermin)
Constant
 
   k21
Value: 1.38   (Units: permin)
Constant
 
   kr21
Value: 2.2E-5   (Units: peritempermin)
Constant
 
   k22
Value: 0.0021   (Units: peritempermin)
Constant
 
   kr22
Value: 6.0   (Units: permin)
Constant
 
   k23
Value: 360.0   (Units: permin)
Constant
 
   kr23
Value: 36.0   (Units: permin)
Constant
 
   k24
Value: 0.0010   (Units: peritempermin)
Constant
 
   kr24
Value: 33.0   (Units: permin)
Constant
 
   kr25
Value: 1.284   (Units: permin)
Constant
 
   k25
Value: 0.0010   (Units: peritempermin)
Constant
 
   k28
Value: 1.0E-4   (Units: peritempermin)
Constant
 
   kr28
Value: 0.318   (Units: permin)
Constant
 
   k29
Value: 60.0   (Units: permin)
Constant
 
   kr29
Value: 7.0E-5   (Units: peritempermin)
Constant
 
   kr32
Value: 2.4E-5   (Units: peritempermin)
Constant
 
   k32
Value: 6.0   (Units: permin)
Constant
 
   k33
Value: 12.0   (Units: permin)
Constant
 
   kr33
Value: 0.0021   (Units: peritempermin)
Constant
 
   k34
Value: 1.8   (Units: permin)
Constant
 
   kr34
Value: 4.5E-4   (Units: peritempermin)
Constant
 
   k35
Value: 0.09   (Units: permin)
Constant
 
   kr35
Value: 4.5E-4   (Units: peritempermin)
Constant
 
   Vm36
Value: 61200.0   (Units: itemspermin)
Constant
 
   Km36
Value: 2.0E14   (Units: items)
Constant
 
   k37
Value: 18.0   (Units: permin)
Constant
 
   kr37
Value: 9.0E-5   (Units: peritempermin)
Constant
 
   k40
Value: 0.0030   (Units: peritempermin)
Constant
 
   kr40
Value: 3.84   (Units: permin)
Constant
 
   kr41
Value: 2.574   (Units: permin)
Constant
 
   k41
Value: 0.0030   (Units: peritempermin)
Constant
 
   k42
Value: 0.0071   (Units: peritempermin)
Constant
 
   kr42
Value: 12.0   (Units: permin)
Constant
 
   k43
Value: 60.0   (Units: permin)
Constant
 
   kr44
Value: 1.0998   (Units: permin)
Constant
 
   k44
Value: 0.00111   (Units: peritempermin)
Constant
 
   k45
Value: 210.0   (Units: permin)
Constant
 
   k47
Value: 174.0   (Units: permin)
Constant
 
   kr48
Value: 48.0   (Units: permin)
Constant
 
   k48
Value: 0.00143   (Units: peritempermin)
Constant
 
   k49
Value: 3.48   (Units: permin)
Constant
 
   kr50
Value: 30.0   (Units: permin)
Constant
 
   k50
Value: 2.5E-5   (Units: peritempermin)
Constant
 
   k52
Value: 0.00534   (Units: peritempermin)
Constant
 
   kr52
Value: 1.98   (Units: permin)
Constant
 
   k53
Value: 960.0   (Units: permin)
Constant
 
   k55
Value: 342.0   (Units: permin)
Constant
 
   kr56
Value: 36.0   (Units: permin)
Constant
 
   k56
Value: 0.00145   (Units: peritempermin)
Constant
 
   k57
Value: 16.2   (Units: permin)
Constant
 
   kr58
Value: 30.0   (Units: permin)
Constant
 
   k58
Value: 5.0E-4   (Units: peritempermin)
Constant
 
   k59
Value: 18.0   (Units: permin)
Constant
 
   k60
Value: 0.04002   (Units: permin)
Constant
 
   k61
Value: 0.01002   (Units: permin)
Constant
 
   C_internalization
Value: NaN
 
   total_Receptors
Value: 50000.0   (Units: items)
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000019

Curator's comment: (updated: 14 Jul 2008 18:05:03 BST)

time course of active species as in fig. 2 c,d,e,f in the original publication

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