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BIOMD0000000623 - Orton2009 - Modelling cancerous mutations in the EGFR/ERK pathway - EGF Model

 

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Reference Publication
Publication ID: 19804630
Orton RJ, Adriaens ME, Gormand A, Sturm OE, Kolch W, Gilbert DR.
Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway.
BMC Syst Biol 2009 Oct; 3: 100
Institute of Comparative Medicine, Faculty of Veterinary Medicine, University of Glasgow, Glasgow, UK. r.orton@vet.gla.ac.uk  [more]
Model
Original Model: Orton2009 - Modelling canc...
Submitter: Thawfeek Varusai
Submission ID: MODEL1611280000
Submission Date: 28 Nov 2016 21:13:27 UTC
Last Modification Date: 09 Jan 2017 11:54:49 UTC
Creation Date: 28 Nov 2016 09:09:16 UTC
Encoders:  Thawfeek Varusai
set #1
bqbiol:hasProperty Human Disease Ontology cancer
set #2
bqmodel:isDerivedFrom BioModels Database Brown2004 - NGF and EGF signaling
set #3
bqbiol:occursIn Brenda Tissue Ontology PC-12 cell
set #4
bqbiol:hasTaxon Taxonomy Rattus norvegicus
set #5
bqbiol:isVersionOf Gene Ontology epidermal growth factor receptor signaling pathway
Notes
Orton2009 - Modelling cancerous mutations in the EGFR/ERK pathway - EGF Model
This model studies the aberrations in ERK signalling for different cancer mutations. The authors alter a previously existing EGF model (Brown et al 2004) to include new interactions that better fit empirical data. Predictions show that the ERK signalling is a robust mechanism taking different courses for different cancer mutations. Most parameter values are used from the previous model and the new parameters are estimated using experimental data performed by the authors on PC12 cells (adrenal gland, rat). The authors provide an SBML version of the model in the paper.

This model is described in the article:

Orton RJ, Adriaens ME, Gormand A, Sturm OE, Kolch W, Gilbert DR.
BMC Syst Biol 2009 Oct; 3: 100

Abstract:

The Epidermal Growth Factor Receptor (EGFR) activated Extracellular-signal Regulated Kinase (ERK) pathway is a critical cell signalling pathway that relays the signal for a cell to proliferate from the plasma membrane to the nucleus. Deregulation of the EGFR/ERK pathway due to alterations affecting the expression or function of a number of pathway components has long been associated with numerous forms of cancer. Under normal conditions, Epidermal Growth Factor (EGF) stimulates a rapid but transient activation of ERK as the signal is rapidly shutdown. Whereas, under cancerous mutation conditions the ERK signal cannot be shutdown and is sustained resulting in the constitutive activation of ERK and continual cell proliferation. In this study, we have used computational modelling techniques to investigate what effects various cancerous alterations have on the signalling flow through the ERK pathway.We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF) receptors.Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications for drug selection strategies. We also conducted a comparison of the critical differences between signalling from different growth factor receptors (namely EGFR, mutated EGFR, NGF, and Insulin) with our results suggesting the difference between the systems are large scale and can be attributed to the presence/absence of entire pathways rather than subtle difference in individual rate constants between the systems.

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: 19804630 Submission Date: 28 Nov 2016 21:13:27 UTC Last Modification Date: 09 Jan 2017 11:54:49 UTC Creation Date: 28 Nov 2016 09:09:16 UTC
Mathematical expressions
Reactions
EGF_Binding_Unbinding Sos_Activation Sos_Deactivation Ras_Activation
Ras_Deactivation Raf1_Activation Raf1_Deactivation Mek_Activation
Mek_Deactivation Erk_Activation Erk_Deactivation P90Rsk_Activation
P90Rsk_Deactivation Sos_Feedback_Deactivation PI3K_Activation_EGFR PI3K_Activation_Ras
PI3K_Deactivation Akt_Activation Akt_Deactivation Raf1_Deactivation_Akt
EGFReceptor_Degradation C3G_Activation C3G_Deactivation Rap1_Activation
Rap1_Deactivation bRaf_Activation bRaf_Deactivation Mek_Activation_bRaf
EGFReceptor_Production EGFReceptor_Degradtion_Free bRaf_Activation_Ras  
Physical entities
Compartments Species
compartment boundEGFReceptor freeEGFReceptor SosActive
SosInactive RasActive RasInactive
Raf1Active Raf1Inactive MekActive
MekInactive ErkActive ErkInactive
P90RskActive P90RskInactive PI3KActive
PI3KInactive AktActive AktInactive
degradedEGFReceptor C3GActive C3GInactive
Rap1Active Rap1Inactive bRafActive
bRafInactive EGF PP2AActive
Raf1PPtase RasGapActive Rap1Gap
proEGFReceptor    
Reactions (31)
 
 EGF_Binding_Unbinding [EGF] + [freeEGFReceptor] ↔ [boundEGFReceptor];  
 
 Sos_Activation [SosInactive] → [SosActive];   {boundEGFReceptor}
 
 Sos_Deactivation [SosActive] → [SosInactive];  
 
 Ras_Activation [RasInactive] → [RasActive];   {SosActive}
 
 Ras_Deactivation [RasActive] → [RasInactive];   {RasGapActive}
 
 Raf1_Activation [Raf1Inactive] → [Raf1Active];   {RasActive}
 
 Raf1_Deactivation [Raf1Active] → [Raf1Inactive];   {Raf1PPtase}
 
 Mek_Activation [MekInactive] → [MekActive];   {Raf1Active}
 
 Mek_Deactivation [MekActive] → [MekInactive];   {PP2AActive}
 
 Erk_Activation [ErkInactive] → [ErkActive];   {MekActive}
 
 Erk_Deactivation [ErkActive] → [ErkInactive];   {PP2AActive}
 
 P90Rsk_Activation [P90RskInactive] → [P90RskActive];   {ErkActive}
 
 P90Rsk_Deactivation [P90RskActive] → [P90RskInactive];  
 
 Sos_Feedback_Deactivation [SosActive] → [SosInactive];   {P90RskActive}
 
 PI3K_Activation_EGFR [PI3KInactive] → [PI3KActive];   {boundEGFReceptor}
 
 PI3K_Activation_Ras [PI3KInactive] → [PI3KActive];   {RasActive}
 
 PI3K_Deactivation [PI3KActive] → [PI3KInactive];  
 
 Akt_Activation [AktInactive] → [AktActive];   {PI3KActive}
 
 Akt_Deactivation [AktActive] → [AktInactive];  
 
 Raf1_Deactivation_Akt [Raf1Active] → [Raf1Inactive];   {AktActive}
 
 EGFReceptor_Degradation [boundEGFReceptor] → [degradedEGFReceptor];  
 
 C3G_Activation [C3GInactive] → [C3GActive];   {boundEGFReceptor}
 
 C3G_Deactivation [C3GActive] → [C3GInactive];  
 
 Rap1_Activation [Rap1Inactive] → [Rap1Active];   {C3GActive}
 
 Rap1_Deactivation [Rap1Active] → [Rap1Inactive];   {Rap1Gap}
 
 bRaf_Activation [bRafInactive] → [bRafActive];   {Rap1Active}
 
 bRaf_Deactivation [bRafActive] → [bRafInactive];   {Raf1PPtase}
 
 Mek_Activation_bRaf [MekInactive] → [MekActive];   {bRafActive}
 
 EGFReceptor_Production [proEGFReceptor] → [freeEGFReceptor];  
 
 EGFReceptor_Degradtion_Free [freeEGFReceptor] → [degradedEGFReceptor];  
 
 bRaf_Activation_Ras [bRafInactive] → [bRafActive];   {RasActive}
 
Functions (23)
 
 Constant flux (irreversible) lambda(v, v)
 
 Menten_Explicit_Enzyme_12 lambda(Kcat, km, species_0, species_15, Kcat*species_0*species_15/(km+species_15))
 
 MM Explicit Enzyme_5 lambda(kcat, km, species_23, species_27, kcat*species_27*species_23/(km+species_23))
 
 Menten_Explicit_Enzyme_14 lambda(Kcat, km, species_14, species_17, Kcat*species_14*species_17/(km+species_17))
 
 Menten_Explicit_Enzyme_9 lambda(Kcat, km, species_10, species_26, Kcat*species_26*species_10/(km+species_10))
 
 MM Explicit Enzyme_7 lambda(kcat, km, species_24, species_4, kcat*species_4*species_24/(km+species_24))
 
 Menten_Explicit_Enzyme_4 lambda(Kcat, km, species_4, species_7, Kcat*species_4*species_7/(km+species_7))
 
 Menten_Explicit_Enzyme_6 lambda(Kcat, km, species_6, species_9, Kcat*species_6*species_9/(km+species_9))
 
 MM Explicit Enzyme_4 lambda(kcat, km, species_21, species_24, kcat*species_21*species_24/(km+species_24))
 
 Menten_Explicit_Enzyme_2 lambda(Kcat, km, species_2, species_5, Kcat*species_2*species_5/(km+species_5))
 
 Menten_Explicit_Enzyme_7 lambda(Kcat, km, species_26, species_8, Kcat*species_26*species_8/(km+species_8))
 
 Menten_Explicit_Enzyme_11 lambda(Kcat, km, species_12, species_2, Kcat*species_12*species_2/(km+species_2))
 
 Menten_Explicit_Enzyme_15 lambda(Kcat, km, species_16, species_6, Kcat*species_16*species_6/(km+species_6))
 
 MM Explicit Enzyme_1 lambda(kcat, km, species_0, species_20, kcat*species_0*species_20/(km+species_20))
 
 Menten_Explicit_Enzyme_10 lambda(Kcat, km, species_10, species_13, Kcat*species_10*species_13/(km+species_13))
 
 Menten_Explicit_Enzyme_5 lambda(Kcat, km, species_27, species_6, Kcat*species_27*species_6/(km+species_6))
 
 Menten_Explicit_Enzyme_8 lambda(Kcat, km, species_11, species_8, Kcat*species_8*species_11/(km+species_11))
 
 Menten_Explicit_Enzyme_13 lambda(Kcat, km, species_15, species_4, Kcat*species_4*species_15/(km+species_15))
 
 Menten_Explicit_Enzyme_3 lambda(Kcat, km, species_28, species_4, Kcat*species_28*species_4/(km+species_4))
 
 MM Explicit Enzyme_2 lambda(kcat, km, species_19, species_22, kcat*species_19*species_22/(km+species_22))
 
 Menten_Explicit_Enzyme_1 lambda(Kcat, km, species_0, species_3, Kcat*species_0*species_3/(km+species_3))
 
 MM Explicit Enzyme_3 lambda(kcat, km, species_21, species_29, kcat*species_29*species_21/(km+species_21))
 
 MM Explicit Enzyme_6 lambda(kcat, km, species_23, species_9, kcat*species_23*species_9/(km+species_9))
 
 compartment Spatial dimensions: 3.0  Compartment size: 1.0
 
 boundEGFReceptor
Compartment: compartment
Initial concentration: 0.0
 
 freeEGFReceptor
Compartment: compartment
Initial concentration: 80000.0
 
 SosActive
Compartment: compartment
Initial concentration: 0.0
 
 SosInactive
Compartment: compartment
Initial concentration: 120000.0
 
 RasActive
Compartment: compartment
Initial concentration: 0.0
 
 RasInactive
Compartment: compartment
Initial concentration: 120000.0
 
 Raf1Active
Compartment: compartment
Initial concentration: 0.0
 
 Raf1Inactive
Compartment: compartment
Initial concentration: 120000.0
 
 MekActive
Compartment: compartment
Initial concentration: 0.0
 
 MekInactive
Compartment: compartment
Initial concentration: 600000.0
 
 ErkActive
Compartment: compartment
Initial concentration: 0.0
 
 ErkInactive
Compartment: compartment
Initial concentration: 600000.0
 
 P90RskActive
Compartment: compartment
Initial concentration: 0.0
 
 P90RskInactive
Compartment: compartment
Initial concentration: 120000.0
 
 PI3KActive
Compartment: compartment
Initial concentration: 0.0
 
 PI3KInactive
Compartment: compartment
Initial concentration: 120000.0
 
 AktActive
Compartment: compartment
Initial concentration: 0.0
 
 AktInactive
Compartment: compartment
Initial concentration: 120000.0
 
 degradedEGFReceptor
Compartment: compartment
Initial concentration: 0.0
 
 C3GActive
Compartment: compartment
Initial concentration: 0.0
 
 C3GInactive
Compartment: compartment
Initial concentration: 120000.0
 
 Rap1Active
Compartment: compartment
Initial concentration: 0.0
 
 Rap1Inactive
Compartment: compartment
Initial concentration: 120000.0
 
 bRafActive
Compartment: compartment
Initial concentration: 0.0
 
 bRafInactive
Compartment: compartment
Initial concentration: 120000.0
 
 EGF
Compartment: compartment
Initial concentration: 1.0002E7
Constant
 
 PP2AActive
Compartment: compartment
Initial concentration: 120000.0
Constant
 
 Raf1PPtase
Compartment: compartment
Initial concentration: 120000.0
Constant
 
 RasGapActive
Compartment: compartment
Initial concentration: 120000.0
Constant
 
 Rap1Gap
Compartment: compartment
Initial concentration: 120000.0
Constant
 
 proEGFReceptor
Compartment: compartment
Initial concentration: 1.0
Constant
 
EGF_Binding_Unbinding (2)
 
   k1
Value: 2.18503E-5
Constant
 
   k2
Value: 0.121008
Constant
 
Sos_Activation (2)
 
   Kcat
Value: 694.731
Constant
 
   km
Value: 6086070.0
Constant
 
Sos_Deactivation (1)
 
   k1
Value: 2.5
Constant
 
Ras_Activation (2)
 
   Kcat
Value: 32.344
Constant
 
   km
Value: 35954.3
Constant
 
Ras_Deactivation (2)
 
   Kcat
Value: 1509.36
Constant
 
   km
Value: 1432410.0
Constant
 
Raf1_Activation (2)
 
   Kcat
Value: 0.884096
Constant
 
   km
Value: 62464.6
Constant
 
Raf1_Deactivation (2)
 
   Kcat
Value: 0.126329
Constant
 
   km
Value: 1061.71
Constant
 
Mek_Activation (2)
 
   Kcat
Value: 185.759
Constant
 
   km
Value: 4768350.0
Constant
 
Mek_Deactivation (2)
 
   Kcat
Value: 2.83243
Constant
 
   km
Value: 518753.0
Constant
 
Erk_Activation (2)
 
   Kcat
Value: 9.85367
Constant
 
   km
Value: 1007340.0
Constant
 
Erk_Deactivation (2)
 
   Kcat
Value: 8.8912
Constant
 
   km
Value: 3496490.0
Constant
 
P90Rsk_Activation (2)
 
   Kcat
Value: 0.0213697
Constant
 
   km
Value: 763523.0
Constant
 
P90Rsk_Deactivation (1)
 
   k1
Value: 0.005
Constant
 
Sos_Feedback_Deactivation (2)
 
   Kcat
Value: 1611.97
Constant
 
   km
Value: 896896.0
Constant
 
PI3K_Activation_EGFR (2)
 
   Kcat
Value: 10.6737
Constant
 
   km
Value: 184912.0
Constant
 
PI3K_Activation_Ras (2)
 
   Kcat
Value: 0.0771067
Constant
 
   km
Value: 272056.0
Constant
 
PI3K_Deactivation (1)
 
   k1
Value: 0.005
Constant
 
Akt_Activation (2)
 
   Kcat
Value: 0.0566279
Constant
 
   km
Value: 653951.0
Constant
 
Akt_Deactivation (1)
 
   k1
Value: 0.005
Constant
 
Raf1_Deactivation_Akt (2)
 
   Kcat
Value: 15.1212
Constant
 
   km
Value: 119355.0
Constant
 
EGFReceptor_Degradation (1)
 
   k1
Value: 0.2
Constant
 
C3G_Activation (2)
 
   kcat
Value: 694.731
Constant
 
   km
Value: 6086070.0
Constant
 
C3G_Deactivation (1)
 
   k1
Value: 2.5
Constant
 
Rap1_Activation (2)
 
   kcat
Value: 32.344
Constant
 
   km
Value: 35954.3
Constant
 
Rap1_Deactivation (2)
 
   kcat
Value: 1509.36
Constant
 
   km
Value: 1432410.0
Constant
 
bRaf_Activation (2)
 
   kcat
Value: 0.884096
Constant
 
   km
Value: 62464.6
Constant
 
bRaf_Deactivation (2)
 
   kcat
Value: 0.126329
Constant
 
   km
Value: 1061.71
Constant
 
Mek_Activation_bRaf (2)
 
   kcat
Value: 185.759
Constant
 
   km
Value: 4768350.0
Constant
 
EGFReceptor_Production (1)
 
   v
Value: 100.0
Constant
 
EGFReceptor_Degradtion_Free (1)
 
   k1
Value: 0.00125
Constant
 
bRaf_Activation_Ras (2)
 
   kcat
Value: 0.884096
Constant
 
   km
Value: 62464.6
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000623

Curator's comment: (updated: 28 Nov 2016 21:21:31 GMT)

The SBML file of this model was provided by the authors in the paper. The file did not have any errors and simulations worked just fine. Figure 4B in the paper is reproduced here. The two curves in the graph indicate active Ras (red) and active Rap1 (blue). One observation was that all the parameters in this model are represented in units of minutes.

Additional file(s)
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