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BIOMD0000000033 - Brown2004 - NGF and EGF signaling

 

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Reference Publication
Publication ID: 16204838
Brown KS, Hill CC, Calero GA, Myers CR, Lee KH, Sethna JP, Cerione RA.
The statistical mechanics of complex signaling networks: nerve growth factor signaling.
Phys Biol 2004 Dec; 1(3-4): 184-195
LASSP, Department of Physics, Cornell University, Clark Hall, Ithaca, NY 14853, USA.  [more]
Model
Original Model: BIOMD0000000033.origin
Submitter: Ryan Gutenkunst
Submission ID: MODEL6619514794
Submission Date: 13 Sep 2005 13:52:33 UTC
Last Modification Date: 18 May 2015 10:53:33 UTC
Creation Date: 10 Jun 2005 14:09:32 UTC
Encoders:  Nicolas Le Novère
   Ryan Gutenkunst
set #1
bqbiol:hasPart Gene Ontology epidermal growth factor receptor signaling pathway
Gene Ontology neurotrophin TRK receptor signaling pathway
set #2
bqbiol:hasProperty Mathematical Modelling Ontology MAMO_0000046
set #3
bqbiol:hasTaxon Taxonomy cellular organisms
set #4
bqbiol:isVersionOf Gene Ontology ERK1 and ERK2 cascade
Notes
Brown2004 - NGF and EGF signaling

This model is described in the article:

Brown KS, Hill CC, Calero GA, Myers CR, Lee KH, Sethna JP, Cerione RA.
Phys Biol 2004 Dec; 1(3-4): 184-195

Abstract:

The inherent complexity of cellular signaling networks and their importance to a wide range of cellular functions necessitates the development of modeling methods that can be applied toward making predictions and highlighting the appropriate experiments to test our understanding of how these systems are designed and function. We use methods of statistical mechanics to extract useful predictions for complex cellular signaling networks. A key difficulty with signaling models is that, while significant effort is being made to experimentally measure the rate constants for individual steps in these networks, many of the parameters required to describe their behavior remain unknown or at best represent estimates. To establish the usefulness of our approach, we have applied our methods toward modeling the nerve growth factor (NGF)-induced differentiation of neuronal cells. In particular, we study the actions of NGF and mitogenic epidermal growth factor (EGF) in rat pheochromocytoma (PC12) cells. Through a network of intermediate signaling proteins, each of these growth factors stimulates extracellular regulated kinase (Erk) phosphorylation with distinct dynamical profiles. Using our modeling approach, we are able to predict the influence of specific signaling modules in determining the integrated cellular response to the two growth factors. Our methods also raise some interesting insights into the design and possible evolution of cellular systems, highlighting an inherent property of these systems that we call 'sloppiness.'


The figures in the paper show results from computations performed over an ensemble of all parameter sets that fit the available data. This file contains only the best fit parameters. The full ensemble of parameters is available at http://www.lassp.cornell.edu/sethna/GeneDynamics/PC12DataFiles/ (Also, the best-fit parameter set produces a curve for DN Rap1 that is less "peakish" than the ensemble average.)

The conversion factors for EGF and NGF concentrations account for their molecular weights and the density of cells in the culture dish. These concentrations are saturating, so the exact values are not critical.

Because the Erk data fit to measure only fold changes in activity, there is no absolute scale for the y-axes. Thus the curves from this file have different magnitudes than those published.

To reproduce the figures from the paper:
2a) For EGF stimulation, set the initial concentration of EGF to 100 ng/ml * 100020 (molecule/cell)/(ng/ml) = 10002000.
For NGF stimulation, set the initial concentration of NGF to 50 ng/ml * 4560 (molecule/cell)/(ng/ml) = 456000
5a) To simulate LY294002 addition, set kPI3KRas and kPI3K to 0.
5b) To simulate a dominant negative Rap1, set kRap1ToBRaf to 0.
To simulate a dominant negative Ras, set kRasToRaf1 and kPI3KRas to 0.

Almost all the data fit with this model by the authors are from Western blots. Given the uncertainties in antibody effectiveness and other factors, one can't a priori derive a conversion between the arbitrary units for a given set of data and molecules per cell. So the authors used an adjustable "scale factor" that converts between molecules per cell and Western blot units.

For the EGF stimulation data in figure 2a) the scale factor conversion is 1.414e-05 (U/mg)/(molecule/cell). For the NGF stimulation data in figure 2a) it is 7.135e-06 (U/mg)/(molecule/cell).

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: 16204838 Submission Date: 13 Sep 2005 13:52:33 UTC Last Modification Date: 18 May 2015 10:53:33 UTC Creation Date: 10 Jun 2005 14:09:32 UTC
Mathematical expressions
Reactions
EGF binding EFG unbinding NGF binding NGF unbinding
SOS activation by EGF SOS activation by NGF SOS deactivation Ras activation
Ras deactivation Raf1 activation by Ras Mek activation by Raf1 Mek activation by B-Raf
Erk activation Mek deactivation Erk deactivation Raf1 deactivation by PPase
P90Rsk activation PI3K activation by EGFR PI3K activation by Ras Akt activation
Raf1 deactivation by Akt C3G activation Rap1 activation Rap1 deactivation
BRaf activation by Rap1 BRaf deactivation by PPase    
Physical entities
Compartments Species
cell EGF NGF freeEGFReceptor
boundEGFReceptor freeNGFReceptor boundNGFReceptor
SosInactive SosActive P90RskInactive
P90RskActive RasInactive RasActive
RasGapActive Raf1Inactive Raf1Active
BRafInactive BRafActive MekInactive
MekActive ErkInactive ErkActive
PI3KInactive PI3KActive AktInactive
AktActive C3GInactive C3GActive
Rap1Inactive Rap1Active RapGapActive
PP2AActive Raf1PPtase  
Global parameters
krbEGF kruEGF krbNGF kruNGF
kEGF KmEGF kNGF KmNGF
kdSos KmdSos kSos KmSos
kRasGap KmRasGap kRasToRaf1 KmRasToRaf1
kpRaf1 KmpRaf1 kpBRaf KmpBRaf
kdMek KmdMek kpMekCytoplasmic KmpMekCytoplasmic
kdErk KmdErk kpP90Rsk KmpP90Rsk
kPI3K KmPI3K kPI3KRas KmPI3KRas
kAkt KmAkt kdRaf1ByAkt KmRaf1ByAkt
kC3GNGF KmC3GNGF kC3G KmC3G
kRapGap KmRapGap kRap1ToBRaf KmRap1ToBRaf
kdRaf1 KmdRaf1 kdBRaf KmdBRaf
Reactions (26)
 
 EGF binding [EGF] + [freeEGFReceptor] → [boundEGFReceptor];  
 
 EFG unbinding [boundEGFReceptor] → [EGF] + [freeEGFReceptor];  
 
 NGF binding [NGF] + [freeNGFReceptor] → [boundNGFReceptor];  
 
 NGF unbinding [boundNGFReceptor] → [NGF] + [freeNGFReceptor];  
 
 SOS activation by EGF [SosInactive] ↔ [SosActive];   {boundEGFReceptor}
 
 SOS activation by NGF [SosInactive] ↔ [SosActive];   {boundNGFReceptor}
 
 SOS deactivation [SosActive] ↔ [SosInactive];   {P90RskActive}
 
 Ras activation [RasInactive] ↔ [RasActive];   {SosActive}
 
 Ras deactivation [RasActive] ↔ [RasInactive];   {RasGapActive}
 
 Raf1 activation by Ras [Raf1Inactive] ↔ [Raf1Active];   {RasActive}
 
 Mek activation by Raf1 [MekInactive] ↔ [MekActive];   {Raf1Active}
 
 Mek activation by B-Raf [MekInactive] ↔ [MekActive];   {BRafActive}
 
 Erk activation [ErkInactive] ↔ [ErkActive];   {MekActive}
 
 Mek deactivation [MekActive] ↔ [MekInactive];   {PP2AActive}
 
 Erk deactivation [ErkActive] ↔ [ErkInactive];   {PP2AActive}
 
 Raf1 deactivation by PPase [Raf1Active] ↔ [Raf1Inactive];   {Raf1PPtase}
 
 P90Rsk activation [P90RskInactive] ↔ [P90RskActive];   {ErkActive}
 
 PI3K activation by EGFR [PI3KInactive] ↔ [PI3KActive];   {boundEGFReceptor}
 
 PI3K activation by Ras [PI3KInactive] ↔ [PI3KActive];   {RasActive}
 
 Akt activation [AktInactive] ↔ [AktActive];   {PI3KActive}
 
 Raf1 deactivation by Akt [Raf1Active] ↔ [Raf1Inactive];   {AktActive}
 
 C3G activation [C3GInactive] ↔ [C3GActive];   {boundNGFReceptor}
 
 Rap1 activation [Rap1Inactive] ↔ [Rap1Active];   {C3GActive}
 
 Rap1 deactivation [Rap1Active] ↔ [Rap1Inactive];   {RapGapActive}
 
 BRaf activation by Rap1 [BRafInactive] ↔ [BRafActive];   {Rap1Active}
 
 BRaf deactivation by PPase [BRafActive] ↔ [BRafInactive];   {Raf1PPtase}
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 EGF
Compartment: cell
Initial concentration: 1.0002E7
 
 NGF
Compartment: cell
Initial concentration: 456000.0
 
 freeEGFReceptor
Compartment: cell
Initial concentration: 80000.0
 
 boundEGFReceptor
Compartment: cell
Initial concentration: 0.0
 
 freeNGFReceptor
Compartment: cell
Initial concentration: 10000.0
 
 boundNGFReceptor
Compartment: cell
Initial concentration: 0.0
 
 SosInactive
Compartment: cell
Initial concentration: 120000.0
 
 SosActive
Compartment: cell
Initial concentration: 0.0
 
 P90RskInactive
Compartment: cell
Initial concentration: 120000.0
 
 P90RskActive
Compartment: cell
Initial concentration: 0.0
 
 RasInactive
Compartment: cell
Initial concentration: 120000.0
 
 RasActive
Compartment: cell
Initial concentration: 0.0
 
 RasGapActive
Compartment: cell
Initial concentration: 120000.0
Constant
 
 Raf1Inactive
Compartment: cell
Initial concentration: 120000.0
 
 Raf1Active
Compartment: cell
Initial concentration: 0.0
 
 BRafInactive
Compartment: cell
Initial concentration: 120000.0
 
 BRafActive
Compartment: cell
Initial concentration: 0.0
 
 MekInactive
Compartment: cell
Initial concentration: 600000.0
 
 MekActive
Compartment: cell
Initial concentration: 0.0
 
 ErkInactive
Compartment: cell
Initial concentration: 600000.0
 
 ErkActive
Compartment: cell
Initial concentration: 0.0
 
 PI3KInactive
Compartment: cell
Initial concentration: 120000.0
 
 PI3KActive
Compartment: cell
Initial concentration: 0.0
 
 AktInactive
Compartment: cell
Initial concentration: 120000.0
 
 AktActive
Compartment: cell
Initial concentration: 0.0
 
 C3GInactive
Compartment: cell
Initial concentration: 120000.0
 
 C3GActive
Compartment: cell
Initial concentration: 0.0
 
 Rap1Inactive
Compartment: cell
Initial concentration: 120000.0
 
 Rap1Active
Compartment: cell
Initial concentration: 0.0
 
 RapGapActive
Compartment: cell
Initial concentration: 120000.0
Constant
 
 PP2AActive
Compartment: cell
Initial concentration: 120000.0
Constant
 
   Raf1PPtase
Compartment: cell
Initial concentration: 120000.0
Constant
 
Global Parameters (48)
 
   krbEGF
Value: 2.18503E-5
Constant
 
   kruEGF
Value: 0.0121008
Constant
 
   krbNGF
Value: 1.38209E-7
Constant
 
   kruNGF
Value: 0.00723811
Constant
 
   kEGF
Value: 694.731
Constant
 
   KmEGF
Value: 6086070.0
Constant
 
   kNGF
Value: 389.428
Constant
 
   KmNGF
Value: 2112.66
Constant
 
   kdSos
Value: 1611.97
Constant
 
   KmdSos
Value: 896896.0
Constant
 
   kSos
Value: 32.344
Constant
 
   KmSos
Value: 35954.3
Constant
 
   kRasGap
Value: 1509.36
Constant
 
   KmRasGap
Value: 1432410.0
Constant
 
   kRasToRaf1
Value: 0.884096
Constant
 
   KmRasToRaf1
Value: 62464.6
Constant
 
   kpRaf1
Value: 185.759
Constant
 
   KmpRaf1
Value: 4768350.0
Constant
 
   kpBRaf
Value: 125.089
Constant
 
   KmpBRaf
Value: 157948.0
Constant
 
   kdMek
Value: 2.83243
Constant
 
   KmdMek
Value: 518753.0
Constant
 
   kpMekCytoplasmic
Value: 9.85367
Constant
 
   KmpMekCytoplasmic
Value: 1007340.0
Constant
 
   kdErk
Value: 8.8912
Constant
 
   KmdErk
Value: 3496490.0
Constant
 
   kpP90Rsk
Value: 0.0213697
Constant
 
   KmpP90Rsk
Value: 763523.0
Constant
 
   kPI3K
Value: 10.6737
Constant
 
   KmPI3K
Value: 184912.0
Constant
 
   kPI3KRas
Value: 0.0771067
Constant
 
   KmPI3KRas
Value: 272056.0
Constant
 
   kAkt
Value: 0.0566279
Constant
 
   KmAkt
Value: 653951.0
Constant
 
   kdRaf1ByAkt
Value: 15.1212
Constant
 
   KmRaf1ByAkt
Value: 119355.0
Constant
 
   kC3GNGF
Value: 146.912
Constant
 
   KmC3GNGF
Value: 12876.2
Constant
 
   kC3G
Value: 1.40145
Constant
 
   KmC3G
Value: 10965.6
Constant
 
   kRapGap
Value: 27.265
Constant
 
   KmRapGap
Value: 295990.0
Constant
 
   kRap1ToBRaf
Value: 2.20995
Constant
 
   KmRap1ToBRaf
Value: 1025460.0
Constant
 
   kdRaf1
Value: 0.126329
Constant
 
   KmdRaf1
Value: 1061.71
Constant
 
   kdBRaf
Value: 441.287
Constant
 
   KmdBRaf
Value: 1.08795E7
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000033

Curator's comment: (updated: 13 Dec 2006 16:55:21 GMT)

Figure 5a reproduced in COPASI 4.0 build 19

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