BioModels Database logo

BioModels Database

spacer

BIOMD0000000048 - Kholodenko1999 - EGFR signaling

 

 |   |   |  Send feedback
Reference Publication
Publication ID: 10514507
Kholodenko BN, Demin OV, Moehren G, Hoek JB.
Quantification of short term signaling by the epidermal growth factor receptor.
J. Biol. Chem. 1999 Oct; 274(42): 30169-30181
Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. Boris.Kholodenko@mail.tju.edu  [more]
Model
Original Model: JWS logo
Submitter: Lu Li
Submission ID: MODEL6624193277
Submission Date: 05 Dec 2005 23:11:21 UTC
Last Modification Date: 14 Feb 2014 21:36:18 UTC
Creation Date: 23 Nov 2005 21:53:17 UTC
Encoders:  Jacky L Snoep
   Lu Li
set #1
bqmodel:is BioModels Database MODEL6624193277
bqbiol:hasTaxon Taxonomy Rattus norvegicus
bqbiol:occursIn Gene Ontology epidermal growth factor receptor signaling pathway
set #2
bqmodel:is BioModels Database Kholodenko1999_EGFRsignaling
Notes
Kholodenko1999 - EGFR signaling

This model has been generated by the JWS Online project by Jacky Snoep using PySCeS
Run this model online at http://jjj.biochem.sun.ac.za
To cite JWS Online please refer to: Olivier, B.G. and Snoep, J.L. (2004) Web-based modelling using JWS Online , Bioinformatics, 20:2143-2144

This model is described in the article:

Kholodenko BN, Demin OV, Moehren G, Hoek JB
J. Biol. Chem. 1999 Oct; 274(42): 30169-30181

Abstract:

During the past decade, our knowledge of molecular mechanisms involved in growth factor signaling has proliferated almost explosively. However, the kinetics and control of information transfer through signaling networks remain poorly understood. This paper combines experimental kinetic analysis and computational modeling of the short term pattern of cellular responses to epidermal growth factor (EGF) in isolated hepatocytes. The experimental data show transient tyrosine phosphorylation of the EGF receptor (EGFR) and transient or sustained response patterns in multiple signaling proteins targeted by EGFR. Transient responses exhibit pronounced maxima, reached within 15-30 s of EGF stimulation and followed by a decline to relatively low (quasi-steady-state) levels. In contrast to earlier suggestions, we demonstrate that the experimentally observed transients can be accounted for without requiring receptor-mediated activation of specific tyrosine phosphatases, following EGF stimulation. The kinetic model predicts how the cellular response is controlled by the relative levels and activity states of signaling proteins and under what conditions activation patterns are transient or sustained. EGFR signaling patterns appear to be robust with respect to variations in many elemental rate constants within the range of experimentally measured values. On the other hand, we specify which changes in the kinetic scheme, rate constants, and total amounts of molecular factors involved are incompatible with the experimentally observed kinetics of signal transfer. Quantitation of signaling network responses to growth factors allows us to assess how cells process information controlling their growth and differentiation.

The model correctly reproduces all the figures from the paper. The curation has been done using SBMLodeSolver.

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: 10514507 Submission Date: 05 Dec 2005 23:11:21 UTC Last Modification Date: 14 Feb 2014 21:36:18 UTC Creation Date: 23 Nov 2005 21:53:17 UTC
Mathematical expressions
Reactions
EGF_binds_to_EGFR association_of_2_Ra_into_dimer phosphorylation_of_R2 dephosphorylation_of_RP
binding_of_PLCg_to_RP phosphorylation_of_PLCg dissociation_of_RPLCgP dephosphorylation_of_PLCgP
binding_of_Grb2_to_RP binding_of_SOS_to_RG dissociation_of_RGS dissociation_of_GS
binding_of_Shc_to_RP phosphorylation_of_RSh dissociation_of_RShp dephosphorylation_of_ShP
binding_of_Grb2_to_RShP dissociation_of_RShG binding_of_SOS_to_RShG dissociation_of_RShGS
binding_of_Grb2_to_ShP binding_of_SOS_to_ShG dissociation_of_ShGS association_of_RShP_and_GS
translocation_of_PLCgP      
Physical entities
Compartments Species
cytoplasm Epidermal_Growth_Factor EGFR EGF_EGFR
(EGF_EGFR)2 (EGF_EGFR)2-P PLCg
(EGF_EGFR)2_PLCg (EGF_EGFR)2_PLCg-P PLCg-P
Grb2 (EGF_EGFR)2_Grb2 SOS
(EGF_EGFR)2_Grb2_SOS Grb2_SOS Shc
(EGF_EGFR)2_Shc (EGF_EGFR)_Shc-P Shc-P
(EGF_EGFR)2_Shc_Grb2 Shc_Grb2 (EGF_EGFR)2_Shc_Grb2_SOS
Shc_Grb2_SOS PLCgP-I  
Reactions (25)
 
 EGF_binds_to_EGFR [EGFR] + [Epidermal_Growth_Factor] ↔ [EGF_EGFR];  
 
 association_of_2_Ra_into_dimer 2.0 × [EGF_EGFR] ↔ [(EGF_EGFR)2];  
 
 phosphorylation_of_R2 [(EGF_EGFR)2] ↔ [(EGF_EGFR)2-P];  
 
 dephosphorylation_of_RP [(EGF_EGFR)2-P] → [(EGF_EGFR)2];  
 
 binding_of_PLCg_to_RP [(EGF_EGFR)2-P] + [PLCg] ↔ [(EGF_EGFR)2_PLCg];  
 
 phosphorylation_of_PLCg [(EGF_EGFR)2_PLCg] ↔ [(EGF_EGFR)2_PLCg-P];  
 
 dissociation_of_RPLCgP [(EGF_EGFR)2_PLCg-P] ↔ [PLCg-P] + [(EGF_EGFR)2-P];  
 
 dephosphorylation_of_PLCgP [PLCg-P] → [PLCg];  
 
 binding_of_Grb2_to_RP [Grb2] + [(EGF_EGFR)2-P] ↔ [(EGF_EGFR)2_Grb2];  
 
 binding_of_SOS_to_RG [(EGF_EGFR)2_Grb2] + [SOS] ↔ [(EGF_EGFR)2_Grb2_SOS];  
 
 dissociation_of_RGS [(EGF_EGFR)2_Grb2_SOS] ↔ [Grb2_SOS] + [(EGF_EGFR)2-P];  
 
 dissociation_of_GS [Grb2_SOS] ↔ [Grb2] + [SOS];  
 
 binding_of_Shc_to_RP [Shc] + [(EGF_EGFR)2-P] ↔ [(EGF_EGFR)2_Shc];  
 
 phosphorylation_of_RSh [(EGF_EGFR)2_Shc] ↔ [(EGF_EGFR)_Shc-P];  
 
 dissociation_of_RShp [(EGF_EGFR)_Shc-P] ↔ [(EGF_EGFR)2-P] + [Shc-P];  
 
 dephosphorylation_of_ShP [Shc-P] → [Shc];  
 
 binding_of_Grb2_to_RShP [(EGF_EGFR)_Shc-P] + [Grb2] ↔ [(EGF_EGFR)2_Shc_Grb2];  
 
 dissociation_of_RShG [(EGF_EGFR)2_Shc_Grb2] ↔ [Shc_Grb2] + [(EGF_EGFR)2-P];  
 
 binding_of_SOS_to_RShG [SOS] + [(EGF_EGFR)2_Shc_Grb2] ↔ [(EGF_EGFR)2_Shc_Grb2_SOS];  
 
 dissociation_of_RShGS [(EGF_EGFR)2_Shc_Grb2_SOS] ↔ [Shc_Grb2_SOS] + [(EGF_EGFR)2-P];  
 
 binding_of_Grb2_to_ShP [Grb2] + [Shc-P] ↔ [Shc_Grb2];  
 
 binding_of_SOS_to_ShG [Shc_Grb2] + [SOS] ↔ [Shc_Grb2_SOS];  
 
 dissociation_of_ShGS [Shc_Grb2_SOS] ↔ [Grb2_SOS] + [Shc-P];  
 
 association_of_RShP_and_GS [(EGF_EGFR)_Shc-P] + [Grb2_SOS] ↔ [(EGF_EGFR)2_Shc_Grb2_SOS];  
 
 translocation_of_PLCgP [PLCg-P] ↔ [PLCgP-I];  
 
 cytoplasm Spatial dimensions: 3.0  Compartment size: 3.0E-12
 
 Epidermal_Growth_Factor
Compartment: cytoplasm
Initial concentration: 680.0
 
 EGFR
Compartment: cytoplasm
Initial concentration: 100.0
 
 EGF_EGFR
Compartment: cytoplasm
Initial concentration: 0.0
 
 (EGF_EGFR)2
Compartment: cytoplasm
Initial concentration: 0.0
 
 (EGF_EGFR)2-P
Compartment: cytoplasm
Initial concentration: 0.0
 
 PLCg
Compartment: cytoplasm
Initial concentration: 105.0
 
 (EGF_EGFR)2_PLCg
Compartment: cytoplasm
Initial concentration: 0.0
 
 (EGF_EGFR)2_PLCg-P
Compartment: cytoplasm
Initial concentration: 0.0
 
 PLCg-P
Compartment: cytoplasm
Initial concentration: 0.0
 
 Grb2
Compartment: cytoplasm
Initial concentration: 85.0
 
 (EGF_EGFR)2_Grb2
Compartment: cytoplasm
Initial concentration: 0.0
 
 SOS
Compartment: cytoplasm
Initial concentration: 34.0
 
 (EGF_EGFR)2_Grb2_SOS
Compartment: cytoplasm
Initial concentration: 0.0
 
 Grb2_SOS
Compartment: cytoplasm
Initial concentration: 0.0
 
 Shc
Compartment: cytoplasm
Initial concentration: 150.0
 
 (EGF_EGFR)2_Shc
Compartment: cytoplasm
Initial concentration: 0.0
 
 (EGF_EGFR)_Shc-P
Compartment: cytoplasm
Initial concentration: 0.0
 
 Shc-P
Compartment: cytoplasm
Initial concentration: 0.0
 
 (EGF_EGFR)2_Shc_Grb2
Compartment: cytoplasm
Initial concentration: 0.0
 
 Shc_Grb2
Compartment: cytoplasm
Initial concentration: 0.0
 
 (EGF_EGFR)2_Shc_Grb2_SOS
Compartment: cytoplasm
Initial concentration: 0.0
 
 Shc_Grb2_SOS
Compartment: cytoplasm
Initial concentration: 0.0
 
 PLCgP-I
Compartment: cytoplasm
Initial concentration: 0.0
 
EGF_binds_to_EGFR (2)
 
   k1f
Value: 0.0030
Constant
 
   k1b
Value: 0.06
Constant
 
association_of_2_Ra_into_dimer (2)
 
   k2f
Value: 0.01
Constant
 
   k2b
Value: 0.1
Constant
 
phosphorylation_of_R2 (2)
 
   k3f
Value: 1.0
Constant
 
   k3b
Value: 0.01
Constant
 
dephosphorylation_of_RP (2)
 
   V4
Value: 450.0
Constant
 
   K4
Value: 50.0
Constant
 
binding_of_PLCg_to_RP (2)
 
   k5f
Value: 0.06
Constant
 
   k5b
Value: 0.2
Constant
 
phosphorylation_of_PLCg (2)
 
   k6f
Value: 1.0
Constant
 
   k6b
Value: 0.05
Constant
 
dissociation_of_RPLCgP (2)
 
   k7f
Value: 0.3
Constant
 
   k7b
Value: 0.0060
Constant
 
dephosphorylation_of_PLCgP (2)
 
   V8
Value: 1.0
Constant
 
   K8
Value: 100.0
Constant
 
binding_of_Grb2_to_RP (2)
 
   k9f
Value: 0.0030
Constant
 
   k9b
Value: 0.05
Constant
 
binding_of_SOS_to_RG (2)
 
   k10f
Value: 0.01
Constant
 
   k10b
Value: 0.06
Constant
 
dissociation_of_RGS (2)
 
   k11f
Value: 0.03
Constant
 
   k11b
Value: 0.0045
Constant
 
dissociation_of_GS (2)
 
   k12f
Value: 0.0015
Constant
 
   k12b
Value: 1.0E-4
Constant
 
binding_of_Shc_to_RP (2)
 
   k13f
Value: 0.09
Constant
 
   k13b
Value: 0.6
Constant
 
phosphorylation_of_RSh (2)
 
   k14f
Value: 6.0
Constant
 
   k14b
Value: 0.06
Constant
 
dissociation_of_RShp (2)
 
   k15f
Value: 0.3
Constant
 
   k15b
Value: 9.0E-4
Constant
 
dephosphorylation_of_ShP (2)
 
   V16
Value: 1.7
Constant
 
   K16
Value: 340.0
Constant
 
binding_of_Grb2_to_RShP (2)
 
   k17f
Value: 0.0030
Constant
 
   k17b
Value: 0.1
Constant
 
dissociation_of_RShG (2)
 
   k18f
Value: 0.3
Constant
 
   k18b
Value: 9.0E-4
Constant
 
binding_of_SOS_to_RShG (2)
 
   k19f
Value: 0.01
Constant
 
   k19b
Value: 0.0214
Constant
 
dissociation_of_RShGS (2)
 
   k20f
Value: 0.12
Constant
 
   k20b
Value: 2.4E-4
Constant
 
binding_of_Grb2_to_ShP (2)
 
   k21f
Value: 0.0030
Constant
 
   k21b
Value: 0.1
Constant
 
binding_of_SOS_to_ShG (2)
 
   k22f
Value: 0.03
Constant
 
   k22b
Value: 0.064
Constant
 
dissociation_of_ShGS (2)
 
   k23f
Value: 0.1
Constant
 
   k23b
Value: 0.021
Constant
 
association_of_RShP_and_GS (2)
 
   k24f
Value: 0.0090
Constant
 
   k24b
Value: 0.0429
Constant
 
translocation_of_PLCgP (2)
 
   k25f
Value: 1.0
Constant
 
   k25b
Value: 0.03
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000048

Curator's comment: (updated: 04 Jan 2007 14:52:24 PST)

Figure 4A reproduced in SBMLodeSolver.

spacer
spacer