Model Identifier
BIOMD0000000175
Short description
This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2009 The BioModels Team.
For more information see the terms of use.
To cite BioModels Database, please use Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.
Format
SBML
(L2V3)
Related Publication
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Ligand-dependent responses of the ErbB signaling network: experimental and modeling analyses.
- Birtwistle MR, Hatakeyama M, Yumoto N, Ogunnaike BA, Hoek JB, Kholodenko BN
- Molecular Systems Biology , 0/ 2007 , Volume 3 , pages: 144 , PubMed ID: 18004277
- Department of Chemical Engineering, University of Delaware, Newark, DE, USA.
- Deregulation of ErbB signaling plays a key role in the progression of multiple human cancers. To help understand ErbB signaling quantitatively, in this work we combine traditional experiments with computational modeling, building a model that describes how stimulation of all four ErbB receptors with epidermal growth factor (EGF) and heregulin (HRG) leads to activation of two critical downstream proteins, extracellular-signal-regulated kinase (ERK) and Akt. Model analysis and experimental validation show that (i) ErbB2 overexpression, which occurs in approximately 25% of all breast cancers, transforms transient EGF-induced signaling into sustained signaling, (ii) HRG-induced ERK activity is much more robust to the ERK cascade inhibitor U0126 than EGF-induced ERK activity, and (iii) phosphoinositol-3 kinase is a major regulator of post-peak but not pre-peak EGF-induced ERK activity. Sensitivity analysis leads to the hypothesis that ERK activation is robust to parameter perturbation at high ligand doses, while Akt activation is not.
Contributors
null Molecular Systems Biology
Metadata information
is
isDescribedBy
hasTaxon
hasVersion
isVersionOf
Curation status
Curated
Tags
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
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| BIOMD0000000175_url.xml | SBML L2V3 representation of Birtwistle2007_ErbB_Signalling | 222.10 KB | Preview | Download |
Additional files |
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| BIOMD0000000175.m | Auto-generated Octave file | 66.76 KB | Preview | Download |
| BIOMD0000000175.svg | Auto-generated Reaction graph (SVG) | 374.34 KB | Preview | Download |
| BIOMD0000000175.sci | Auto-generated Scilab file | 58.85 KB | Preview | Download |
| BIOMD0000000175_urn.xml | Auto-generated SBML file with URNs | 219.79 KB | Preview | Download |
| BIOMD0000000175.png | Auto-generated Reaction graph (PNG) | 4.13 MB | Preview | Download |
| BIOMD0000000175.pdf | Auto-generated PDF file | 784.48 KB | Preview | Download |
| BIOMD0000000175.vcml | Auto-generated VCML file | 916.00 bytes | Preview | Download |
| BIOMD0000000175.xpp | Auto-generated XPP file | 50.36 KB | Preview | Download |
| BIOMD0000000175-biopax3.owl | Auto-generated BioPAX (Level 3) | 335.09 KB | Preview | Download |
| BIOMD0000000175-biopax2.owl | Auto-generated BioPAX (Level 2) | 190.20 KB | Preview | Download |
- Model originally submitted by : null Molecular Systems Biology
- Submitted: 18-Jul-2008 14:45:02
- Last Modified: 08-Apr-2016 16:42:16
Revisions
-
Version: 2
- Submitted on: 08-Apr-2016 16:42:16
- Submitted by: null Molecular Systems Biology
- With comment: Current version of Birtwistle2007_ErbB_Signalling
-
Version: 1
- Submitted on: 18-Jul-2008 14:45:02
- Submitted by: null Molecular Systems Biology
- With comment: Original import of ErbB
Legends
: Variable used inside SBML models
: Variable used inside SBML models
Species
| Species | Initial Concentration/Amount |
|---|---|
| PIP3 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate ; Phosphatidylinositol-3,4,5-trisphosphate |
0.0 nmol |
| Akt 611223; RAC-gamma serine/threonine-protein kinase |
444.0 nmol |
| RasGDP GDP ; GTPase HRas |
95.7 nmol |
| RasGTP GTP ; GTPase HRas |
0.0 nmol |
| MEK* 176872; Dual specificity mitogen-activated protein kinase kinase 1 ; Mitogen-activated protein kinase kinase 1Mitogen-activated protein kinase kinase 1, isoform CRA acDNA FLJ76051, highly similar to Homo sapiens mitogen-activated protein kinase kinase 1 (MAP2K1), mRNA ; Phosphoprotein |
0.0 nmol |
| E12-Shc | 0.0 nmol |
| E23-Grb2 | 0.0 nmol |
| E23-PI-3K | 0.0 nmol |
| E34-Grb2 | 0.0 nmol |
| E24-Grb2 | 0.0 nmol |
| E24-RasGAP | 0.0 nmol |
| E44-PI-3K | 0.0 nmol |
| E44-RasGAP | 0.0 nmol |
Reactions
| Reactions | Rate | Parameters |
|---|---|---|
| (PIP3 + Gab1) => (PIP3-Gab1 + Sum Gab1) ([1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate; Phosphatidylinositol-3,4,5-trisphosphate] + [GRB2-associated-binding protein 1; 604439]) => ([PIP3-Gab1] + [Sum Gab1]) |
membrane*(kon46*P3*A-koff46*P3_A*SigA/(eps+SigA+SigAP+SigAP_S+SigAP_R+SigAP_I+SigAP_T)) membrane*(kon46*[1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate; Phosphatidylinositol-3,4,5-trisphosphate]*[GRB2-associated-binding protein 1; 604439]-koff46*[PIP3-Gab1]*[Sum Gab1]/(eps+[Sum Gab1]+[Sum Gab1_p]+[Sum Gab1_p-Shc]+[Sum Gab1_p-RasGAP]+[Sum Gab1_p-PI-3K]+[SumGab1_p-PTP-1B])) |
kon46 = 0.0148; koff46 = 0.5194; eps = 1.0E-16 |
| (PIP2) => (PIP3) ([CHEBI_28910; 1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate]) => ([1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate; Phosphatidylinositol-3,4,5-trisphosphate]) |
membrane*(kf48*(1-fint*E11P/(E11P+E12P+E23P+E24P+E34P+E44P+E13P+E14P+eps))*SigI*P2/(Kmf48+P2)-3*PTEN*P3/(Kmr48+P3)) membrane*(kf48*(1-[fint]*[Phosphoprotein; Epidermal growth factor receptor]/([Phosphoprotein; Epidermal growth factor receptor]+[Phosphoprotein; Epidermal growth factor receptor; Receptor tyrosine-protein kinase erbB-2]+[E23_p]+[E24_p]+[E34_p]+[E44_p]+[ErbB1-ErbB3_p]+[ErbB1-ErbB3_p]+eps))*[Sum PI-3K]*[CHEBI_28910; 1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate]/(Kmf48+[CHEBI_28910; 1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate])-3*PTEN*[1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate; Phosphatidylinositol-3,4,5-trisphosphate]/(Kmr48+[1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate; Phosphatidylinositol-3,4,5-trisphosphate])) |
Kmr48 = 324.9294; PTEN = 693.5786; Kmf48 = 715.5688; eps = 1.0E-16; kf48 = 16.833 |
| (Akt) => (Aktstar) ([611223; RAC-gamma serine/threonine-protein kinase]) => ([Aktstar]) |
membrane*(kf47*P3*Akt/(Kmf47+Akt)-Vmaxr47*Aktstar/(Kmr47+Aktstar)) membrane*(kf47*[1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate; Phosphatidylinositol-3,4,5-trisphosphate]*[611223; RAC-gamma serine/threonine-protein kinase]/(Kmf47+[611223; RAC-gamma serine/threonine-protein kinase])-Vmaxr47*[Aktstar]/(Kmr47+[Aktstar])) |
kf47 = 24.6048; Vmaxr47 = 590.5058; Kmr47 = 483.8622; Kmf47 = 698.6022 |
| (RasGDP) => (RasGTP) ([GDP; GTPase HRas]) => ([GTP; GTPase HRas]) |
membrane*(((kf49*SigO*RsD/(Kmf49+RsD)-kr49*SigR*RsT/(Kmr49+RsT))-kr49b*SigRP*RsT/(Kmr49b+RsT))-kcon49*RsT) membrane*(((kf49*[Sum SOS]*[GDP; GTPase HRas]/(Kmf49+[GDP; GTPase HRas])-kr49*[Sum RasGAP]*[GTP; GTPase HRas]/(Kmr49+[GTP; GTPase HRas]))-kr49b*[Sum RasGAP_p]*[GTP; GTPase HRas]/(Kmr49b+[GTP; GTPase HRas]))-kcon49*[GTP; GTPase HRas]) |
Kmr49 = 753.1667; kr49 = 552.6746; kcon49 = 9.9783; kf49 = 44.3501; Kmr49b = 381.2208; kr49b = 640.8212; Kmf49 = 343.2483 |
| (ERK + MEK*) => (ERK-MEK*) ([176948; Mitogen-activated protein kinase 1] + [176872; Dual specificity mitogen-activated protein kinase kinase 1; Mitogen-activated protein kinase kinase 1Mitogen-activated protein kinase kinase 1, isoform CRA_acDNA FLJ76051, highly similar to Homo sapiens mitogen-activated protein kinase kinase 1 (MAP2K1), mRNA; Phosphoprotein]) => ([ERK-MEK*]) |
membrane*(kon89*ERK*MEKstar-koff89*ERK_MEKstar) membrane*(kon89*[176948; Mitogen-activated protein kinase 1]*[176872; Dual specificity mitogen-activated protein kinase kinase 1; Mitogen-activated protein kinase kinase 1Mitogen-activated protein kinase kinase 1, isoform CRA_acDNA FLJ76051, highly similar to Homo sapiens mitogen-activated protein kinase kinase 1 (MAP2K1), mRNA; Phosphoprotein]-koff89*[ERK-[176872; Dual specificity mitogen-activated protein kinase kinase 1; Mitogen-activated protein kinase kinase 1Mitogen-activated protein kinase kinase 1, isoform CRA_acDNA FLJ76051, highly similar to Homo sapiens mitogen-activated protein kinase kinase 1 (MAP2K1), mRNA]*]) |
kon89 = 0.1997; koff89 = 99.9637 |
| (ERK-MEK*) => (p_ERK + MEK*) ([ERK-MEK*]) => ([p_ERK] + [176872; Dual specificity mitogen-activated protein kinase kinase 1; Mitogen-activated protein kinase kinase 1Mitogen-activated protein kinase kinase 1, isoform CRA_acDNA FLJ76051, highly similar to Homo sapiens mitogen-activated protein kinase kinase 1 (MAP2K1), mRNA; Phosphoprotein]) |
membrane*kcat90*ERK_MEKstar membrane*kcat90*[ERK-[176872; Dual specificity mitogen-activated protein kinase kinase 1; Mitogen-activated protein kinase kinase 1Mitogen-activated protein kinase kinase 1, isoform CRA_acDNA FLJ76051, highly similar to Homo sapiens mitogen-activated protein kinase kinase 1 (MAP2K1), mRNA]*] |
kcat90 = 20.0037 |
| (E12_p + Shc) => (E12-Shc + Sum Shc) ([Phosphoprotein; Epidermal growth factor receptor; Receptor tyrosine-protein kinase erbB-2] + [SHC-transforming protein 2; 605217]) => ([E12-Shc] + [Sum Shc]) |
membrane*(6*kon20*E12P*S-koff20*SigS/(SigS+SigSP+SigSP_G+eps)*E12S) membrane*(6*kon20*[Phosphoprotein; Epidermal growth factor receptor; Receptor tyrosine-protein kinase erbB-2]*[SHC-transforming protein 2; 605217]-koff20*[Sum Shc]/([Sum Shc]+[Sum Shc_p]+[Sum Shc_p-Grb2]+eps)*[E12-Shc]) |
kon20 = 0.0478; koff20 = 0.6761; eps = 1.0E-16 |
| (E23_p + Grb2) => (E23-Grb2 + Sum Grb2) ([E23_p] + [Growth factor receptor-bound protein 2; 108355]) => ([E23-Grb2] + [Sum Grb2]) |
membrane*(3*kon22*E23P*G-koff22*SigG/(SigG+SigG_A+SigG_O+A_SigG_O+eps)*E23G) membrane*(3*kon22*[E23_p]*[Growth factor receptor-bound protein 2; 108355]-koff22*[Sum Grb2]/([Sum Grb2]+[Sum Grb2-Gab1]+[Sum Grb2-SOS]+[Gab1_SumGrb2-SOS]+eps)*[E23-Grb2]) |
eps = 1.0E-16; koff22 = 3.6962; kon22 = 7.0E-4 |
| (E23_p + PI-3K) => (E23-PI-3K + Sum PI-3K) ([E23_p] + [Phosphoinositide 3-kinase regulatory subunit 5; Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform]) => ([E23-PI-3K] + [Sum PI-3K]) |
membrane*(3*kon24*E23P*I-koff24*E23I) membrane*(3*kon24*[E23_p]*[Phosphoinositide 3-kinase regulatory subunit 5; Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform]-koff24*[E23-PI-3K]) |
koff24 = 4.4226; kon24 = 0.005 |
| (E34_p + Grb2) => (E34-Grb2 + Sum Grb2) ([E34_p] + [Growth factor receptor-bound protein 2; 108355]) => ([E34-Grb2] + [Sum Grb2]) |
membrane*(4*kon26*E34P*G-koff26*SigG/(SigG+SigG_A+SigG_O+A_SigG_O+eps)*E34G) membrane*(4*kon26*[E34_p]*[Growth factor receptor-bound protein 2; 108355]-koff26*[Sum Grb2]/([Sum Grb2]+[Sum Grb2-Gab1]+[Sum Grb2-SOS]+[Gab1_SumGrb2-SOS]+eps)*[E34-Grb2]) |
kon26 = 0.0355; koff26 = 0.0103; eps = 1.0E-16 |
| (E24_p + Grb2) => (E24-Grb2 + Sum Grb2) ([E24_p] + [Growth factor receptor-bound protein 2; 108355]) => ([E24-Grb2] + [Sum Grb2]) |
membrane*(3*kon30*E24P*G-koff30*SigG/(SigG+SigG_A+SigG_O+A_SigG_O+eps)*E24G) membrane*(3*kon30*[E24_p]*[Growth factor receptor-bound protein 2; 108355]-koff30*[Sum Grb2]/([Sum Grb2]+[Sum Grb2-Gab1]+[Sum Grb2-SOS]+[Gab1_SumGrb2-SOS]+eps)*[E24-Grb2]) |
koff30 = 4.9936; kon30 = 0.002; eps = 1.0E-16 |
| (E24_p + RasGAP) => (E24-RasGAP + Sum RasGAP) ([E24_p] + [139150; Ras GTPase-activating protein 1]) => ([E24-RasGAP] + [Sum RasGAP]) |
membrane*(2*kon33*E24P*R-koff33*SigR/(SigR+SigRP+eps)*E24R) membrane*(2*kon33*[E24_p]*[139150; Ras GTPase-activating protein 1]-koff33*[Sum RasGAP]/([Sum RasGAP]+[Sum RasGAP_p]+eps)*[E24-RasGAP]) |
kon33 = 0.0335; eps = 1.0E-16; koff33 = 1.2817 |
| (E44_p + PI-3K) => (E44-PI-3K + Sum PI-3K) ([E44_p] + [Phosphoinositide 3-kinase regulatory subunit 5; Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform]) => ([E44-PI-3K] + [Sum PI-3K]) |
membrane*(2*kon36*E44P*I-koff36*E44I) membrane*(2*kon36*[E44_p]*[Phosphoinositide 3-kinase regulatory subunit 5; Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform]-koff36*[[Pro-neuregulin-1, membrane-bound isoform; Receptor tyrosine-protein kinase erbB-4]-PI-3K]) |
kon36 = 0.0043; koff36 = 1.2567 |
| (E44_p + RasGAP) => (E44-RasGAP + Sum RasGAP) ([E44_p] + [139150; Ras GTPase-activating protein 1]) => ([E44-RasGAP] + [Sum RasGAP]) |
membrane*(2*kon37*E44P*R-koff37*SigR/(SigR+SigRP+eps)*E44R) membrane*(2*kon37*[E44_p]*[139150; Ras GTPase-activating protein 1]-koff37*[Sum RasGAP]/([Sum RasGAP]+[Sum RasGAP_p]+eps)*[[Pro-neuregulin-1, membrane-bound isoform; Receptor tyrosine-protein kinase erbB-4]-RasGAP]) |
koff37 = 0.4059; kon37 = 0.0791; eps = 1.0E-16 |
Curator's comment:
(added: 18 Jul 2008, 14:35:48, updated: 18 Jul 2008, 14:35:48)
(added: 18 Jul 2008, 14:35:48, updated: 18 Jul 2008, 14:35:48)
reproduction of figure 4 using SBMLodeSolver (20080507)