Birtwistle2007_ErbB_Signalling

  public model
Model Identifier
BIOMD0000000175
Short description
Format
SBML (L2V3)
Related Publication
  • 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
BioModels Database MODEL5563731079
BioModels Database BIOMD0000000175
isDescribedBy
PubMed 18004277
hasTaxon
Taxonomy Homo sapiens
hasVersion
Gene Ontology MAPK cascade
Reactome Signalling to ERKs
isVersionOf
Gene Ontology ERBB signaling pathway

Curation status
Curated

Tags
Name Description Size Actions

Model files

BIOMD0000000175_url.xml SBML L2V3 representation of Birtwistle2007_ErbB_Signalling 222.10 KB Preview | Download

Additional files

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 public model Download this version
    • Submitted on: 08-Apr-2016 16:42:16
    • Submitted by: null Molecular Systems Biology
    • With comment: Current version of Birtwistle2007_ErbB_Signalling
  • Version: 1 public model Download this version
    • 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


Species
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)
reproduction of figure 4 using SBMLodeSolver (20080507)