Birtwistle2007_ErbB_Signalling

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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.
Metadata information
Name | Description | Size | Actions |
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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.svg | Auto-generated Reaction graph (SVG) | 374.34 KB | Preview | Download |
BIOMD0000000175.xpp | Auto-generated XPP file | 50.36 KB | Preview | Download |
BIOMD0000000175.vcml | Auto-generated VCML file | 916.00 Bytes | Preview | Download |
BIOMD0000000175.png | Auto-generated Reaction graph (PNG) | 4.13 MB | Preview | Download |
BIOMD0000000175_urn.xml | Auto-generated SBML file with URNs | 219.79 KB | Preview | Download |
BIOMD0000000175-biopax2.owl | Auto-generated BioPAX (Level 2) | 190.20 KB | Preview | Download |
BIOMD0000000175-biopax3.owl | Auto-generated BioPAX (Level 3) | 335.09 KB | Preview | Download |
BIOMD0000000175.sci | Auto-generated Scilab file | 58.85 KB | Preview | Download |
BIOMD0000000175.m | Auto-generated Octave file | 66.76 KB | Preview | Download |
BIOMD0000000175.pdf | Auto-generated PDF file | 784.48 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
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Version: 2
- Submitted on: 08-Apr-2016 16:42:16
- Submitted by: null Molecular Systems Biology
- With comment: Current version of Birtwistle2007_ErbB_Signalling
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Version: 1
- Submitted on: 18-Jul-2008 14:45:02
- Submitted by: null Molecular Systems Biology
- With comment: Original import of ErbB
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revisions as only public revisions are displayed here. Any private revisions
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: Variable used inside SBML models
Species | Initial Concentration/Amount |
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SigS | 0.0 nmol |
SigI | 0.0 nmol |
SigR | 0.0 nmol |
SigA | 0.0 nmol |
SigSP | 0.0 nmol |
E4 PT | 0.0 nmol |
H E4 PT | 0.0 nmol |
Reactions | Rate | Parameters |
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SigAP + S => SigAP_S + SigS; SigSP, SigSP_G | membrane*(3*kon43*SigAP*S-koff43*SigAP_S*SigS/(SigS+SigSP+SigSP_G+eps)) | koff43 = 0.5441; eps = 1.0E-16; kon43 = 0.0127 |
E11S + SigS => S | membrane*kdeg*E11S | kdeg = 0.0259 |
E34P + I => E34I + SigI | membrane*(4*kon28*E34P*I-koff28*E34I) | koff28 = 4.6432; kon28 = 0.0074 |
E44P + I => E44I + SigI | membrane*(2*kon36*E44P*I-koff36*E44I) | kon36 = 0.0043; koff36 = 1.2567 |
E13P + I => E13I + SigI | membrane*(3*kon67*E13P*I-koff67*E13I) | kon67 = 6.6667E-5; koff67 = 1.6142 |
E11P + R => E11R + SigR; SigRP | membrane*(2*kon18*E11P*R-koff18*SigR/(SigR+SigRP+eps)*E11R) | kon18 = 0.0117; eps = 1.0E-16; koff18 = 2.2768 |
E23P + R => E23R + SigR; SigRP | membrane*(2*kon25*E23P*R-koff25*SigR/(SigR+SigRP+eps)*E23R) | kon25 = 0.0995; eps = 1.0E-16; koff25 = 2.225 |
E24P + R => E24R + SigR; SigRP | membrane*(2*kon33*E24P*R-koff33*SigR/(SigR+SigRP+eps)*E24R) | kon33 = 0.0335; eps = 1.0E-16; koff33 = 1.2817 |
E13P + R => E13R + SigR; SigRP | membrane*(2*kon68*E13P*R-koff68*SigR/(SigR+SigRP+eps)*E13R) | eps = 1.0E-16; kon68 = 0.0045; koff68 = 2.8871 |
SigA => SigAP; E11P, E12P, E23P, E24P, E34P, E44P, E13P, E14P, SigT | membrane*((kf39*SigA*(E11P+E12P+E23P+E24P+E34P+E44P+E13P+E14P)-VmaxPY*SigAP/(KmPY+SigAP))-kPTP39*SigT*SigAP) | kPTP39 = 79.6132; kf39 = 385.7428; KmPY = 486.1398; VmaxPY = 223.8776 |
SigG + A => SigG_A + SigA; SigAP, SigAP_S, SigAP_R, SigAP_I, SigAP_T | membrane*(kon41*SigG*A-koff41*SigG_A*SigA/(eps+SigA+SigAP+SigAP_S+SigAP_R+SigAP_I+SigAP_T)) | eps = 1.0E-16; kon41 = 0.0051; koff41 = 7.0487 |
P3 + A => P3_A + SigA; SigAP, SigAP_S, SigAP_R, SigAP_I, SigAP_T | membrane*(kon46*P3*A-koff46*P3_A*SigA/(eps+SigA+SigAP+SigAP_S+SigAP_R+SigAP_I+SigAP_T)) | kon46 = 0.0148; koff46 = 0.5194; eps = 1.0E-16 |
SigS => SigSP; E11P, E12P, E23P, E24P, E34P, E44P, E13P, E14P, SigT | membrane*((kf38*SigS*(E11P+E12P+E23P+E24P+E34P+E44P+E13P+E14P)-VmaxPY*SigSP/(KmPY+SigSP))-kPTP38*SigT*SigSP) | kf38 = 279.9929; kPTP38 = 83.4465; KmPY = 486.1398; VmaxPY = 223.8776 |
E4 => E4_PT; ERKstar | membrane*(kf83*E4*ERKstar/(Kmf83+E4)-Vmaxr83*E4_PT/(Kmr83+E4_PT)) | Kmf83 = 609.4766; Kmr83 = 653.5184; kf83 = 1.7628; Vmaxr83 = 534.0531 |
E4_PT => H_E4_PT; H | membrane*(kon87*H*E4_PT-HRGoff_4*H_E4_PT) | HRGoff_4 = 0.0973; kon87 = 8.0E-4 |
(added: 18 Jul 2008, 14:35:48, updated: 18 Jul 2008, 14:35:48)