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Orton2009 - Modelling cancerous mutations in the EGFR/ERK pathway - EGF Model

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SBML (L2V4)
Related Publication
  • Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway.
  • Orton RJ, Adriaens ME, Gormand A, Sturm OE, Kolch W, Gilbert DR
  • BMC systems biology , 10/ 2009 , Volume 3 , pages: 100
  • Institute of Comparative Medicine, Faculty of Veterinary Medicine, University of Glasgow, Glasgow, UK. r.orton@vet.gla.ac.uk
  • The Epidermal Growth Factor Receptor (EGFR) activated Extracellular-signal Regulated Kinase (ERK) pathway is a critical cell signalling pathway that relays the signal for a cell to proliferate from the plasma membrane to the nucleus. Deregulation of the EGFR/ERK pathway due to alterations affecting the expression or function of a number of pathway components has long been associated with numerous forms of cancer. Under normal conditions, Epidermal Growth Factor (EGF) stimulates a rapid but transient activation of ERK as the signal is rapidly shutdown. Whereas, under cancerous mutation conditions the ERK signal cannot be shutdown and is sustained resulting in the constitutive activation of ERK and continual cell proliferation. In this study, we have used computational modelling techniques to investigate what effects various cancerous alterations have on the signalling flow through the ERK pathway.We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF) receptors.Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications for drug selection strategies. We also conducted a comparison of the critical differences between signalling from different growth factor receptors (namely EGFR, mutated EGFR, NGF, and Insulin) with our results suggesting the difference between the systems are large scale and can be attributed to the presence/absence of entire pathways rather than subtle difference in individual rate constants between the systems.
Contributors
Thawfeek Varusai, administrator

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Curated
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Model files

BIOMD0000000623.xml.origin SBML L2V4 representation of Orton2009 - Modelling cancerous mutations in the EGFR/ERK pathway - EGF Model 159.97 KB Preview | Download

Additional files

Orton2009.cps Time Course of Active Ras and Rap1 can be found here. 180.44 KB Preview | Download
Orton2009.sedml Time course of active Ras and Rap1 can be found here. The SEDML file was generated from Copasi 4.16 14.46 KB Preview | Download

  • Model originally submitted by : Thawfeek Varusai
  • Submitted: Nov 28, 2016 9:13:27 PM
  • Last Modified: Dec 21, 2018 6:20:00 PM
Revisions
  • Version: 3 public model Download this version
    • Submitted on: Dec 21, 2018 6:20:00 PM
    • Submitted by: administrator
    • With comment: Include the additional files provided by the submitter in the original submission: Orton2009.sedml, Orton2009.cps
  • Version: 2 public model Download this version
    • Submitted on: Jan 9, 2017 11:54:49 AM
    • Submitted by: Thawfeek Varusai
    • With comment: Current version of Orton2009 - Modelling cancerous mutations in the EGFR/ERK pathway - EGF Model
  • Version: 1 public model Download this version
    • Submitted on: Nov 28, 2016 9:13:27 PM
    • Submitted by: Thawfeek Varusai
    • With comment: Original import of Orton2009 - Modelling cancerous mutations in the EGFR/ERK pathway - EGF Model
Curator's comment:
(added: 28 Nov 2016, 21:21:31, updated: 28 Nov 2016, 21:21:31)
The SBML file of this model was provided by the authors in the paper. The file did not have any errors and simulations worked just fine. Figure 4B in the paper is reproduced here. The two curves in the graph indicate active Ras (red) and active Rap1 (blue). One observation was that all the parameters in this model are represented in units of minutes.