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

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Short description
Orton2009 - Modelling cancerous mutations in the EGFR/ERK pathway - EGF Model
This model studies the aberrations in ERK signalling for different cancer mutations. The authors alter a previously existing EGF model (Brown et al 2004) to include new interactions that better fit empirical data. Predictions show that the ERK signalling is a robust mechanism taking different courses for different cancer mutations. Most parameter values are used from the previous model and the new parameters are estimated using experimental data performed by the authors on PC12 cells (adrenal gland, rat). The authors provide an SBML version of the model in the paper.

This model is described in the article:

Orton RJ, Adriaens ME, Gormand A, Sturm OE, Kolch W, Gilbert DR.
BMC Syst Biol 2009 Oct; 3: 100

Abstract:

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.

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.

Format
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

Metadata information

is
BioModels Database MODEL1611280000
BioModels Database BIOMD0000000623
isDerivedFrom
BioModels Database BIOMD0000000033
isDescribedBy
PubMed 19804630
hasTaxon
occursIn
Brenda Tissue Ontology PC-12 cell
hasProperty
Human Disease Ontology cancer
Curation status
Curated
Original model(s)
Orton2009 - Modelling cancerous mutations in the EGFR_ERK Pathway
  • Model originally submitted by : Thawfeek Varusai
  • Submitted: 28-Nov-2016 21:13:27
  • Last Modified: 09-Jan-2017 11:54:49
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 09-Jan-2017 11:54:49
    • 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: 28-Nov-2016 21:13:27
    • 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.