ABSTRACT:
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:
Computational
modelling of cancerous mutations in the EGFR/ERK signalling
pathway.
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.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000623.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
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.
Thawfeek Varusai 
