Computational modeling of the EGFR network elucidates control mechanisms regulating signal dynamics
-
* Corresponding author: Jasmin Fisher jasmin.fisher@microsoft.com
1 MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
2 Microsoft Research, Cambridge, UK
3 Department of Computing, Imperial College London, UK
BMC Systems Biology 2009, 3:118 doi:10.1186/1752-0509-3-118
Published: 22 December 2009Additional files
Additional file 1:
Stochastic pi-calculus model of the biochemical interactions involved in the EGFR signalling pathways. The model is based on the reaction map of Figure 1. Essentially, each connected graph represents the set of possible states of a given protein, where each node represents a protein in a particular state. For example, in the top right there are three graphs for proteins Phase1, Phase2 and Phase3, where each of these proteins can be in two possible states, bound or free. Proteins can change their state by interacting with each other over shared channels, where each labelled edge represents an action that a protein can perform in order to change from its current state to a new state. For example, the protein Phase1 can become bound by interacting on channel phase1, and can then become free by interacting on channel p. The channel phase1 is parameterised by p, written phase1(p). This indicates that the protein becomes bound on p after the interaction takes place. In this figure we have grouped sets of proteins together into subsystems, denoted by rectangular boxes. For example, in the top right we have grouped the proteins Phase1, Phase2, Phase3, Raf, MEK and ERK into a cascade subsystem. All the channels inside a given subsystem are local to that subsystem, apart from those that are represented between boxes. For example, in the cascade subsystem the channels phase1, phase2 and phase3 are local and cannot interact with any of the other subsystems, while channels rasgtp and erkpp can interact with two other subsystems. This gives an overall schematic for the interactions between the various subsystems. We observe that the ERK subsystem can interact with the Grb2 subsystem on channel erkpp. Similarly, the EGF subsystem can interact with the Grb2 subsystem on channel complex, representing the EGF-EGFR'2-GAP complex. Finally, we observe that the RasGTP subsystem can interact with both the cascade and the Grb2 subsystem. Note that the interactions with RasGTP are parameterised by channels r, r' and rd, indicating that the bound RasGTP protein can unbind in three different ways, resulting in RasGTP, RasGTP' or RasGDP. A corresponding set of chemical reactions can be automatically generated for the entire system, but note that the translation does not preserve the modular description of the system. The model is available at http://research.microsoft.com/en-us/um/people/aphillip/egfr09/ webcite and the SPiM simulator is available at http://research.microsoft.com/spim/ webcite
Format: PDF Size: 472KB Download file
This file can be viewed with: Adobe Acrobat Reader
Additional file 2:
Behaviour of ERK-PP in response to complete inhibition of key reactions in the EGF module.
Format: PDF Size: 740KB Download file
This file can be viewed with: Adobe Acrobat Reader
Additional file 3:
Behaviour of ERK-PP in response to complete inhibition of key reactions in the Grb2 module.
Format: PDF Size: 1.5MB Download file
This file can be viewed with: Adobe Acrobat Reader
Additional file 4:
Behaviour of ERK-PP in response to complete inhibition of key reactions in the Ras Shc-independent module.
Format: PDF Size: 636KB Download file
This file can be viewed with: Adobe Acrobat Reader
Additional file 5:
Behaviour of ERK-PP in response to complete inhibition of key reactions in the Ras Shc-dependent module.
Format: PDF Size: 964KB Download file
This file can be viewed with: Adobe Acrobat Reader
Additional file 6:
Behaviour of ERK-PP in response to complete inhibition of key reactions in the Raf module.
Format: PDF Size: 732KB Download file
This file can be viewed with: Adobe Acrobat Reader
Additional file 7:
Behaviour of ERK-PP in response to complete inhibition of key reactions in the MEK module.
Format: PDF Size: 1.1MB Download file
This file can be viewed with: Adobe Acrobat Reader
Additional file 8:
Behaviour of ERK-PP in response to complete inhibition of key reactions in the ERK module.
Format: PDF Size: 1.7MB Download file
This file can be viewed with: Adobe Acrobat Reader
Additional file 9:
Boolean table for inferring logical inputs for (EGF-EGFRi)2*.
Format: TIFF Size: 15KB Download file
Additional file 10:
Boolean table for inferring logical inputs for (EGF-EGFR*)2-GAP.
Format: TIFF Size: 42KB Download file
Additional file 11:
Boolean table for inferring logical inputs for (EGF-EGFR*)2-GAP-Shc*.
Format: TIFF Size: 29KB Download file
Additional file 12:
Boolean table for inferring logical inputs for (EGF-EGFR*)2-GAP-Grb2-Sos.
Format: TIFF Size: 39KB Download file
Additional file 13:
Boolean table for inferring logical inputs for (EGF-EGFR*)2-GAP-Shc*-Grb2-Sos.
Format: TIFF Size: 42KB Download file
Additional file 14:
Boolean table for inferring logical inputs for Ras-GTP.
Format: TIFF Size: 42KB Download file
Additional file 15:
Boolean table for inferring logical inputs for Raf*.
Format: TIFF Size: 13KB Download file
Additional file 16:
Boolean table for inferring logical inputs for MEK-PP.
Format: TIFF Size: 13KB Download file
Additional file 17:
Molecular profiles of interface components as a result of perturbations on two different input signals. See highlighted rows in Additional Files 10, 11, 12, 13, 14.
Format: TIFF Size: 101KB Download file
Additional file 18:
Molecular profile of ERK-PP in response to signal from the EGF-EGFR complex as simulated by the abstract pi-calculus model.
Format: TIFF Size: 24KB Download file
Additional file 19:
Molecular profile of ERK-PP in response to signal from the EGF-EGFR complex as simulated by the abstract pi-calculus model, but without abstraction of the Grb module.
Format: TIFF Size: 26KB Download file
