Muller2008 - Simplified MAPK activation Dynamics (Model B)

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Model Identifier
BIOMD0000000664
Short description
Muller2008 - Simplified MAPK activation Dynamics (Model B)
Simplified mathematical model (model B) for predicting MAPK signal expression.

This model is described in the article:

Muller M, Obeyesekere M, Mills GB, Ram PT.
FASEB J. 2008 May; 22(5): 1393-1403

Abstract:

Activation of the fibroblast growth factor (FGFR) and melanocyte stimulating hormone (MC1R) receptors stimulates B-Raf and C-Raf isoforms that regulate the dynamics of MAPK1,2 signaling. Network topology motifs in mammalian cells include feed-forward and feedback loops and bifans where signals from two upstream molecules integrate to modulate the activity of two downstream molecules. We computationally modeled and experimentally tested signal processing in the FGFR/MC1R/B-Raf/C-Raf/MAPK1,2 network in human melanoma cells; identifying 7 regulatory loops and a bifan motif. Signaling from FGFR leads to sustained activation of MAPK1,2, whereas signaling from MC1R results in transient activation of MAPK1,2. The dynamics of MAPK activation depends critically on the expression level and connectivity to C-Raf, which is critical for a sustained MAPK1,2 response. A partially incoherent bifan motif with a feedback loop acts as a logic gate to integrate signals and regulate duration of activation of the MAPK signaling cascade. Further reducing a 106-node ordinary differential equations network encompassing the complete network to a 6-node network encompassing rate-limiting processes sustains the feedback loops and the bifan, providing sufficient information to predict biological responses.

This model is hosted on BioModels Database and identified by: BIOMD0000000664.

To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8.

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
  • Network topology determines dynamics of the mammalian MAPK1,2 signaling network: bifan motif regulation of C-Raf and B-Raf isoforms by FGFR and MC1R.
  • Muller M, Obeyesekere M, Mills GB, Ram PT
  • FASEB journal : official publication of the Federation of American Societies for Experimental Biology , 5/ 2008 , Volume 22 , Issue 5 , pages: 1393-1403 , PubMed ID: 18171696
  • Department of Systems Biology, UT M.D. Anderson Cancer Center, 7435 Fannin St., Houston, TX 77054, USA.
  • Activation of the fibroblast growth factor (FGFR) and melanocyte stimulating hormone (MC1R) receptors stimulates B-Raf and C-Raf isoforms that regulate the dynamics of MAPK1,2 signaling. Network topology motifs in mammalian cells include feed-forward and feedback loops and bifans where signals from two upstream molecules integrate to modulate the activity of two downstream molecules. We computationally modeled and experimentally tested signal processing in the FGFR/MC1R/B-Raf/C-Raf/MAPK1,2 network in human melanoma cells; identifying 7 regulatory loops and a bifan motif. Signaling from FGFR leads to sustained activation of MAPK1,2, whereas signaling from MC1R results in transient activation of MAPK1,2. The dynamics of MAPK activation depends critically on the expression level and connectivity to C-Raf, which is critical for a sustained MAPK1,2 response. A partially incoherent bifan motif with a feedback loop acts as a logic gate to integrate signals and regulate duration of activation of the MAPK signaling cascade. Further reducing a 106-node ordinary differential equations network encompassing the complete network to a 6-node network encompassing rate-limiting processes sustains the feedback loops and the bifan, providing sufficient information to predict biological responses.
Contributors
Submitter of the first revision: Vijayalakshmi Chelliah
Submitter of this revision: administrator
Modellers: administrator, Vijayalakshmi Chelliah

Metadata information

is (2 statements)
BioModels Database MODEL8687732743
BioModels Database BIOMD0000000664

isDescribedBy (1 statement)
PubMed 18171696

hasTaxon (1 statement)
Taxonomy Homo sapiens

hasProperty (2 statements)
Mathematical Modelling Ontology Ordinary differential equation model
Gene Ontology regulation of MAPK cascade

occursIn (1 statement)
Brenda Tissue Ontology melanoma cell


Curation status
Curated


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Model files

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MODEL8687732743.cps COPASI file 94.16 KB Preview | Download
MODEL8687732743.sedml File for figure 4b. To generate figures 2b and 2c, adjust g1 and g2 parameter value expressions accordingly. 1.65 KB Preview | Download

  • Model originally submitted by : Vijayalakshmi Chelliah
  • Submitted: Apr 23, 2009 2:17:41 PM
  • Last Modified: Jan 29, 2018 12:55:14 PM
Revisions
  • Version: 3 public model Download this version
    • Submitted on: Jan 29, 2018 12:55:14 PM
    • Submitted by: administrator
    • With comment: Model name updated using online editor.
  • Version: 2 public model Download this version
    • Submitted on: Apr 23, 2009 2:17:41 PM
    • Submitted by: Vijayalakshmi Chelliah
    • With comment: Current version of Muller2008_MAPKactivation_Dynamics
  • Version: 1 public model Download this version
    • Submitted on: Apr 23, 2009 2:17:41 PM
    • Submitted by: Vijayalakshmi Chelliah
    • With comment: Original import of Muller2008_MAPKactivation_Dynamics

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

Legends
: Variable used inside SBML models


Species
Reactions
Reactions Rate Parameters
C_Raf => C_Raf_inactive; MSH Compartment*h36_y3*MSH*C_Raf h36_y3 = 0.1 0.06*ml/(mol*s)
FGFR => Compartment*d1*FGFR d1 = 0.2 1/(59.9999*s)
=> MSH; g2_0 Compartment*a2*g2/(b2+g2) b2 = 10.0; a2 = 10.0 0.06*mmol/(l*s); g2 = 1.0
MSH => Compartment*d2*MSH d2 = 0.1 1/(59.9999*s)
=> FGFR; g1_0 Compartment*a1*g1/(b1+g1) b1 = 10.0; a1 = 10.0 0.06*mmol/(l*s); g1 = 0.0
=> B_Raf; MSH Compartment*f24*MSH f24 = 0.8 1/(59.9999*s)
=> C_Raf; C_Raf_inactive, MAPK Compartment*f53*((E-C_Raf)-C_Raf_inactive)*MAPK E = 10.0; f53 = 1.5 0.06*ml/(mol*s)
g1_0 = g1 [] g1 = 0.0
MAPK => Compartment*d5*MAPK d5 = 1.0 1/(59.9999*s)
=> B_Raf; FGFR Compartment*f14*FGFR f14 = 0.1 1/(59.9999*s)
Curator's comment:
(added: 29 Jan 2018, 12:41:59, updated: 29 Jan 2018, 12:41:59)
Figures 2c, 2d and 4b of the reference publication have been reproduced. Figures 2c, 2d and 4b show MAPK activity following MHS-only, FGFR-only and MHS followed by FGFR stimulation respectively. Simulations were performed in COPASI 4.22 (Build 170) and figures were generated in MATLAB R2014.