Muller, Obeyesekere, Mills, Ram, 2008

Model Status

This cellML model is known to run in both OpenCell and COR to recreate the published results. The units have been checked and they are consistent. Please note that this CellML model corresponds to the reduced 6-node network, not the full 106-node network. Also, we have chosen the parameters such that the model recreates figure 4B in the paper (experiment 3, where there is a stimulus of MSH at 0–5 min followed by a stimulus of FGF at 5–10 min).

Model Structure

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.

Schematic diagram of the model proposed for the activation of MAPK1,2 when initiated due to upstream activation of the FGFR and MC1R.

The original paper reference is cited below:

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, Melissa Muller, Mandri Obeyesekere, Gordon B. Mills and Prahlad T. Ram, 2008, The FASEB Journal PubMed ID: 18171696