Wang, Cirit, Haugh, 2009

Model Status

This CellML model runs in both COR and OpenCell to replicate the published results (figure 7) with L=1.0nM and the model's parameter values taken as the median of the estimated parameters given on pages 8 and 9 of the supplementary material. The units have been checked and they are consistent.

Model Structure

ABSTRACT: Although it is appreciated that canonical signal-transduction pathways represent dominant modes of regulation embedded in larger interaction networks, relatively little has been done to quantify pathway cross-talk in such networks. Through quantitative measurements that systematically canvas an array of stimulation and molecular perturbation conditions, together with computational modeling and analysis, we have elucidated cross-talk mechanisms in the platelet-derived growth factor (PDGF) receptor signaling network, in which phosphoinositide 3-kinase (PI3K) and Ras/extracellular signal-regulated kinase (Erk) pathways are prominently activated. We show that, while PI3K signaling is insulated from cross-talk, PI3K enhances Erk activation at points both upstream and downstream of Ras. The magnitudes of these effects depend strongly on the stimulation conditions, subject to saturation effects in the respective pathways and negative feedback loops. Motivated by those dynamics, a kinetic model of the network was formulated and used to precisely quantify the relative contributions of PI3K-dependent and -independent modes of Ras/Erk activation.

Conceptual model of the PDGF receptor signaling network. Cross-talk interactions from PI3K lipid products (3' PIs) affect Ras-specific GEF (e.g. Grb2-Sos complex) recruitment and activation of MEK kinases, which might or might not be the same as those activated by Ras. It is recognized that those cross-talk effects might entail multiple steps, and that a more refined model would account for the effect of JNK activation on the MKP negative feedback loop.

The original paper reference is cited below:

PI3K-dependent cross-talk interactions converge with Ras as quantifiable inputs integrated by Erk, Wang CC, Cirit M, and Haugh JM, 2009, Molecular Systems Biology, 5, article 246. PubMed ID: 19225459