Mathematical modeling of epidermal growth factor receptor signaling through the phospholipase C pathway: mechanistic insights and predictions for molecular interventions.

Combining engineering analyses and mathematical modeling with intervention and detection methodologies at the molecular level will allow manipulation of intracellular signal transduction pathways, and therefore rational control of functional processes central to medicine and biotechnology. We have formulated a simple mathematical model of a key signaling pathway required for regulated migration of fibroblasts and other cell types: activation of the intracellular enzyme phospholipase C (PLC) mediated by epidermal growth factor receptor (EGFR) and a multitude of other transmembrane receptors. One of the interesting features of this pathway is that the substrate of PLC, the lipid phosphatidylinositol (4,5)-bisphosphate (PIP(2)), is turned over quite rapidly and must be constantly resupplied to the plasma membrane by a known transfer mechanism. The model, which accounts for regulation of PIP(2) concentration, is sufficiently detailed to explain unique quantitative features of recent experimental data. We find that competitive pathways that deplete PIP(2) from the membrane, as well as receptor-mediated enhancement of PIP(2) supply, must be significant for agreement between model and experiment. Importantly, the mechanistic nature of the model also allowed us to predict the efficacy of various molecular intervention strategies, including overexpression of wild-type and variant proteins in the pathway as well as treatment with specific drug inhibitors. For many parameter conditions the intuitive strategy of targeting the enzyme itself is actually predicted to be relatively inefficient, with a novel and potentially useful alternative being disruption of the reactant supply mechanism. Copyright 2000 John Wiley & Sons, Inc.