Large-scale simulations of eukaryotic cell signaling processes

A database of rate constants and related quantities has been assembled by Schoeberl et al. for intracellular signaling downstream of the epidermal growth factor receptor (EGFR). This information was combined with data on metalloprotease activation to build a model of autocrine signal transduction by cancer cells exposed to ionizing radiation. The model predicts prompt activation of mitogen-activated-protein-kinase (MAPK) pathways in response to a radiation-induced shift in the RasGDP↔RasGTP equilibrium toward more RasGTP. A secondary MAPK activation is predicted due to metalloprotease activity that releases transforming growth factor alpha (TGFα), an autocrine ligand of EGFR. Model predictions were compared to data by Dent et al. on extracellular regulated kinase (ERK) activation following a 2 Gy exposure of carcinoma cells in vitro. Good agreement was obtained with the magnitude of prompt and secondary ERK activation; however, the experimental secondary response was delayed relative the prompt peak more than predicted by our model. A mechanistic understanding of radiation-induced growth factors is needed to improve treatment of cancer by radiation therapy. Inhibitors of the signaling pathways modeled in this study may reduce a potentially self-limiting aspect of radiation therapy whereby induced growth factors accelerate repopulation of treated tumor volumes.