Large-scale simulations of cellular signaling processes

A database of rate constants and related quantities has been assembled by [Nature Biotech. 20 (2002) 370] for intracellular signaling downstream of the epidermal growth factor receptor (EGFR). This information was combined with data on metalloprotease activation [Proc. Natl. Acad. Sci. USA 96 (1999) 6235] 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 a (TGFα), an autocrine ligand of EGFR. Model predictions were compared to data by [Mol. Biol. Cell 10 (1999) 2493] 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 to the prompt peak more than predicted by our model.