Relationship between epidermal growth factor receptor occupancy and mitogenic response. Quantitative analysis using a steady state model system.

Abstract

Because mitogenic stimulation by epidermal growth factor (EGF) requires at least an 8--12-h exposure to commit the majority of the cells to divide, a number of complicating processes must be evaluated in an analysis of the relationship between receptor occupancy and the biological response. During this period, the number of cellular EGF receptors changes and the cells continuously bind, internalize, and degrade the hormone. To deal with these changes, we utilized our previously described steady state model that permits an analysis of EGF interactions with cells under steady state conditions. For these studies we derived and measured a number of steady state rate constants to describe the interaction of 125I-EGF with cultured human and mouse fibroblast-like cells. The validity of these constants was established by demonstrating the close agreement between experimentally determined results and predicted results from computer simulations using these constants. These approaches in conjunction with experiments on the mitogenic stimulation of the cells with EGF led to the conclusion that there is a linear relationship between mitogenic stimulation and EGF receptor occupancy at steady state, with no apparent "spare" EGF receptors.