Current challenges in quantitative modeling of epidermal growth factor signaling

Over the last decade, epidermal growth factor (EGF) signaling has been used repeatedly as a testbed for pioneering computational systems biology. Recent breakthroughs in our molecular understanding of EGF signaling pose new challenges for mathematical modeling strategies. Three key areas emerge as particularly relevant: the pervasive importance of compartmentalization and endosomal trafficking; the complexity of signalosome complexes; and the regulatory influence of diffusion and spatiality. Each one of them demands a drastic change in current computational approaches. We discuss recent developments in the field that address these emerging aspects in a new generation of more realistic – and potential more useful – models of EGF signaling.