Specificity and Robustness of the Mammalian MAPK-IEG Network

The mitogen-activated protein kinase cascade is a conserved signal transduction pathway found in organisms of complexity spanning from yeast to humans. In many mammalian tissue types, this pathway can correctly transduce signals from different extracellular messengers, leading to specific and often mutually exclusive cellular responses. The transduced signal is tuned by a complicated set of positive and negative feedback control mechanisms and fed into a downstream gene expression network. This network, based on the immediate early gene system, has two possible, mutually exclusive outcomes. Using a mathematical model, we study how different stimuli lead to different temporal signal structure. Further, we investigate how each of the feedback controls contributes to the overall specificity of the gene expression output, and hypothesize that the complicated nature of the mammalian mitogen-activated protein kinase pathway results in a system able to robustly identify and transduce the proper signal without investing in two completely separate signal cascades. Finally, we quantify the role of the RKIP protein in shaping the signal, and propose a novel mechanism of its involvement in cancer metastasis.