B-Raf and C-Raf signaling investigated in a simplified model of the mitogenic kinase cascade.

Signaling pathways based on the reversible phosphorylation of proteins control most aspects of cellular life in higher organisms. Extracellular stimuli can induce growth, differentiation, survival and the stress response through a number of highly conserved signaling pathways. We discuss how the intensity and duration of signals may have dramatic consequences on the way cells respond to stimuli. Picking the central Ras-Raf-MEK-ERK signal cascade, we developed a mathematical model of how stimuli induce different signal patterns and thereby different cellular responses, depending on cell type and the ratio between B-Raf and C-Raf. Based on biochemical data for activation and dephosphorylation, as well as the differential equations of our model, we suggest a different signaling pattern and response result for B-Raf (strong activation, sustained signal) and C-Raf (steep activation, transient signal). We further support the significance of such differential modulatory signaling by showing different Raf isoform expression in various cell lines and experimental testing of the predicted kinase activities in B-Raf, C-Raf and mutated versions.