Concentration-dependent effects on the rapid and efficient activation of the MAP kinase signaling cascade

Modern proteomic techniques are making it possible to identify and quantitate increasingly complex mixtures of cellular proteins. Translating the relative expression measurements collected in these experiments into an understanding of the associated physiological phenomena continues to be a challenge for the field of systems biology. We demonstrate how methods of mathematical and computational systems biology permit us to proffer explanations for the observed concentration ranges of signaling components found in the highly conserved mitogen-activated protein kinase (MAPK) cascade. The analysis demonstrates that alterations in the naturally occurring MAPK and MAPK kinase (MAPKK) concentrations would negatively affect the efficiency of short-term responses of the cascade. Thus, while there seems to be no a priori rationale for particular features of the involved kinases, the observed ranges of their characteristic parameters appear to be far from coincidental. This result is deduced from the first principles of mass action kinetics and holds for wide variations in MAPKK kinase (MAPKKK) concentrations, differential preference for unphosphorylated and monophosphorylated forms of kinase substrates, and for cases where the monophosphorylated MAPKK exhibits kinase activity. The results demonstrate how theoretical systems biology complements molecular biology by providing specific rationale for observed natural designs in a fashion hardly achievable with experimentation alone.