A comparative study of parameters affecting direct or retroactive responses in signaling cascades

SIMONA CATOZZI; JUAN PABLO DI BELLA; ALEJANDRA C VENTURA; JACQUES-A. SEPULCHRE

Buenos Aires

Conferencia; Latin American Conference on Mathematical Modeling of Biological Systems; 2015

Mincyt, CELFI

orchestrating the whole process of signal transduction. They consist in anordered sequence of proteins, coupled three by three, involved inphosphorylation-dephosphorylation reactions. The first protein is activated(phosphorylated) by an input signal, then each protein is activated by theprevious one. Moreover, according to common drug therapies applied tocascades, we assume that the last protein can be inhibited by a compound(drug).Having the sequence length fixed to 3, we study the dynamical equilibriumof such a system according to the direction of the information flow alongthe cascade and as a function of the biochemical parameters (which arerandomly sampled), like reaction rates, total concentrations, or substrateenzymeaffinities.Particularly, our investigation is based on the effect of two different stimuli,namely the input signal and the inhibiting drug, which generate differentstimulus-response curves, where the response is the proteins´ variation.These two curves are respectively associated to opposite working regimes:the downstream (direct) and the upstream (retroactive) propagation.Our analysis shows the probabilities for a cascade to work in several (evenopposite) regimes, and highlights which choices of parameter values maypromote specific signaling directions and dwindle other ones. We alsodevelop a graphic representation of the seven possible working regimes,built from the concepts of saturation, sequestration and cycles? activation.Therefore, these results furnish interesting bases and precise data formaking experiments in synthetic biology, and possibly furtherunderstanding some existing cascades and predicting their response (mayberelated to side effects) to drug administration.