Control and prediction of the direct and retroactive propagation flow in a signaling cascade model

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

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Conferencia; 2nd Labex Signalife Meeting Cell Sginaling; 2015

Signaling cascades are part of a very complex molecular network orchestrating the whole process of signal transduction. They consist in an ordered sequence of proteins, coupled three by three, involved in phosphorylation-dephosphorylation reactions. The first protein is activated (phosphorylated) by an input signal, then each protein is activated by the previous one. Moreover, according to common drug therapies applied to cascades, we assume that the last protein can be inhibited by a compound (drug). Having the sequence length fixed to 3, we study the dynamical equilibrium of such a system according to the direction of the information flow along the cascade and as a function of the biochemical parameters (which are randomly sampled), like reaction rates, total concentrations, or substrate-enzyme affinities. Particularly, our investigation is based on the effect of two different stimuli, namely the input signal and the inhibiting drug, which generate different stimulus-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 (even opposite) regimes, and highlights which choices of parameter values may promote specific signaling directions and dwindle other ones. We also develop 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 for making experiments in synthetic biology, and possibly further understanding some existing cascades and predicting their response (maybe related to side effects) to drug administration.