Prediction of reverse stimulus-responses in signaling cascades

JACQUES-A. SEPULCHRE; ALEJANDRA C VENTURA; SOFIA D MERAJVER

Göteborg, Sweeden

Conferencia; 9th International Conference on Systems Biology; 2008

The International Society for Systems Biology (ISSB)

The concept of intracellular signaling cascade is a basic motif of signaling pathway, consisting of a chain biochemical of cycles, e.g. phosphorylation/dephosphorylation modifications, in which the activated protein in one cycle promotes the activation of the next protein in the chain and so on. In a systems biology perspective, signaling cascades are viewed as feedforward input/output devices. Quantitatively, they are characterized by a stimulus-response curve describing how the steady state values of the activated proteins at the output of the cascade depend on control parameters affecting an upstream cycle of the chain.  In the present work we propose the novel concept of reverse stimulus-responses. We show that varying the state of the last biochemical cycle in a signaling cascade can bring about a response in the considered "input" cycle of the chain, therefore challenging the idea of unidirectionality in signaling cascade, as we suggested already in a recent work [1]. In this paper, our idea is first explained in the simplest case of a bicyclic cascade.  In the literature this system is usually represented as a motif comprising 2 cycles and a single arrow linking the activated protein of the first unit onto the second cycle. Despite the clear polarity of this system, and in absence of explicit feedback, we show that a variation of the parameters affecting the second cycle (e.g. increasing the total protein concentration in this cycle) can induce an upstream response in variables of the first cycle. This can be achieved in biochemical relevant conditions. We have named the obtained relationship as “reverse stimulus-response curve”, and this can be computed numerically, as well as analytically estimated. The result is next generalized to a cascade of several cycles and to more complex pathways. In each case we describe the corresponding reverse stimulus responses. These results currently have the status of theoretical predictions, but they prompt for new experiments concerning signaling cascades and possibly new ways to interpret previous results. As an interesting significance of our study we conclude by analyzing some consequences of this new backward property on signaling pathways with crosstalk.