Downstream versus upstream stimulus-responses in biochemical signaling cascades

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

Nice

Conferencia; 1st Labex Signalife Meeting Cell Sginaling; 2014

We present a perspective of new principle of intracellular signaling. Our work is under earlydevelopment, and our goal is to prompt possible experimental works to associate to our theoretical development, with possible applications in the field of drug design.The representation of signaling cascades implicitly conveys the idea of unidirectionality of signal propagation. However, [1] shows that an intrinsic feedback (retroactivity) emerges naturally, so that a cascade can actually exhibit bidirectional propagation. Moreover, recent experiments [2] confirm some of our theoretical predictions [3] and show that the retroactive effects may not be negligible. Notably, some off-target effects can arise when kinase inhibitors are used in anti-cancer therapies [4]. Therefore we propose to study a new type of signaling, that we call upstream signaling in contrast with the usual downstream signaling that is naturally considered in a cascade. The ?signal? of the upstream signaling would be a kinase inhibitor acting at the bottom of the cascade and the ?response? would be the phosphorylated protein fraction at the top of the cascade. In the simplest case of a 2-stage signaling cascade, we show that by changing the concntration of the phosphataseacting on the second stage, one can switch between the two forms of signaling, downstream to upstream, and vice-versa. Then, in an arbitrary long signaling cascade, we propose a theoretical approach to compare the two forms of signaling. One can show that the dose-response curve (downstream signaling) and drug-response curve (upstream signaling) can be computed by means of two iterative maps that are roughly inverse from each other.In the current literature, there is no study about the parameter conditions of a signaling pathway, that would compare downstream versus upstream signaling. Would such parameter conditions be mutually exclusive? That would partly explain why the idea of upstream signaling has so far been overlooked compared with downstream signaling