Signaling cascades transmit information downstream and upstream but unlikely simultaneously

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

BMC SYSTEMS BIOLOGY

BIOMED CENTRAL LTD

Lugar: Londres; Año: 2016

1752-0509

AbstractBackground: Signal transduction is the process through which cells communicate with the external environment, interpret stimuli and respond to them. This mechanism is controlled by signaling cascades, which play the role of intracellular transmitter, being able to transmit biochemical information between cell membrane and nucleus. In theory as well as in practice, it has been shown that a perturbation can propagate upstream (and not only downstream) a cascade, by a mechanism known as retroactivity. This study aims to compare the conditions on biochemical parameters which favor one or the other direction of signaling in such a cascade.Results: From a mathematical point of view, we show that the steady states of a cascade of arbitrary length n are described by an iterative map of second order, meaning that the cascade tiers are actually coupled three-by-three. We study the influence of the biochemical parameters in the control of the direction of transmission { upstream and/or downstream { along a signaling cascade. A numerical and statistical approach, based on the random scan of parameters describing a 3-tier signaling cascade, provides complementary findingsto the analytical study. In particular, computing the likelihood of parameters with respect to various signaling regimes, we identify conditions on biochemical parameters which enhance a specic direction of propagation corresponding to forward or retro-signaling regimes. A compact graphical representation is designed to relay the gist of these conditions.Conclusions: The values of biochemical parameters such as kinetic rates, Michaelis-Menten constants, total concentrations of kinases and of phosphatases, determine the propensity of a cascade to favor or impede downstream or upstream signal transmission. We found that generally there is an opposition between parameter sets favoring forward and retro-signaling regimes. Therefore, on one hand our study supports the idea that in most cases, retroactive eects can be neglected when a cascade which is ecient in forward signaling, is perturbed by an external ligand inhibiting the activation at some tier of the cascade. This result isrelevant for therapeutic methodologies based on kinase inhibition. On the other hand, our study highlights a less-known part of the parameter space where, although the forward signaling is inecient, the cascade can interestingly act as a retro-signaling device.Keywords: signaling cascades; retroactivity; MAPK cascades; drug design; kinase inhibitors