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Abstract:

Background: 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 findings to 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 specific 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 effects can be neglected when a cascade which is efficient in forward signaling, is perturbed by an external ligand inhibiting the activation at some tier of the cascade. This result is relevant 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 inefficient, the cascade can interestingly act as a retro-signaling device. © 2016 The Author(s).

Registro:

Documento: Artículo
Título:Signaling cascades transmit information downstream and upstream but unlikely simultaneously
Autor:Catozzi, S.; Di-Bella, J.P.; Ventura, A.C.; Sepulchre, J.-A.
Filiación:Université Côte d'Azur, CNRS, INLN, 1361 route des lucioles, Valbonne, 06560, France
Universidad de Buenos Aires, IFIBYNE-UBA-CONICET and Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Ciudad Universitaria, Pabellón II, Buenos Aires, C1428EHA, Argentina
Palabras clave:Drug design; Kinase inhibitors; MAPK cascades; Retroactivity; Signaling cascades; phosphatase; protein kinase; biological model; kinetics; metabolism; phosphorylation; signal transduction; Kinetics; Models, Biological; Phosphoric Monoester Hydrolases; Phosphorylation; Protein Kinases; Signal Transduction
Año:2016
Volumen:10
Número:1
DOI: http://dx.doi.org/10.1186/s12918-016-0303-2
Título revista:BMC Systems Biology
Título revista abreviado:BMC Syst. Biol.
ISSN:17520509
CAS:phosphatase, 9013-05-2; protein kinase, 9026-43-1; Phosphoric Monoester Hydrolases; Protein Kinases
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_17520509_v10_n1_p_Catozzi

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Citas:

---------- APA ----------
Catozzi, S., Di-Bella, J.P., Ventura, A.C. & Sepulchre, J.-A. (2016) . Signaling cascades transmit information downstream and upstream but unlikely simultaneously. BMC Systems Biology, 10(1).
http://dx.doi.org/10.1186/s12918-016-0303-2
---------- CHICAGO ----------
Catozzi, S., Di-Bella, J.P., Ventura, A.C., Sepulchre, J.-A. "Signaling cascades transmit information downstream and upstream but unlikely simultaneously" . BMC Systems Biology 10, no. 1 (2016).
http://dx.doi.org/10.1186/s12918-016-0303-2
---------- MLA ----------
Catozzi, S., Di-Bella, J.P., Ventura, A.C., Sepulchre, J.-A. "Signaling cascades transmit information downstream and upstream but unlikely simultaneously" . BMC Systems Biology, vol. 10, no. 1, 2016.
http://dx.doi.org/10.1186/s12918-016-0303-2
---------- VANCOUVER ----------
Catozzi, S., Di-Bella, J.P., Ventura, A.C., Sepulchre, J.-A. Signaling cascades transmit information downstream and upstream but unlikely simultaneously. BMC Syst. Biol. 2016;10(1).
http://dx.doi.org/10.1186/s12918-016-0303-2