Signaling cascades transmit information downstream and upstream but unlikely simultaneously

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.Fil: Catozzi, Simona. Université Côte d’Azur; FranciaFil: Di Bella, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Ventura, Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Sepulchre, Jacques Alexandre. Université Côte d’Azur; Franci

High rates of fuel consumption are not required by insulating motifs to suppress retroactivity in biochemical circuits

Retroactivity arises when the coupling of a molecular network $\mathcal{U}$ to a downstream network $\mathcal{D}$ results in signal propagation back from $\mathcal{D}$ to $\mathcal{U}$. The phenomenon represents a breakdown in modularity of biochemical circuits and hampers the rational design of complex functional networks. Considering simple models of signal-transduction architectures, we demonstrate the strong dependence of retroactivity on the properties of the upstream system, and explore the cost and efficacy of fuel-consuming insulating motifs that can mitigate retroactive effects. We find that simple insulating motifs can suppress retroactivity at a low fuel cost by coupling only weakly to the upstream system $\mathcal{U}$. However, this design approach reduces the signalling network's robustness to perturbations from leak reactions, and potentially compromises its ability to respond to rapidly-varying signals.Comment: 26 pages, 19 figures, To appear in Engineering Biolog

Additional file 1 of Signaling cascades transmit information downstream and upstream but unlikely simultaneously

The inverse iterative map. (PDF 88.9 kb

Additional file 2 of Signaling cascades transmit information downstream and upstream but unlikely simultaneously

Likelihood curves and maxima. (PDF 483 kb

Additional file 4 of Signaling cascades transmit information downstream and upstream but unlikely simultaneously

Threshold robustness. (PDF 249 kb

Additional file 6 of Signaling cascades transmit information downstream and upstream but unlikely simultaneously

Infinite drug and infinite stimulus limits. (PDF 77.9 kb

Estudio de la función de la MAPK codificada por el gen Pc13g11680 de Penicillium chrysogenum y su relación con la vía de transducción de señal de las proteínas G heterotriméricas

Una característica fundamental de los organismos es su capacidad para adaptarse a diferentes condiciones ambientales, para lo cual utilizan vías de señalización que permiten responder de manera adecuada a su entorno. Muchas señales son transmitidas por módulos conservados de proteínas cinasas activadas por mitógenos (MAPK). La parte central de esta vía se encuentra representada por tres MAPKs (MAPKKK, MAPKK, MAPK), que se fosforilan de manera consecutiva hasta la MAPK y que desembocan en la activación o represión transcripcional de diversos genes. Existe un grupo denominado SAPK que son MAPK activadas bajo diversas condiciones de estrés, por ejemplo, las mutantes Hog1 (una MAPK) de Saccharomyces cerevisiae son sensibles a una alta osmolaridad mientras que las mutantes spc1 de Schizosaccharomyces pombe son sensibles a alta osmolaridad, choque térmico y estrés oxidante. El objetivo del presente trabajo fue comprobar el papel que juega la MAPK codificada por el gen Pc13g11680 (que aquí llamamos PcHog) en transformantes silenciadas mediante RNAi de P. chrysogenum bajo tratamientos de estrés. Nuestros hallazgos indican que las transformantes RNAi son susceptibles a estrés. En condiciones hiperosmóticas se encontró que concentraciones crecientes de sorbitol provocan una menor extensión del micelio y falta de conidiación, mientras que en los conidios no se observó una disminución (no estadísticamente significativa) en las unidades formadoras de colonia (UFC), pero con daños al germinar y un tamaño más pequeño que los de la cepa silvestre bajo tratamiento. Las condiciones oxidantes resultaron ser más letales, se observó un retraso en la aparición del micelio conforme se aumentó la concentración de H2O2 y la ausencia de coloración verde. También se estudió en qué grado se ve afectada la producción de penicilina, encontrándose que mientras en la cepa parental disminuye la biosíntesis del metabolito en las últimas etapas del ensayo, las transformantes continúan con la producción. Finalmente, para conocer si la PcHog tiene conectividad con la vía de señalización mediada por la subunidad Gα Pga1, se realizó un análisis mediante western blot. Esto permitió encontrar una mayor expresión de la proteína PcHog en una cepa con el gen pga1 delecionado (Δga1), por lo que la conexión es evidente. Tas realizar un estudio de interactómica in silico se encontró, además, un alto grado de conectividad de PcHog con múltiples procesos celulares.A fundamental characteristic of organisms is their ability to adapt to different environmental conditions, for which they use signaling pathways that allow them to respond appropriately to their environment. Many signals are transmitted by conserved modules of mitogen-activated protein kinases (MAPKs). The central part of this pathway is represented by three MAPKs (MAPKKK, MAPKK, MAPK), which are consecutively phosphorylated to MAPK and lead to the transcriptional activation or repression of various genes. There is a group called SAPK that are MAPKs activated under various stress conditions, for example, the Hog1 mutants (a MAPK) of Saccharomyces cerevisiae are sensitive to high osmolarity while the spc1 mutants of Schizosaccharomyces pombe are sensitive to high osmolarity, heat shock and oxidative stress. The objective of this work was to verify the role played by MAPK encoded by the Pc13g11680 gene (named here PcHog) in RNAi-silenced transformants of P. chrysogenum under stress treatments. Our findings indicate that RNAi transformants are susceptible to stress. In hyperosmotic conditions, it was found that increasing concentrations of sorbitol cause a smaller extension of the mycelium and lack of conidiation, while in the conidia a decrease (not statistically significant) in the colony-forming units (CFU) was not observed, but with damage to the conidia. germinate and a smaller size than those of the wild strain under treatment. The oxidizing conditions turned out to be more lethal, a delay in the appearance of the mycelium was observed as the concentration of H2O2 increased and the absence of green coloration. The degree to which penicillin production is affected was also studied, finding that while in the parental strain the biosynthesis of the metabolite decreases in the last stages of the assay, the transformants continue with production. Finally, to determine if PcHog has connectivity with the signaling pathway mediated by the Gα Pga1 subunit, a western blot analysis was performed. This allowed us to find a higher expression of the PcHog protein in a strain with the pga1 gene deleted (Δga1), so the connection is evident. After performing an in silico interactomic study, a high degree of connectivity of PcHog with multiple cellular processes was also found