Kinase inhibitors can produce off-target effects and activate linked pathways by retroactivity

Background: It has been shown in experimental and theoretical work that covalently modified signaling cascades naturally exhibit bidirectional signal propagation via a phenomenon known as retroactivity. An important consequence of retroactivity, which arises due to enzyme sequestration in covalently modified signaling cascades, is that a downstream perturbation can produce a response in a component upstream of the perturbation without the need for explicit feedback connections. Retroactivity may, therefore, play an important role in the cellular response to a targeted therapy. Kinase inhibitors are a class of targeted therapies designed to interfere with a specific kinase molecule in a dysregulated signaling pathway. While extremely promising as anti-cancer agents, kinase inhibitors may produce undesirable off-target effects by non-specific interactions or pathway cross-talk. We hypothesize that targeted therapies such as kinase inhibitors can produce off-target effects as a consequence of retroactivity alone.Results: We used a computational model and a series of simple signaling motifs to test the hypothesis. Our results indicate that within physiologically and therapeutically relevant ranges for all parameters, a targeted inhibitor can naturally induce an off-target effect via retroactivity. The kinetics governing covalent modification cycles in a signaling network were more important for propagating an upstream off-target effect in our models than the kinetics governing the targeted therapy itself. Our results also reveal the surprising and crucial result that kinase inhibitors have the capacity to turn "on" an otherwise "off" parallel cascade when two cascades share an upstream activator.Conclusions: A proper and detailed characterization of a pathway's structure is important for identifying the optimal protein to target as well as what concentration of the targeted therapy is required to modulate the pathway in a safe and effective manner. We believe our results support the position that such characterizations should consider retroactivity as a robust potential source of off-target effects induced by kinase inhibitors and other targeted therapies.Fil: Wynn, Michelle L.. University of Michigan Medical School; Estados UnidosFil: 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; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular. Laboratorio de Fisiología y Biología Molecular; Argentina. University of Michigan Medical School; Estados UnidosFil: Sepulchre, Jacques Alexandre. Centre National de la Recherche Scientifique; FranciaFil: García, Héctor J.. University of Michigan; Estados UnidosFil: Merajver, Sofia D.. University of Michigan Medical School; Estados Unido

Simple molecular networks that respond optimally to time-periodic stimulation

<p>Abstract</p> <p>Background</p> <p>Bacteria or cells receive many signals from their environment and from other organisms. In order to process this large amount of information, Systems Biology shows that a central role is played by regulatory networks composed of genes and proteins. The objective of this paper is to present and to discuss simple regulatory network motifs having the property to maximize their responses under time-periodic stimulations. In elucidating the mechanisms underlying these responses through simple networks the goal is to pinpoint general principles which optimize the oscillatory responses of molecular networks.</p> <p>Results</p> <p>We took a look at basic network motifs studied in the literature such as the Incoherent Feedforward Loop (IFFL) or the interlerlocked negative feedback loop. The former is also generalized to a diamond pattern, with network components being either purely genetic or combining genetic and signaling pathways. Using standard mathematics and numerical simulations, we explain the types of responses exhibited by the IFFL with respect to a train of periodic pulses. We show that this system has a non-vanishing response only if the inter-pulse interval is above a threshold. A slight generalisation of the IFFL (the diamond) is shown to work as an ideal pass-band filter. We next show a mechanism by which average of oscillatory response can be maximized by bursting temporal patterns. Finally we study the interlerlocked negative feedback loop, i.e. a 2-gene motif forming a loop where the nodes respectively activate and repress each other, and show situations where this system possesses a resonance under periodic stimulation.</p> <p>Conclusion</p> <p>We present several simple motif designs of molecular networks producing optimal output in response to periodic stimulations of the system. The identified mechanisms are simple and based on known network motifs in the literature, so that that they could be embodied in existing organisms, or easily implementable by means of synthetic biology. Moreover we show that these designs can be studied in different contexts of molecular biology, as for example in genetic networks or in signaling pathways.</p

Phénomènes spatio-temporels dans des réseaux d'oscillateurs

Doctorat en Sciencesinfo:eu-repo/semantics/nonPublishe

Phénomènes spatio-temporels dans des réseaux d'oscillateurs

Doctorat en Sciencesinfo:eu-repo/semantics/nonPublishe

Aspects temporel et spatial dans des systèmes de régulation génétique

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Effective Hamiltonian for travelling discrete breathers

Hamiltonian chains of oscillators in general probably do not sustain exact travelling discrete breathers. However solutions which look like moving discrete breathers for some time are not di#cult to observe in numerics. In this paper we propose an abstract framework for the description of approximate travelling discrete breathers in Hamiltonian chains of oscillators. The method is based on the construction of an e#ective Hamiltonian enabling one to describe the dynamics of the translation degree of freedom of moving breathers

Intrinsic Feedbacks in MAPK Signaling Cascades Lead to Bistability and Oscillations

Previous studies have demonstrated that double phosphorylation of a protein can lead to bistability if some conditions are fulfilled. It was also shown that the signaling behavior of a covalent modification cycle can be quantitatively and, more importantly, qualitatively modified when this cycle is coupled to a signaling pathway as opposed to being isolated. This property was named retroactivity. These two results are studied together in this paper showing the existence of interesting phenomena—oscillations and bistability—in signaling cascades possessing at least one stage with a double-phosphorylation cycle as in MAPK cascades.Fil: Sepulchre, Jacques Alexandre. Universite Nice; FranciaFil: 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; Argentin

Linear response, susceptibility and resonances in chaotic toy models

16International audienceWe consider simple examples illustrating some new features of the linear response theory developed by Ruelle for dissipative and chaotic systems [D. Ruelle, Smooth dynamics and new theoretical ideas in nonequilibrium statistical mechanics, J. Stat. Phys. 95 (1999) 393–468]. In this theory the concepts of linear response, susceptibility and resonance, which are familiar to physicists, have been revisited due to the dynamical contraction of the whole phase space onto attractors. In particular the standard framework of the “fluctuation–dissipation” theorem breaks down and new resonances can show up outside the power spectrum. In previous papers we proposed and used new numerical methods to demonstrate the presence of the new resonances predicted by Ruelle in a model of chaotic neural networks. In this article we deal with simpler models which can be worked out analytically in order to gain more insights into the genesis of the “stable” resonances and their consequences on the linear response of the system. We consider a class of two-dimensional time-discrete maps describing simple rotator models with a contracting radial dynamics onto the unit circle and a chaotic angular dynamics ?t+1=2?t(mod2?). A generalisation of this system to a network of interconnected rotators is also analysed and related with our previous studies [B. Cessac, J.-A. Sepulchre, Stable resonances and signal propagation in a chaotic network of coupled units, Phys. Rev. E 70 (2004) 056111; B. Cessac, J.-A. Sepulchre, Transmitting a signal by amplitude modulation in a chaotic network, Chaos 16 (2006) 013104-1–13104-12]. These models permit us to classify the different types of resonances in the susceptibility and to discuss in particular the relation between the relaxation time of the system to equilibrium with the mixing time given by the decay of the correlation functions. Also it enables one to propose some general mechanisms responsible for the creation of stable resonances with arbitrary frequencies, widths, and dependence on the pair of perturbed/observed variables