Load-Induced Modulation of Signal Transduction Networks

Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109-0606, USA.
Science Signaling (Impact Factor: 6.28). 10/2011; 4(194):ra67. DOI: 10.1126/scisignal.2002152
Source: PubMed


Biological signal transduction networks are commonly viewed as circuits that pass along information--in the process amplifying signals, enhancing sensitivity, or performing other signal-processing tasks--to transcriptional and other components. Here, we report on a "reverse-causality" phenomenon, which we call load-induced modulation. Through a combination of analytical and experimental tools, we discovered that signaling was modulated, in a surprising way, by downstream targets that receive the signal and, in doing so, apply what in physics is called a load. Specifically, we found that non-intuitive changes in response dynamics occurred for a covalent modification cycle when load was present. Loading altered the response time of a system, depending on whether the activity of one of the enzymes was maximal and the other was operating at its minimal rate or whether both enzymes were operating at submaximal rates. These two conditions, which we call "limit regime" and "intermediate regime," were associated with increased or decreased response times, respectively. The bandwidth, the range of frequency in which the system can process information, decreased in the presence of load, suggesting that downstream targets participate in establishing a balance between noise-filtering capabilities and a circuit's ability to process high-frequency stimulation. Nodes in a signaling network are not independent relay devices, but rather are modulated by their downstream targets.

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Available from: Alejandra C Ventura, Aug 20, 2014
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    • "It has been demonstrated in vivo that retroactivity can affect the level of MAPK (mitogen-activated protein kinase) phosphorylation depending on substrate concentration [8]. It has also been reported that retroactivity can change the response time of a uridylyltransferase/uridylyl-removing enzyme (UTase/UR)–PII system [9], and induce time delays in gene transcription networks [10], thus affecting the dynamic behavior of biomolecular systems. To attenuate retroactivity effects, which can disrupt a module functionality, the implementation of insulation devices was proposed [6][11]. "
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    ABSTRACT: This paper considers the problem of attenuating retroactivity, that is, the effect of loads in biological networks and demonstrates that signal transduction cascades incorporating phosphotransfer modules have remarkable retroactivity attenuation ability. Uncovering the biological mechanisms for retroactivity attenuation is relevant in synthetic biology to enable bottom-up modular composition of complex circuits. It is also important in systems biology for deepening our current understanding of natural principles of modular organization. In this paper, we perform a combined theoretical and computational study of a cascade system comprising two phosphotransfer modules, ubiquitous in eukaryotic signal transduction, when subject to load from downstream targets. Employing singular perturbation on the finite time interval, we demonstrate that this system implements retroactivity attenuation when the input signal is sufficiently slow. Employing trajectory sensitivity analysis about nominal parameters that we have identified from in vivo data, we further demonstrate that the key parameters for retroactivity attenuation are those controlling the timescale of the system.
    2014 American Control Conference - ACC 2014; 06/2014
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    • "Further theoretical work along these lines was reported in [5] [6]. Experimental verifications were reported in [7] and in [8], using a covalent modification cycle based on a reconstituted uridylyltransferase/uridylyl-removing enzyme PII cycle, which is a model system derived from the nitrogen assimilation control network of Escherichia coli. "
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    ABSTRACT: Complex networks of biochemical reactions, such as intracellular protein signaling pathways and genetic networks, are often conceptualized in terms of modules-semiindependent collections of components that perform a well-defined function and which may be incorporated in multiple pathways. However, due to sequestration of molecular messengers during interactions and other effects, collectively referred to as retroactivity, real biochemical systems do not exhibit perfect modularity. Biochemical signaling pathways can be insulated from impedance and competition effects, which inhibit modularity, through enzymatic futile cycles that consume energy, typically in the form of ATP. We hypothesize that better insulation necessarily requires higher energy consumption. We test this hypothesis through a combined theoretical and computational analysis of a simplified physical model of covalent cycles, using two innovative measures of insulation, as well as a possible new way to characterize optimal insulation through the balancing of these two measures in a Pareto sense. Our results indicate that indeed better insulation requires more energy. While insulation may facilitate evolution by enabling a modular plug-and-play interconnection architecture, allowing for the creation of new behaviors by adding targets to existing pathways, our work suggests that this potential benefit must be balanced against the metabolic costs of insulation necessarily incurred in not affecting the behavior of existing processes.
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    • "Even if an isolated network can perform a function, does it still behave the same when it is linked to other upstream and downstream modules? Or does the network behavior change when you place this kind of functional load on it (i.e., can downstream effectors compete with feedback or feedforward interactions with an output node?) (Jiang et al., 2011)? A Question of Utility Ultimately, like other abstract theoretical constructs such as the periodic table and valency in chemistry, the bottom-line question concerns the utility of this framework. "
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