Ultrasensitive response motifs: Basic amplifiers in molecular signalling networks

Center for Dose Response Modeling, Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA.
Open Biology (Impact Factor: 5.78). 04/2013; 3(4):130031. DOI: 10.1098/rsob.130031
Source: PubMed


Multi-component signal transduction pathways and gene regulatory circuits underpin integrated cellular responses to perturbations. A recurring set of network motifs serve as the basic building blocks of these molecular signalling networks. This review focuses on ultrasensitive response motifs (URMs) that amplify small percentage changes in the input signal into larger percentage changes in the output response. URMs generally possess a sigmoid input-output relationship that is steeper than the Michaelis-Menten type of response and is often approximated by the Hill function. Six types of URMs can be commonly found in intracellular molecular networks and each has a distinct kinetic mechanism for signal amplification. These URMs are: (i) positive cooperative binding, (ii) homo-multimerization, (iii) multistep signalling, (iv) molecular titration, (v) zero-order covalent modification cycle and (vi) positive feedback. Multiple URMs can be combined to generate highly switch-like responses. Serving as basic signal amplifiers, these URMs are essential for molecular circuits to produce complex nonlinear dynamics, including multistability, robust adaptation and oscillation. These dynamic properties are in turn responsible for higher-level cellular behaviours, such as cell fate determination, homeostasis and biological rhythm.

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Available from: Melvin Andersen, Apr 21, 2014
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    • "strongly amplify the signal representing the altered cellular state, leading to a high induction of stress proteins (Zhang et al., 2013). Our simulations illustrated that sustained oscillations readily arise with transcriptionally-mediated feedback containing ultrasensitive gene induction (Fig. 3E). "
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    ABSTRACT: Although transcriptional induction of stress genes constitutes a major cellular defense program against a variety of stressors, posttranslational control directly regulating the activities of preexisting stress proteins provides a faster-acting alternative response. We propose that posttranslational control is a general adaptive mechanism operating in many stress pathways. Here with the aid of computational models, we first show that posttranslational control fulfills two roles: (1) handling small, transient stresses quickly and (2) stabilizing the negative feedback transcriptional network. We then review the posttranslational control pathways for major stress responses—oxidative stress, metal stress, hyperosmotic stress, DNA damage, heat shock, and hypoxia. Posttranslational regulation of stress protein activities occurs by reversible covalent modifications, allosteric or non-allosteric enzymatic regulations, and physically induced protein structural changes. Acting in feedback or feedforward networks, posttranslational control may establish a threshold level of cellular stress. Sub-threshold stresses are handled adequately by posttranslational control without invoking gene transcription. With supra-threshold stress levels, cellular homeostasis cannot be maintained and transcriptional induction of stress genes and other gene programs, eg, those regulating cell metabolism, proliferation, and apoptosis, takes place. The loss of homeostasis with consequent changes in cellular function may lead to adverse cellular outcomes. Overall, posttranslational and transcriptional control pathways constitute a stratified cellular defense system, handling stresses coherently across time and intensity. As cell-based assays become a focus for chemical testing anchored on toxicity pathways, examination of proteomic and metabolomic changes as a result of posttranslational control occurring in the absence of transcriptomic alterations deserves more attention.
    Toxicological Sciences 10/2015; 147(2). DOI:10.1093/toxsci/kfv130 · 3.85 Impact Factor
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    • "Curiously, a minimum threshold quantity of S-RNase in the style is required to trigger the self-incompatibility reaction [30], [32], [51], but to date, no mechanism has yet been proposed to account for this. The threshold phenomenon is conceptually akin to a sigmoidal or ultrasensitive response for which a variety of mechanisms, including co-operativity, positive feedback loops and molecular titration [52] have been proposed. It is an intriguing possibility that eEF1A may potentially act to titrate the amount of free S-RNase following import into the pollen tube cytoplasm. "
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    PLoS ONE 02/2014; 9(2):e90206. DOI:10.1371/journal.pone.0090206 · 3.23 Impact Factor
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    • "Biological systems are inherently non-linear with respect to dose response and pathways are populated with a variety of recurring motifs that serve, through negative feedback, to maintain systems against perturbations and to move systems from one state to another (Alon, 2007; Zhang et al., 2013). There are homeostatic regions where the cell responds to maintain normal function over some region of perturbation. "
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    Toxicology 02/2014; 332. DOI:10.1016/j.tox.2014.02.007 · 3.62 Impact Factor
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