22 research outputs found
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Network Topologies That Can Achieve Dual Function of Adaptation and Noise Attenuation.
Many signaling systems execute adaptation under circumstances that require noise attenuation. Here, we identify an intrinsic trade-off existing between sensitivity and noise attenuation in the three-node networks. We demonstrate that although fine-tuning timescales in three-node adaptive networks can partially mediate this trade-off in this context, it prolongs adaptation time and imposes unrealistic parameter constraints. By contrast, four-node networks can effectively decouple adaptation and noise attenuation to achieve dual function without a trade-off, provided that these functions are executed sequentially. We illustrate ideas in seven biological examples, including Dictyostelium discoideum chemotaxis and the p53 signaling network and find that adaptive networks are often associated with a noise attenuation module. Our approach may be applicable to finding network design principles for other dual and multiple functions
Noise control and utility: From regulatory network to spatial patterning
Stochasticity (or noise) at cellular and molecular levels has been observed
extensively as a universal feature for living systems. However, how living
systems deal with noise while performing desirable biological functions remains
a major mystery. Regulatory network configurations, such as their topology and
timescale, are shown to be critical in attenuating noise, and noise is also
found to facilitate cell fate decision. Here we review major recent findings on
noise attenuation through regulatory control, the benefit of noise via
noise-induced cellular plasticity during developmental patterning, and
summarize key principles underlying noise control
Design principles of improving the dose-response alignment in coupled GTPase switches
Abstract âDose-response alignmentâ (DoRA), where the downstream response of cellular signaling pathways closely matches the fraction of activated receptor, can improve the fidelity of dose information transmission. The negative feedback has been experimentally identified as a key component for DoRA, but numerical simulations indicate that negative feedback is not sufficient to achieve perfect DoRA, i.e., perfect match of downstream response and receptor activation level. Thus a natural question is whether there exist design principles for signaling motifs within only negative feedback loops to improve DoRA to near-perfect DoRA. Here, we investigated several model formulations of an experimentally validated circuit that couples two molecular switchesâmGTPase (monomeric GTPase) and tGTPase (heterotrimeric GTPases) â with negative feedback loops. In the absence of feedback, the low and intermediate mGTPase activation levels benefit DoRA in mass action and Hill-function models, respectively. Adding negative feedback has versatile roles on DoRA: it may impair DoRA in the mass action model with low mGTPase activation level and Hill-function model with intermediate mGTPase activation level; in other cases, i.e., the mass action model with a high mGTPase activation level or the Hill-function model with a non-intermediate mGTPase activation level, it improves DoRA. Furthermore, we found that DoRA in a longer cascade (i.e., tGTPase) can be obtained using Hill-function kinetics under certain conditions. In summary, we show how ranges of activity of mGTPase, reaction kinetics, the negative feedback, and the cascade length affect DoRA. This work provides a framework for improving the DoRA performance in signaling motifs with negative feedback
Recommended from our members
Design principles of improving the dose-response alignment in coupled GTPase switches.
"Dose-response alignment" (DoRA), where the downstream response of cellular signaling pathways closely matches the fraction of activated receptor, can improve the fidelity of dose information transmission. The negative feedback has been experimentally identified as a key component for DoRA, but numerical simulations indicate that negative feedback is not sufficient to achieve perfect DoRA, i.e., perfect match of downstream response and receptor activation level. Thus a natural question is whether there exist design principles for signaling motifs within only negative feedback loops to improve DoRA to near-perfect DoRA. Here, we investigated several model formulations of an experimentally validated circuit that couples two molecular switches-mGTPase (monomeric GTPase) and tGTPase (heterotrimeric GTPases) - with negative feedback loops. In the absence of feedback, the low and intermediate mGTPase activation levels benefit DoRA in mass action and Hill-function models, respectively. Adding negative feedback has versatile roles on DoRA: it may impair DoRA in the mass action model with low mGTPase activation level and Hill-function model with intermediate mGTPase activation level; in other cases, i.e., the mass action model with a high mGTPase activation level or the Hill-function model with a non-intermediate mGTPase activation level, it improves DoRA. Furthermore, we found that DoRA in a longer cascade (i.e., tGTPase) can be obtained using Hill-function kinetics under certain conditions. In summary, we show how ranges of activity of mGTPase, reaction kinetics, the negative feedback, and the cascade length affect DoRA. This work provides a framework for improving the DoRA performance in signaling motifs with negative feedback