Tuning the activation threshold of a kinase network by nested feedback loops.
Ontology highlight
ABSTRACT:
SUBMITTER: Justman QA
PROVIDER: S-EPMC2880456 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:MicroRNAs (miRNAs) are regulatory molecules that participate in diverse biological processes in animals and plants. While thousands of mammalian genes are potentially targeted by miRNAs, the functions of miRNAs in the context of gene networks are not well understood. Specifically, it is unknown whether miRNA-containing networks have recurrent circuit motifs, as has been observed in regulatory networks of bacteria and yeast. Here we develop a computational method that utilizes gene expression data to show that two classes of circuits-corresponding to positive and negative transcriptional coregulation of a miRNA and its targets-are prevalent in the human and mouse genomes. Additionally, we find that neuronal-enriched miRNAs tend to be coexpressed with their target genes, suggesting that these miRNAs could be involved in neuronal homeostasis. Our results strongly suggest that coordinated transcriptional and miRNA-mediated regulation is a recurrent motif to enhance the robustness of gene regulation in mammalian genomes.
| S-EPMC2072999 | biostudies-literature
Project description:BackgroundMany biological networks such as protein-protein interaction networks, signaling networks, and metabolic networks have topological characteristics of a scale-free degree distribution. Preferential attachment has been considered as the most plausible evolutionary growth model to explain this topological property. Although various studies have been undertaken to investigate the structural characteristics of a network obtained using this growth model, its dynamical characteristics have received relatively less attention.ResultsIn this paper, we focus on the robustness of a network that is acquired during its evolutionary process. Through simulations using Boolean network models, we found that preferential attachment increases the number of coupled feedback loops in the course of network evolution. Whereas, if networks evolve to have more coupled feedback loops rather than following preferential attachment, the resulting networks are more robust than those obtained through preferential attachment, although both of them have similar degree distributions.ConclusionThe presented analysis demonstrates that coupled feedback loops may play an important role in network evolution to acquire robustness. The result also provides a hint as to why various biological networks have evolved to contain a number of coupled feedback loops.
| S-EPMC2249609 | biostudies-literature
Project description:A simple three-component negative feedback loop is a recurring motif in biochemical oscillators. This motif oscillates as it has the three necessary ingredients for oscillations: a three-step delay, negative feedback, and nonlinearity in the loop. However, to oscillate, this motif under the common Goodwin formulation requires a high degree of cooperativity (a measure of nonlinearity) in the feedback that is biologically "unlikely." Moreover, this recurring negative feedback motif is commonly observed augmented by positive feedback interactions. Here we show that these positive feedback interactions promote oscillation at lower degrees of cooperativity, and we can thus unify several common kinetic mechanisms that facilitate oscillations, such as self-activation and Michaelis-Menten degradation. The positive feedback loops are most beneficial when acting on the shortest lived component, where they function by balancing the lifetimes of the different components. The benefits of multiple positive feedback interactions are cumulative for a majority of situations considered, when benefits are measured by the reduction in the cooperativity required to oscillate. These positive feedback motifs also allow oscillations with longer periods than that determined by the lifetimes of the components alone. We can therefore conjecture that these positive feedback loops have evolved to facilitate oscillations at lower, kinetically achievable, degrees of cooperativity. Finally, we discuss the implications of our conclusions on the mammalian molecular clock, a system modeled extensively based on the three-component negative feedback loop.
| S-EPMC4134231 | biostudies-literature
Project description:Centrioles are duplicated once in every cell cycle, ensuring the bipolarity of the mitotic spindle. How the core components cooperate to achieve high fidelity in centriole duplication remains poorly understood. By live-cell imaging of endogenously tagged proteins in human cells throughout the entire cell cycle, we quantitatively tracked the dynamics of the critical duplication factors: Plk4, STIL and HsSAS6. Centriolar Plk4 peaks and then starts decreasing during the late G1 phase, which coincides with the accumulation of STIL at centrioles. Shortly thereafter, the HsSAS6 level increases steeply at the procentriole assembly site. We also show that both STIL and HsSAS6 are necessary for attenuating Plk4 levels. Furthermore, our mathematical modeling and simulation suggest that the STIL-HsSAS6 complex in the cartwheel has a negative feedback effect on centriolar Plk4. Combined, these findings illustrate how the dynamic behavior of and interactions between critical duplication factors coordinate the centriole-duplication process.This article has an associated First Person interview with the first author of the paper.
| S-EPMC6777370 | biostudies-literature
Project description:Iron is required for key metabolic processes but is toxic in excess. This circumstance forces organisms across the tree of life to tightly regulate iron homeostasis. In hypersaline lakes dominated by archaeal species, iron levels are extremely low and subject to environmental change; however, mechanisms regulating iron homeostasis in archaea remain unclear. In previous work, we demonstrated that two transcription factors (TFs), Idr1 and Idr2, collaboratively regulate aspects of iron homeostasis in the model species Halobacterium salinarum. Here we show that Idr1 and Idr2 are part of an extended regulatory network of four TFs of the bacterial DtxR family that maintains intracellular iron balance. We demonstrate that each TF directly regulates at least one of the other DtxR TFs at the level of transcription. Dynamical modeling revealed interlocking positive feedback loop architecture, which exhibits bistable or oscillatory network dynamics depending on iron availability. TF knockout mutant phenotypes are consistent with model predictions. Together, our results support that this network regulates iron homeostasis despite variation in extracellular iron levels, consistent with dynamical properties of interlocking feedback architecture in eukaryotes. These results suggest that archaea use bacterial-type TFs in a eukaryotic regulatory network topology to adapt to harsh environments.
| S-EPMC5737653 | biostudies-literature
Project description:Organisms are equipped with regulatory systems that display a variety of dynamical behavior ranging from simple stable steady states, to switching and multistability, to oscillations. Earlier work has shown that oscillations in protein concentrations or gene expression levels are related to the presence of at least one negative feedback loop in the regulatory network. Here, we study the dynamics of a very general class of negative feedback loops. Our main result is that, when a single negative feedback loop dominates the dynamical behavior, the sequence of maxima and minima of the concentrations exhibit a pattern that uniquely identifies the interactions of the loop. This allows us to devise an algorithm to (i) test whether observed oscillating time series are consistent with a single underlying negative feedback loop, and if so, (ii) reconstruct the precise structure of the loop, i.e., the activating/repressing nature of each interaction. This method applies even when some variables are missing from the data set, or if the time series shows transients, like damped oscillations. We illustrate the relevance and the limits of validity of our method with three examples: p53-Mdm2 oscillations, circadian gene expression in cyanobacteria, and cyclic binding of cofactors at the estrogen-sensitive pS2 promoter.
| S-EPMC1871820 | biostudies-other
Project description:BackgroundA number of studies on biological networks have been carried out to unravel the topological characteristics that can explain the functional importance of network nodes. For instance, connectivity, clustering coefficient, and shortest path length were previously proposed for this purpose. However, there is still a pressing need to investigate another topological measure that can better describe the functional importance of network nodes. In this respect, we considered a feedback loop which is ubiquitously found in various biological networks.ResultsWe discovered that the number of feedback loops (NuFBL) is a crucial measure for evaluating the importance of a network node and verified this through a signal transduction network in the hippocampal CA1 neuron of mice as well as through generalized biological network models represented by Boolean networks. In particular, we observed that the proteins with a larger NuFBL are more likely to be essential and to evolve slowly in the hippocampal CA1 neuronal signal transduction network. Then, from extensive simulations based on the Boolean network models, we proved that a network node with the larger NuFBL is likely to be more important as the mutations of the initial state or the update rule of such a node made the network converge to a different attractor. These results led us to infer that such a strong positive correlation between the NuFBL and the importance of a network node might be an intrinsic principle of biological networks in view of network dynamics.ConclusionThe presented analysis on topological characteristics of biological networks showed that the number of feedback loops is positively correlated with the functional importance of network nodes. This result also suggests the existence of unknown feedback loops around functionally important nodes in biological networks.
| S-EPMC2100072 | biostudies-literature
Project description:How dynamic interactions between nervous system regions in mammals performs online motor control remains an unsolved problem. In this paper, we show that feedback control is a simple, yet powerful way to understand the neural dynamics of sensorimotor control. We make our case using a minimal model comprising spinal cord, sensory and motor cortex, coupled by long connections that are plastic. It succeeds in learning how to perform reaching movements of a planar arm with 6 muscles in several directions from scratch. The model satisfies biological plausibility constraints, like neural implementation, transmission delays, local synaptic learning and continuous online learning. Using differential Hebbian plasticity the model can go from motor babbling to reaching arbitrary targets in less than 10 min of in silico time. Moreover, independently of the learning mechanism, properly configured feedback control has many emergent properties: neural populations in motor cortex show directional tuning and oscillatory dynamics, the spinal cord creates convergent force fields that add linearly, and movements are ataxic (as in a motor system without a cerebellum).
| S-EPMC9699696 | biostudies-literature
Project description:The hexosamine pathway (HP) is a key anabolic pathway whose product uridine 5'-diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc) is an essential precursor for glycosylation processes in mammals. It modulates the ER stress response and HP activation extends lifespan in Caenorhabditis elegans. The highly conserved glutamine fructose-6-phosphate amidotransferase 1 (GFAT-1) is the rate-limiting HP enzyme. GFAT-1 activity is modulated by UDP-GlcNAc feedback inhibition and via phosphorylation by protein kinase A (PKA). Molecular consequences of GFAT-1 phosphorylation, however, remain poorly understood. Here, we identify the GFAT-1 R203H substitution that elevates UDP-GlcNAc levels in C. elegans. In human GFAT-1, the R203H substitution interferes with UDP-GlcNAc inhibition and with PKA-mediated Ser205 phosphorylation. Our data indicate that phosphorylation affects the interactions of the two GFAT-1 domains to control catalytic activity. Notably, Ser205 phosphorylation has two discernible effects: it lowers baseline GFAT-1 activity and abolishes UDP-GlcNAc feedback inhibition. PKA controls the HP by uncoupling the metabolic feedback loop of GFAT-1.
| S-EPMC8041777 | biostudies-literature
Project description:The hexosamine pathway (HP) is a key anabolic pathway whose product uridine 5’-diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc) is an essential precursor for all glycosylation processes in mammals. It modulates the ER stress response, is implicated in cancer and diabetes, and HP activation extends lifespan in Caenorhabditis elegans. The highly conserved glutamine fructose-6-phosphate amidotransferase 1 (GFAT 1) is the first and rate-limiting HP enzyme. GFAT 1 activity is modulated through UDP-GlcNAc feedback inhibition and by kinase signaling, including Ser205 phosphorylation by protein kinase A (PKA). The consequence and molecular mechanism of GFAT 1 PKA phosphorylation, however, remains poorly understood. Here, we identify the GFAT 1 R203H substitution that elevates UDP-GlcNAc levels in C. elegans, leading to ER stress resistance. In human GFAT-1, the R203H substitution interfered with UDP-GlcNAc inhibition and with PKA-mediated Ser205 phosphorylation. Of note, Ser205 phosphorylation had two discernible effects: It lowered baseline GFAT 1 activity while abolishing UDP-GlcNAc feedback inhibition. Thus, GFAT-1 phosphorylation by PKA uncoupled the feedback loop of the HP and depending on UDP-GlcNAc availability, phosphorylation by PKA lowers or enhances GFAT 1 activity in vivo. Mechanistically, our data indicate that the relative positioning of the two GFAT 1 domains might be affected by phosphorylation and we propose a model how Ser205 phosphorylation modulates the activity and feedback inhibition of GFAT 1.
2020-07-23 | PXD020451 | Pride