ArticlePLoS computational biology2008
A hidden feedback in signaling cascades is revealed.
Article in PLoS computational biology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed.
- Mathematical basis and toolchain for hierarchical optimization of biochemical networks.PLoS computational biology · 2024Article
- Transient frequency preference responses in cell signaling systems.NPJ systems biology and applications · 2024Article
- Design patterns of biological cells.BioEssays : news and reviews in molecular, cellular and developmental biology · 2024Review
- Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases.Viruses · 2023Review
- A nested bistable module within a negative feedback loop ensures different types of oscillations in signaling systems.Scientific reports · 2023Article
- Dynamics and Sensitivity of Signaling Pathways.Current pathobiology reports · 2022Article
- Frequency-preference response in covalent modification cycles under substrate sequestration conditions.NPJ systems biology and applications · 2021Article
- Article
- Optimizing enzymatic catalysts for rapid turnover of substrates with low enzyme sequestration.Biological cybernetics · 2020Article
- Emergent memory in cell signaling: Persistent adaptive dynamics in cascades can arise from the diversity of relaxation time-scales.Scientific reports · 2018Article
- Modelling compartmentalization towards elucidation and engineering of spatial organization in biochemical pathways.Scientific reports · 2017Article
- Signaling Architectures that Transmit Unidirectional Information Despite Retroactivity.Biophysical journal · 2017Article
- Ultrasensitivity in signaling cascades revisited: Linking local and global ultrasensitivity estimations.PloS one · 2017Article
- Article
- Push-Pull and Feedback Mechanisms Can Align Signaling System Outputs with Inputs.Cell systems · 2016Article
- Core signalling motif displaying multistability through multi-state enzymes.Journal of the Royal Society, Interface · 2016Article
- Signaling cascades transmit information downstream and upstream but unlikely simultaneously.BMC systems biology · 2016Article
- Ultrasensitive Negative Feedback Control: A Natural Approach for the Design of Synthetic Controllers.PloS one · 2016Article
- Spatial Control of Biochemical Modification Cascades and Pathways.Biophysical journal · 2015Article
- Retroactivity in the Context of Modularly Structured Biomolecular Systems.Frontiers in bioengineering and biotechnology · 2015Review
Corrections and comments
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Authors and funding
3 authors.
Funding
Abstract
Cycles involving covalent modification of proteins are key components of the intracellular signaling machinery. Each cycle is comprised of two interconvertable forms of a particular protein. A classic signaling pathway is structured by a chain or cascade of basic cycle units in such a way that the activated protein in one cycle promotes the activation of the next protein in the chain, and so on. Starting from a mechanistic kinetic description and using a careful perturbation analysis, we have derived, to our knowledge for the first time, a consistent approximation of the chain with one variable per cycle. The model we derive is distinct from the one that has been in use in the literature for several years, which is a phenomenological extension of the Goldbeter-Koshland biochemical switch. Even though much has been done regarding the mathematical modeling of these systems, our contribution fills a gap between existing models and, in doing so, we have unveiled critical new properties of this type of signaling cascades. A key feature of our new model is that a negative feedback emerges naturally, exerted between each cycle and its predecessor. Due to this negative feedback, the system displays damped temporal oscillations under constant stimulation and, most important, propagates perturbations both forwards and backwards. This last attribute challenges the widespread notion of unidirectionality in signaling cascades. Concrete examples of applications to MAPK cascades are discussed. All these properties are shared by the complete mechanistic description and our simplified model, but not by previously derived phenomenological models of signaling cascades.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.