ArticleBiophysical journal2007
Competing docking interactions can bring about bistability in the MAPK cascade.
Article in Biophysical journal, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 95 citations in OpenAlex.
- A computational rule-based model of MAPK/ERK system regulation.Scientific reports · 2026Article
- A Histone Methylation-MAPK Signaling Axis Drives Durable Epithelial-Mesenchymal Transition in Hypoxic Pancreatic Cancer.Cancer research · 2024Article
- Modeling Cellular Signaling Variability Based on Single-Cell Data: The TGFβ-SMAD Signaling Pathway.Methods in molecular biology (Clifton, N.J.) · 2023Review
- 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
- Analysis of mechanotransduction dynamics during combined mechanical stimulation and modulation of the extracellular-regulated kinase cascade uncovers hidden information within the signalling noise.Interface focus · 2021Article
- Multiple random phosphorylations in clock proteins provide long delays and switches.Scientific reports · 2020Article
- Revealing hidden information in osteoblast's mechanotransduction through analysis of time patterns of critical events.BMC bioinformatics · 2020Article
- Computational modelling unravels the precise clockwork of cyanobacteria.Interface focus · 2018Review
- When More Is Less: Dual Phosphorylation Protects Signaling Off State against Overexpression.Biophysical journal · 2018Article
- Emergent memory in cell signaling: Persistent adaptive dynamics in cascades can arise from the diversity of relaxation time-scales.Scientific reports · 2018Article
- Dissipative structures in biological systems: bistability, oscillations, spatial patterns and waves.Philosophical transactions. Series A, Mathematical, physical, and engineering sciences · 2018Review
- Sampling-based Bayesian approaches reveal the importance of quasi-bistable behavior in cellular decision processes on the example of the MAPK signaling pathway in PC-12 cell lines.BMC systems biology · 2017Article
- From invasion to latency: intracellular noise and cell motility as key controls of the competition between resource-limited cellular populations.Journal of mathematical biology · 2016Article
- Article
- The effects of intrinsic noise on the behaviour of bistable cell regulatory systems under quasi-steady state conditions.The Journal of chemical physics · 2015Article
- Novel Reporter for Faithful Monitoring of ERK2 Dynamics in Living Cells and Model Organisms.PloS one · 2015Article
- MAP kinase modules: the excursion model and the steps that count.Biophysical journal · 2014Review
- Enhancement of tunability of MAPK cascade due to coexistence of processive and distributive phosphorylation mechanisms.Biophysical journal · 2014Article
- Integrative modelling of the influence of MAPK network on cancer cell fate decision.PLoS computational biology · 2013Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mitogen-activated protein kinases are crucial regulators of various cell fate decisions including proliferation, differentiation, and apoptosis. Depending on the cellular context, the Raf-Mek-Erk mitogen-activated protein kinase cascade responds to extracellular stimuli in an all-or-none manner, most likely due to bistable behavior. Here, we describe a previously unrecognized positive-feedback mechanism that emerges from experimentally observed sequestration effects in the core Raf-Mek-Erk cascade. Unphosphorylated/monophosphorylated Erk sequesters Mek into Raf-inaccessible complexes upon weak stimulation, and thereby inhibits cascade activation. Mek, once phosphorylated by Raf, triggers Erk phosphorylation, which in turn induces dissociation of Raf-inaccessible Mek-Erk heterodimers, and thus further amplifies Mek phosphorylation. We show that this positive circuit can bring about bistability for parameter values measured experimentally in living cells. Previous studies revealed that bistability can also arise from enzyme depletion effects in the Erk double (de)phosphorylation cycle. We demonstrate that the feedback mechanism proposed in this article synergizes with such enzyme depletion effects to bring about a much larger bistable range than either mechanism alone. Our results show that stable docking interactions and competition effects, which are common in protein kinase cascades, can result in sequestration-based feedback, and thus can have profound effects on the qualitative behavior of signaling pathways.
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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.