ArticleScientific reports2017
Relaxation oscillations and hierarchy of feedbacks in MAPK signaling.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed.
- Modified frequency-based sensitivity analysis for oscillatory system models.Journal of pharmacokinetics and pharmacodynamics · 2026Article
- Dual-MEK Inhibitor Atebimetinib Displays Broad Activity in RAS- and RAF-Mutant Tumors via Deep Cyclic Inhibition and Resisting RAF Bypass.Cancer research · 2026Article
- PAK1 activation drives divergent resistance mechanisms to aromatase inhibition and tamoxifen in a luminal: A breast cancer model.Molecular oncology · 2026Article
- Dual RAF inhibition outperforms RAF-MEK combinations for suppressing ERK signaling in KRAS mutant cells.NPJ systems biology and applications · 2026Article
- A computational rule-based model of MAPK/ERK system regulation.Scientific reports · 2026Article
- Variable thresholds for phosphorylation targets of the ERK signaling pathway.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Increasing certainty in systems biology models using Bayesian multimodel inference.Nature communications · 2025Article
- Bimodality in Ras signaling originates from processivity of the Ras activator SOS without deterministic bistability.Science advances · 2024Article
- Comprehensive molecular interaction map of TGFβ induced epithelial to mesenchymal transition in breast cancer.NPJ systems biology and applications · 2024Article
- A guide to ERK dynamics, part 1: mechanisms and models.The Biochemical journal · 2023Article
- Predictive power of non-identifiable models.Scientific reports · 2023Article
- The MAPK/ERK channel capacity exceeds 6 bit/hour.PLoS computational biology · 2023Article
- Review
- Network regulation meets substrate modification chemistry.Journal of the Royal Society, Interface · 2023Article
- Dynamic regulation of RAS and RAS signaling.The Biochemical journal · 2023Article
- A nested bistable module within a negative feedback loop ensures different types of oscillations in signaling systems.Scientific reports · 2023Article
- Pseudo-nullclines enable the analysis and prediction of signaling model dynamics.Frontiers in cell and developmental biology · 2023Article
- Optogenetic actuator - ERK biosensor circuits identify MAPK network nodes that shape ERK dynamics.Molecular systems biology · 2022Article
- Live imaging approach of dynamic multicellular responses in ERK signaling during vertebrate tissue development.The Biochemical journal · 2022Review
- Implications of glutathione-S transferase P1 in MAPK signaling as a CRAF chaperone: In memory of Dr. Irving Listowsky.Proceedings of the Japan Academy. Series B, Physical and biological sciences · 2022Review
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9 authors.
Funding
Abstract
We formulated a computational model for a MAPK signaling cascade downstream of the EGF receptor to investigate how interlinked positive and negative feedback loops process EGF signals into ERK pulses of constant amplitude but dose-dependent duration and frequency. A positive feedback loop involving RAS and SOS, which leads to bistability and allows for switch-like responses to inputs, is nested within a negative feedback loop that encompasses RAS and RAF, MEK, and ERK that inhibits SOS via phosphorylation. This negative feedback, operating on a longer time scale, changes switch-like behavior into oscillations having a period of 1 hour or longer. Two auxiliary negative feedback loops, from ERK to MEK and RAF, placed downstream of the positive feedback, shape the temporal ERK activity profile but are dispensable for oscillations. Thus, the positive feedback introduces a hierarchy among negative feedback loops, such that the effect of a negative feedback depends on its position with respect to the positive feedback loop. Furthermore, a combination of the fast positive feedback involving slow-diffusing membrane components with slower negative feedbacks involving faster diffusing cytoplasmic components leads to local excitation/global inhibition dynamics, which allows the MAPK cascade to transmit paracrine EGF signals into spatially non-uniform ERK activity pulses.
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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.