ArticleBMC systems biology2012
Emergence of bimodal cell population responses from the interplay between analog single-cell signaling and protein expression noise.
Article in BMC systems biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed.
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- Modeling Cellular Signaling Variability Based on Single-Cell Data: The TGFβ-SMAD Signaling Pathway.Methods in molecular biology (Clifton, N.J.) · 2023Review
- Relating individual cell division events to single-cell ERK and Akt activity time courses.Scientific reports · 2022Article
- Differential Expression Analysis of Single-Cell RNA-Seq Data: Current Statistical Approaches and Outstanding Challenges.Entropy (Basel, Switzerland) · 2022Review
- MarcoPolo: a method to discover differentially expressed genes in single-cell RNA-seq data without depending on prior clustering.Nucleic acids research · 2022Article
- ZERO-INFLATED QUANTILE RANK-SCORE BASED TEST (ZIQRANK) WITH APPLICATION TO SCRNA-SEQ DIFFERENTIAL GENE EXPRESSION ANALYSIS.The annals of applied statistics · 2021Article
- Computational methods for characterizing and learning from heterogeneous cell signaling data.Current opinion in systems biology · 2021Article
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- Oncogenic mutant RAS signaling activity is rescaled by the ERK/MAPK pathway.Molecular systems biology · 2020Article
- ERK Activation in CAR T Cells Is Amplified by CD28-Mediated Increase in CD3ζ Phosphorylation.iScience · 2020Article
- Data-driven analysis of a mechanistic model of CAR T cell signaling predicts effects of cell-to-cell heterogeneity.Journal of theoretical biology · 2020Article
- Macrophages employ quorum licensing to regulate collective activation.Nature communications · 2020Article
- The "C3aR Antagonist" SB290157 is a Partial C5aR2 Agonist.Frontiers in pharmacology · 2020Article
- Heterogeneity and emergent behaviour in the vascular endothelium.Current opinion in pharmacology · 2019Review
- New insights into RAS biology reinvigorate interest in mathematical modeling of RAS signaling.Seminars in cancer biology · 2019Review
- Article
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9 authors.
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Abstract
backgroundCell-to-cell variability in protein expression can be large, and its propagation through signaling networks affects biological outcomes. Here, we apply deterministic and probabilistic models and biochemical measurements to study how network topologies and cell-to-cell protein abundance variations interact to shape signaling responses.
resultsWe observe bimodal distributions of extracellular signal-regulated kinase (ERK) responses to epidermal growth factor (EGF) stimulation, which are generally thought to indicate bistable or ultrasensitive signaling behavior in single cells. Surprisingly, we find that a simple MAPK/ERK-cascade model with negative feedback that displays graded, analog ERK responses at a single cell level can explain the experimentally observed bimodality at the cell population level. Model analysis suggests that a conversion of graded input-output responses in single cells to digital responses at the population level is caused by a broad distribution of ERK pathway activation thresholds brought about by cell-to-cell variability in protein expression.
conclusionsOur results show that bimodal signaling response distributions do not necessarily imply digital (ultrasensitive or bistable) single cell signaling, and the interplay between protein expression noise and network topologies can bring about digital population responses from analog single cell dose responses. Thus, cells can retain the benefits of robustness arising from negative feedback, while simultaneously generating population-level on/off responses that are thought to be critical for regulating cell fate decisions.
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