ArticleProceedings of the National Academy of Sciences of the United States of America2021
Relating cellular signaling timescales to single-molecule kinetics: A first-passage time analysis of Ras activation by SOS.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 20 citations in OpenAlex.
- Mesoscale simulations of membrane-tethered reactions to parameterize cell-scale models of signaling.Biophysical journal · 2026Article
- Unmasking complex kinetics in viral entry by inferring hypoexponential models.Biophysical journal · 2025Article
- Strategies for multimodal spatiotemporal profiling of phosphorylation in cilia biology.Journal of cell science · 2025Review
- Article
- Positive feedback in Ras activation by full-length SOS arises from autoinhibition release mechanism.Biophysical journal · 2024Article
- Ras signaling mechanisms: New insights from single-molecule biophysics.Biophysical journal · 2024Article
- Bimodality in Ras signaling originates from processivity of the Ras activator SOS without deterministic bistability.Science advances · 2024Article
- Progress in Targeting KRAS Directly.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Two-dimensional molecular condensation in cell signaling and mechanosensing.Acta biochimica et biophysica Sinica · 2023Review
- Targeting small GTPases: emerging grasps on previously untamable targets, pioneered by KRAS.Signal transduction and targeted therapy · 2023Review
- A two-component protein condensate of the EGFR cytoplasmic tail and Grb2 regulates Ras activation by SOS at the membrane.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Son of Sevenless (SOS) is a Ras guanine nucleotide exchange factor (GEF) that plays a central role in numerous cellular signaling pathways. Like many other signaling molecules, SOS is autoinhibited in the cytosol and activates only after recruitment to the membrane. The mean activation time of individual SOS molecules has recently been measured to be ∼60 s, which is unexpectedly long and seemingly contradictory with cellular signaling timescales, which have been measured to be as fast as several seconds. Here, we rectify this discrepancy using a first-passage time analysis to reconstruct the effective signaling timescale of multiple SOS molecules from their single-molecule activation kinetics. Along with corresponding experimental measurements, this analysis reveals how the functional response time, comprised of many slowly activating molecules, can become substantially faster than the average molecular kinetics. This consequence stems from the enzymatic processivity of SOS in a highly out-of-equilibrium reaction cycle during receptor triggering. Ultimately, rare, early activation events dominate the macroscopic reaction dynamics.
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