The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index.
Digital signaling and hysteresis characterize Ras activation in lymphoid cells.
Open accessAbstract
Activation of Ras proteins underlies functional decisions in diverse cell types. Two molecules, RasGRP and SOS, catalyze Ras activation in lymphocytes. Binding of active Ras to SOS' allosteric pocket markedly increases SOS' activity establishing a positive feedback loop for SOS-mediated Ras activation. Integrating in silico and in vitro studies, we demonstrate that digital signaling in lymphocytes (cells are "on" or "off") is predicated upon feedback regulation of SOS. SOS' feedback loop leads to hysteresis in the dose-response curve, which can enable a capacity to sustain Ras activation as stimuli are withdrawn and exhibit "memory" of past encounters with antigen. Ras activation via RasGRP alone is analog (graded increase in amplitude with stimulus). We describe how complementary analog (RasGRP) and digital (SOS) pathways act on Ras to efficiently convert analog input to digital output. Numerous predictions regarding the impact of our findings on lymphocyte function and development are noted.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“A number of studies have investigated the effects of positive feedback loops on decision making [24], [29].”
From A Model for How Signal Duration Can Determine Distinct Outcomes of Gene Transcription Programs (2012) · cites this paper as [24]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Exact stochastic simulation of coupled chemical reactions
Gillespie, D. T. (1977) · The Journal of Physical Chemistry · doi:10.1021/j100540a008 · Cited by 10,215 · cited 4×
“The simulations were carried out using the Gillespie algorithm ( Gillespie, 1977 ), which has been used Figure 1. A Minimal Model of the Catalytic Domain of SOS Predicts Three Possible States of Ras Activation (A) SOS’ protein domains, GEF pocket, and allosteric pocket.”
MethodInfluentialStochastic Processes in Physics and Chemistry
(2007) · Elsevier eBooks · doi:10.1016/b978-0-444-52965-7.x5000-4 · Cited by 9,096
Stochastic Processes in Physics and Chemistry
Kampen, V. (1992) · Cited by 3,301
A new algorithm for Monte Carlo simulation of Ising spin systems
Bortz, A. B., Kalos, M. H., & Lebowitz, J. L. (1975) · Journal of Computational Physics · doi:10.1016/0021-9991(75)90060-1 · Cited by 2,424 · cited 1×
“Stochastic Simulations of the Model Shown in Figures 2 and 4 We used the Gillespie algorithm (Bortz et al., 1975; Gillespie, 1977; McAdams and Arkin, 1997) to perform stochastic simulations that effectively solve the Master equation (van Kampen, 1992) corresponding to the chemical reactions in the…”
MethodHartigan, J. A., & Hartigan, P. M. (1985) · The Annals of Statistics · doi:10.1214/aos/1176346577 · Cited by 2,088 · cited 2×
“We adapted Hartigan’s test (Hartigan and Hartigan, 1985), which allows for a qualitative determination of whether a response in a population of cells is bimodal or unimodal.”
Stochastic mechanisms in gene expression.
McAdams, H., & Arkin, A. (1997) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.94.3.814 · Cited by 1,970 · cited 4×
“Stochastic Simulations of the Model Shown in Figures 2 and 4 We used the Gillespie algorithm (Bortz et al., 1975; Gillespie, 1977; McAdams and Arkin, 1997) to perform stochastic simulations that effectively solve the Master equation (van Kampen, 1992) corresponding to the chemical reactions in the…”
InfluentialEmergent Properties of Networks of Biological Signaling Pathways
Bhalla, U. S., & Iyengar, R. (1999) · Science · doi:10.1126/science.283.5400.381 · Cited by 1,686 · cited 4×
“…Nationwide Children’s Hospital and Department of Pediatrics, Biophysics Graduate Program, Ohio State University, 700 Children’s Drive, Columbus, OH 43205, USA *Correspondence: aweiss@medicine.ucsf.edu (A.W.), arupc@mit.edu (A.K.C.), jeroen.roose@ucsf.edu (J.P.R.) DOI 10.1016/j.cell.2008.11.051”
InfluentialPositive and negative selection of T cells
Starr, T. K., Jameson, S. C., & Hogquist, K. A. (2003) · Annual Review of Immunology · doi:10.1146/annurev.immunol.21.120601.141107 · Cited by 1,601 · cited 1×
“Receptor Stimulation Results in Digital Signaling with SOS and Analog Responses with RasGRP Alone Thestrengthof lymphocyte receptorstimulation impactsoutcomes (e.g., T cell activation, thymocyte development; Starr et al., 2003).”
A Cytoplasmic Protein Stimulates Normal N- ras p21 GTPase, But Does Not Affect Oncogenic Mutants
Trahey, M., & McCormick, F. (1987) · Science · doi:10.1126/science.2821624 · Cited by 1,211
Ferrell, J. E. (2002) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(02)00314-9 · Cited by 1,121 · cited 6×
“…is one of many nonlinear mechanisms that can result in ‘‘digital’’ responses of gene regulation programs and signaling networks (Barkai and Leibler, 2000; Bhalla and Iyengar, 1999; Elf and Ehrenberg, 2004; Ferrell, 2002; Kholodenko et al., 2002; Kussell et al., 2005; McAdams and Arkin, 1997).”
Influential
Cited by
Sorted by citations
Diet dominates host genotype in shaping the murine gut microbiota
Carmody, R. N., Gerber, G. K., Luevano, J. M., Gatti, D. M., Somes, L., Svenson, K. L., & Turnbaugh, P. J. (2015) · Cell Host & Microbe · doi:10.1016/j.chom.2014.11.010 · Cited by 1,103
“, 2001), immunology (Das et al., 2009), developmental biology (Sha et al.”
BackgroundSignalling ballet in space and time
Kholodenko, B. Ν., Hancock, J. F., & Kölch, W. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2901 · Cited by 612
TCR Signaling: Mechanisms of Initiation and Propagation
Courtney, A. H., Lo, W., & Weiss, A. (2017) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2017.11.008 · Cited by 600
“MEK, and ultimately the MAP kinase ERK [9].”
BackgroundSelf-citationFrequency-Modulated Pulses of ERK Activity Transmit Quantitative Proliferation Signals
Albeck, J. G., Mills, G. B., & Brugge, J. S. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.11.002 · Cited by 494
“…of ERK to respond in an all-or-none manner has been noted Frequency-Modulated ERK Signaling in Proliferation (Altan-Bonnet and Germain, 2005; Das et al., 2009; Markevich et al., 2004; Qiao et al., 2007; Sturm et al., 2010), we show that transitions between the ‘‘on’’ and ‘‘off’’ state are…”
BackgroundEnhancer Features that Drive Formation of Transcriptional Condensates
Shrinivas, K., Sabari, B. R., Coffey, E. L., Klein, I. A., Boija, A., Zamudio, A. V., Schuijers, J., Hannett, N. M., Sharp, P. A., Young, R. A., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.07.009 · Cited by 414
Self-citation
Metadata
- Authors
- Das, J., Ho, M., Zikherman, J., Govern, C., Yang, M., Weiss, A., Chakraborty, A. K., & Roose, J. P.
- Affiliations
- Massachusetts Institute of Technology (US)
- University of California, San Francisco (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Weiss, Arthur
- Chakraborty, Arup K.
- Roose, Jeroen P.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2009-01
- Volume
- 136
- Issue
- 2
- Pages
- 337-351
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2662698
- OpenAlex
- W2153683741
- Cited by
- 398
- References
- 42
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 12 · 2023: 15 · 2022: 10 · 2021: 20 · 2020: 18 · 2019: 32 · 2018: 23 · 2017: 20 · 2016: 26 · 2015: 23 · 2014: 32 · 2013: 44 · 2012: 30
- FWCI
- 13.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Elsevier eBooks
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5p01ai071195-05)
- National Cancer Institute (K01CA113367)
- National Institute of Allergy and Infectious Diseases (P01AI-071195, 1P01/AI071195/01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- Ras activation, lymphocytes, SO, RasGRP, digital signaling, hysteresis, positive feedback loop, allosteric regulation, dose-response curves, signal transduction, analog-to-digital conversion, lymphocyte development
- MeSH terms
- Animals, B-Lymphocytes, Cell Line, Chickens, Computer Simulation, Humans, Lymphocyte Activation, T-Lymphocytes, Signal Transduction, ras Proteins, Jurkat Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
