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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leads to hysteresis in the dose-response curve, which can enable a capacity to sustain Ras activation as stimuli are withdrawn and exhibit "memory" of past encounters with antigen.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.
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“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]
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Self-citationRasgrp1-Mediated Dampening of EGFR Signals Supports Coordinated Mammary Gland Development
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Self-citationNatural killer cell receptor signaling and activation depend on cell cycle stages
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“However, certain signaling reactions can involve positive feedback where the product promotes its own production and displays digital response to stimulations, e.g., Ras activation in T-and B-cells showing a digital response depending on abundances of RasGEFs such as SOS1 and Rasgrp1 [45].”
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“An analog to digital switch is thought to occur at the level of Ras activation (80, 249).”
BackgroundInfluential
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
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