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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leads to hysteresis in the dose-response curve, which can enable a capacity to sustain Ras activation as stimuli are withdrawn and exhibit "memory" of past encounters with antigen.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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MethodInfluentialSelf-citationTHEMIS: a critical TCR signal regulator for ligand discrimination
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MethodThe topology design principles that determine the spatiotemporal dynamics of G-protein cascades
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What Scales the T Cell Response?
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Systems biology approaches to understanding stem cell fate choice
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“Thus, as reported earlier (42, 43), the early activation response of individual naive CD8 T cells was binary.”
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“The authors then linked this pathway to the bimodal expression of CD69 (27).”
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“This pathway displays ultrasensitivity in T cells and is thought to help make an on/off activation decision from the graded upstream inputs after TCR binding.(15) Several models have explored the ERK/MAPK pathway and its role in T-cell activation.”
BackgroundHuman CD8+ T Cells Exhibit a Shared Antigen Threshold for Different Effector Responses
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“A digital switch has been reported in the TCR signalling pathway (10, 11) and a large number of T cell responses, including cytokine production, have been shown to be digital (31, 38, 39).”
BackgroundKlinke, D. J., Cheng, N., & Chambers, E. S. (2012) · Science Signaling · doi:10.1126/scisignal.2002657 · Cited by 28
“Ras activation in T cells has also been suggested to exhibit hysteresis as a mechanism to inhibit spurious T cell activation in response to weak stimulation and to integrate interrupted serial encounters within the lymph node with APCs bearing the cognate antigen [48].”
BackgroundApproaches in Immunotherapy, Regenerative Medicine, and Bioengineering for Type 1 Diabetes
Kopan, C., Tucker, T. R., Alexander, M., Mohammadi, M. R., Pone, E. J., & Lakey, J. R. T. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01354 · Cited by 28
Mertens, R. T., Misra, A., Xiao, P., Baek, S., Rone, J. M., Mangani, D., Sivanathan, K. N., Arojojoye, A. S., Awuah, S. G., Lee, I., et al. (2024) · Immunity · doi:10.1016/j.immuni.2024.06.001 · Cited by 27
Bilal, M. Y., & Houtman, J. C. D. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00141 · Cited by 32
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Network risk and forecasting power in phase-flipping dynamical networks
Boris Podobnik, A., Majdandzic, A., Curme, C., Qiao, Z., Zhou, W., Stanley, E., & Li, B. (2014) · Physical Review E · doi:10.1103/physreve.89.042807 · Cited by 26
Cooperative Clustering Digitizes Biochemical Signaling and Enhances its Fidelity
Roob, E., Trendel, N., ten Wolde, P. R., & Mugler, A. (2016) · Biophysical Journal · doi:10.1016/j.bpj.2016.02.031 · Cited by 26
“For example, it is been shown that enzyme-mediated positive feedback leads to digital, twostate activation of Ras (34), which could very well enhance the subsequent cluster-induced digitization elucidated here.”
BackgroundLoads Bias Genetic and Signaling Switches in Synthetic and Natural Systems
Lyons, S. M., Xu, W., Medford, J. I., & Prasad, A. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003533 · Cited by 27
“Ras goes from a GDP-bound inactive form to a GTP-bound active form, often in a digital manner [30], and previous studies in lymphocytes have shown that RasGDP is activated to RasGTP via a bistable switch that arises from a positive feedback loop on its own activation via SOS (Son of Sevenless) [30].”
BackgroundMethodInfluentialNoise Attenuation in the ON and OFF States of Biological Switches
Chen, M., Wang, L., Liu, C. C., & Nie, Q. H. (2013) · ACS Synthetic Biology · doi:10.1021/sb400044g · Cited by 25
RasGRP1 is a potential biomarker for stratifying anti-EGFR therapy response in colorectal cancer
Gbenedio, O. M., Bonnans, C., Grün, D., Wang, C., Hatch, A. J., Mahoney, M. R., Barras, D., Matli, M. R., Miao, Y., García, K. C., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.127552 · Cited by 26
Self-citationT Cell Receptor Signaling Kinetics Takes the Stage
Sykulev, Y. K. (2010) · Science Signaling · doi:10.1126/scisignal.3153pe50 · Cited by 25
Fructose-1,6-bisphosphate promotes PI3K and glycolysis in T cells?
Icard, P., Alifano, M., Donnadieu, E., & Simula, L. (2021) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2021.04.013 · Cited by 25
Harris, M. J., Fuyal, M., & James, J. R. (2021) · Molecular Systems Biology · doi:10.15252/msb.202010091 · Cited by 25
“ERK is a classical member of the mitogen-activated protein kinase (MAPK) family, and previous studies have suggested that ERK activation in T cells is digital (Altan-Bonnet & Germain, 2005; Das et al, 2009).”
Nur77-Tempo mice reveal T cell steady state antigen recognition
Elliot, T. A. E., Jennings, E. K., Lecky, D. A. J., Rouvray, S., Mackie, G. M., Scarfe, L., Sheriff, L., Ono, M., Maslowski, K. M., & Bending, D. (2022) · Discovery Immunology · doi:10.1093/discim/kyac009 · Cited by 23
“Similar binary signalling occurs in the Rat Sarcoma Virus/Extracellular Signal Related-Kinase (RAS/ ERK) pathway [2].”
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“Thus in addition to de-phosphorylating Raf and MEK-1/2, PP2A is also likely to function in regulating the balance between the phosphorylated and non-phosphorylated pools of MKP3.”
BackgroundInfluentialA stochastic T cell response criterion
Currie, J., Castro, M., Lythe, G., Palmer, E., & Molina-Parı́s, C. (2012) · Journal of The Royal Society Interface · doi:10.1098/rsif.2012.0205 · Cited by 24
Chakraborty, A. K., Das, J., Zikherman, J., Yang, M., Govern, C. C., Ho, M., Weiss, A., & Roose, J. P. (2009) · Science Signaling · doi:10.1126/scisignal.266pt2 · Cited by 24
Self-citationConstitutive Activation of BCR Explains Dysfunctional Signaling in Chronic Lymphocytic Leukemia
Ziegler, C. G. K., Kim, J., Piersanti, K., Oyler‐Yaniv, A., Argyropoulos, K. V., van den Brink, M. R. M., Palomba, M. L., Altan‐Bonnet, N., & Altan-Bonnet, G. Y. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.06.069 · Cited by 26
“A system whose intrinsic activation structure is highly sensitive to prior stimuli exhibits a memory of recent cellular context, making it inherently tunable by cell-specific microenvironmental stimuli (Das et al., 2009).”
InfluentialHuang, W. Y. C., Alvarez, S. A., Kondo, Y., Kuriyan, J., & Groves, J. T. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2103598118 · Cited by 23
Gallagher, M. P., Conley, J. M., & Berg, L. J. (2018) · ImmunoHorizons · doi:10.4049/immunohorizons.1800032 · Cited by 25
“A later study with human Jurkat T cells discovered that this sharp threshold in TCR-induced MAPK signaling was due to a feedback loop in Son of Sevenless signaling that amplifies Ras activation (23).”
BackgroundLiu, W., Tundwal, K., Liang, Q., Goplen, N., Rozario, S., Quayum, N., Gorska, M. M., Wenzel, S. E., Balzar, S., & Alam, R. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.01003-09 · Cited by 23
Fcμ receptor as a Costimulatory Molecule for T Cells
Meryk, A., Pangrazzi, L., Hagen, M., Hatzmann, F. M., Jenewein, B., Jakic, B., Hermann‐Kleiter, N., Baier, G., Jylhävä, J., Hurme, M., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.02.024 · Cited by 23
A Focused Review of Ras Guanine Nucleotide-Releasing Protein 1 in Immune Cells and Cancer
Hsu, T. C., Rodrigues, G. O. L., Winer, H. Y., Hixon, J. A., Li, W., Tarasova, N. I., & Durum, S. K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24021652 · Cited by 23
T cell responses to antigen: hasty proposals resolved through long engagements
Tkach, K. E., & Altan-Bonnet, G. Y. (2012) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.12.001 · Cited by 22
“Paradoxically, many characteristics of the T cell signaling have been documented as essentially all-or-none [3,5,15].”
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Andrada, E., Almena, M., de Guinoa, J. S., Merino-Cortés, S. V., Liébana, R., Arcos, R., Carrasco, S., Carrasco, Y. R., & Mérida, I. (2016) · Science Signaling · doi:10.1126/scisignal.aaf7714 · Cited by 23
“The generation and metabolism of the lipid diacylglycerol (DAG) downstream of the TCR is one of the key mechanisms that enable T lymphocytes to integrate qualitative signals into quantitative biological responses (2).”
BackgroundGermain, R. N. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a033308 · Cited by 22
“This is quite distinct from more analog responses, where it takes a hundredfold input change to go from modest but detectable output to full response (Altan-Bonnet and Germain 2005; Das et al. 2009; Gottschalk et al. 2016).”
BackgroundHernandez, C., Thomas‐Chollier, M., Naldi, A., & Thieffry, D. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.558606 · Cited by 21
A Stochastic Chemical Dynamic Approach to Correlate Autoimmunity and Optimal Vitamin-D Range
Roy, S., Shrinivas, K., & Bagchi, B. (2014) · PLoS ONE · doi:10.1371/journal.pone.0100635 · Cited by 20
“[62] and the enzyme catalysis model proposed by Min, Xie and Bagchi earlier [64].”
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Self-citationEberhardt, M., Lai, X., Tomar, N., Gupta, S. K., Schmeck, B., Steinkasserer, A., Schuler, G., & Vera, J. (2015) · Methods in molecular biology · doi:10.1007/978-1-4939-3283-2_9 · Cited by 21
Towards multiscale modeling of the CD8+T cell response to viral infections
Baral, S., Raja, R., Sen, P., & Dixit, N. M. (2019) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1446 · Cited by 20
“Sophisticated models that consider explicitly the large number of molecular players involved and their interactions have been constructed (Altan-Bonnet & Germain, 2005; J. Das et al., 2009; Lip-niacki, Hat, Faeder, & Hlavacek, 2008; Stefanova et al., 2003).”
BackgroundMiquelianin Inhibits Allergic Responses in Mice by Suppressing CD4+ T Cell Proliferation
Choi, D. W., Jung, S. Y., Kim, G.-D., Lee, S., & Shin, H. S. (2021) · Antioxidants · doi:10.3390/antiox10071120 · Cited by 21
Plasma membrane rafts engaged in T cell signalling: new developments in an old concept
Harder, T., & Sangani, D. (2009) · Cell Communication and Signaling · doi:10.1186/1478-811x-7-21 · Cited by 21
“Recent computer-based in silico models show the profound consequences of Ras-anchorage and raft-lipid dependent Ras-clustering in plasma membrane domains for Ras-downstream signalling [2,65].”
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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