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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leads to hysteresis in the dose-response curve, which can enable a capacity to sustain Ras activation as stimuli are withdrawn and exhibit "memory" of past encounters with antigen.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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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).”
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Items 201–300 of 398
TCR ligand potency differentially impacts PD-1 inhibitory effects on diverse signaling pathways
Chan, W., Cao, Y. M., Zhao, X., Schrom, E. C., Jia, D., Song, J., Sibener, L. V., Dong, S., Fernandes, R. A., Bradfield, C. J., et al. (2023) · The Journal of Experimental Medicine · doi:10.1084/jem.20231242 · Cited by 21
“…to low-threshold signaling events that become saturated earlier than other TCR-induced signaling events such as NFAT2 and p38 activations, in accord with earlier studies showing a near “ digital ” response of the ERK pathway to TCR engagement (Altan-Bonnet and Germain, 2005; Das et al., 2009).”
ResultPredicting the Lifetime of Dynamic Networks Experiencing Persistent Random Attacks
Boris Podobnik, A., Lipić, T., Horvatić, D., Majdandzic, A., Bishop, S. R., & Stanley, E. (2015) · Scientific Reports · doi:10.1038/srep14286 · Cited by 20
“old and the system abruptly shifts from one phase to another [8–10].”
Ca 2+ -dependent Ras/Erk signaling mediates negative selection of autoreactive B cells
Limnander, A., & Weiss, A. (2011) · Small GTPases · doi:10.4161/sgtp.2.5.17794 · Cited by 20
“The synergistic activation of these two GEFs would then account for the unusually high RasGTP production observed in lymphocytes.(10,11) Although DAG production has been extensively associated with activation of Ras/Erk signaling in lymphocytes, Ras/ Erk pathway activation in lymphocytes has been thought to be largely…”
BackgroundSelf-citationAxon growth regulation by a bistable molecular switch
Padmanabhan, P., & Goodhill, G. J. (2018) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2017.2618 · Cited by 20
Kruse, J., Merkens, S., Chuvilin, A. L., & Grzelczak, M. (2020) · ACS Applied Nano Materials · doi:10.1021/acsanm.0c02249 · Cited by 20
Noise-Driven Causal Inference in Biomolecular Networks
Prill, R. J., VOGEL, R. M., Cecchi, G., Altan-Bonnet, G. Y., & Stolovitzky, G. A. (2015) · PLoS ONE · doi:10.1371/journal.pone.0125777 · Cited by 20
Dine, E., Reed, E. H., & Toettcher, J. E. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109280 · Cited by 19
“…prior optogenetic experiments done in fibroblasts (Dine et al., 2018; Toettcher et al., 2013) but slower than the 2-min timescale reported for T cells (Houtman et al., 2005), possibly reflecting additional sources of feedback or gain unique to T cells (Das et al., 2009; Huang et al., 2019).”
Mj, R., Bloch, O., Amit-Vazina, M., Yona, E., & Molad, Y. (2011) · Lupus · doi:10.1177/0961203311418790 · Cited by 19
An Interaction Library for the FcεRI Signaling Network
Chylek, L. A., Holowka, D. A., Baird, B. A., & Hlavacek, W. S. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00172 · Cited by 19
New insights into RAS biology reinvigorate interest in mathematical modeling of RAS signaling
Erickson, K. E., Rukhlenko, O. S., Posner, R. G., Hlavacek, W. S., & Kholodenko, B. Ν. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.02.008 · Cited by 21
Dichotomy of cellular inhibition by small-molecule inhibitors revealed by single-cell analysis
VOGEL, R. M., Erez, A., & Altan-Bonnet, G. Y. (2016) · Nature Communications · doi:10.1038/ncomms12428 · Cited by 19
Kortum, R. L., Rouquette‐Jazdanian, A. K., Miyaji, M., Merrill, R. K., Markegard, E., Pinski, J. M., Wesselink, A. K., Nath, N. N., Alexander, C. P., Li, W., et al. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1201458 · Cited by 20
“2 activation or of the presence of a RasGRP1/Ras/Sos/Raspositive feedback loop (8, 9).”
BackgroundSelf-citationThe Ras GTPase-activating protein neurofibromin 1 promotes the positive selection of thymocytes
Oliver, J. A., Lapinski, P. E., Lubeck, B. A., Turner, J. S., Parada, L. F., Zhu, Y., & King, P. D. (2013) · Molecular Immunology · doi:10.1016/j.molimm.2013.03.005 · Cited by 18
“…its ability to recruit to membranes and activate mammalian son of sevenless (mSOS) and Ras guanine nucleotide releasing protein 1 (RasGRP1) molecules (Das et al., 2009; Ebinu et al., 2000; Kortum et al., 2012; Lapinski and King, 2012; Priatel et al., 2002; Roose et al., 2005; Roose et al., 2007).”
BackgroundStaggered starts in the race to T cell activation
Richard, A. C., Frazer, G. L., Ma, C. Y., & Griffiths, G. M. (2021) · Trends in Immunology · doi:10.1016/j.it.2021.09.004 · Cited by 15
Temporally-regulated quick activation and inactivation of Ras is important for olfactory behaviour
Uozumi, T., Hirotsu, T., Yoshida, K., Yamada, R., Suzuki, A., Taniguchi, G., Iino, Y., & Ishihara, T. (2012) · Scientific Reports · doi:10.1038/srep00500 · Cited by 18
Jun, J. E., Kulhanek, K. R., Chen, H., Chakraborty, A. K., & Roose, J. P. (2019) · Science Signaling · doi:10.1126/scisignal.aao0736 · Cited by 18
Self-citationMultiple sources of signal amplification within the B-cell Ras/MAPK pathway
Mclaurin, J. D., & Weiner, O. D. (2019) · Molecular Biology of the Cell · doi:10.1091/mbc.e18-09-0560 · Cited by 16
“BCR-driven Ras activation is highly switch-like (nH=3), while PDBu driven Ras activation is graded (nH=0.3), supporting the model that cooperation between RasGRP and SOS gives rise to nonlinear Ras pathway activation (Das et al, 2009.)”
InfluentialFrom Discrete to Continuous Modeling of Lymphocyte Development and Plasticity in Chronic Diseases
Enciso, J., Pelayo, R., & Villarreal, C. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01927 · Cited by 16
Antigen perception in T cells by long-term Erk and NFAT signaling dynamics
Wither, M. J., White, W. L., Pendyala, S., Leanza, P. J., Fowler, D. M., & Kueh, H. Y. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2308366120 · Cited by 17
Germain, R. N. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.10.027 · Cited by 17
“This digital behavior, see previously using transcriptional reporters in hybridoma cells [53] and verified since by others at the biochemical level [54,55], has major implications for understanding T cell responses.”
MethodStochastic transitions in a bistable reaction system on the membrane
Kochańczyk, M., Jaruszewicz-Błońska, J., & Tomasz Lipniacki, B. (2013) · Journal of The Royal Society Interface · doi:10.1098/rsif.2013.0151 · Cited by 17
“Remarkably, many key biological regulatory and signalling modules are controlled by bistable switches, often leading to binary cellular responses of crucial importance, such as death or survival, senescence or proliferation [4,5].”
BackgroundAn Orthosteric Inhibitor of the RAS–SOS Interaction
Nickerson, S., Joy, S. T., Arora, P. S., & Bar‐Sagi, D. (2013) · The Enzymes · doi:10.1016/b978-0-12-420146-0.00002-0 · Cited by 17
Moreau, H. D., Bogle, G., & Bousso, P. (2016) · Immunology and Cell Biology · doi:10.1038/icb.2016.36 · Cited by 16
“12,13 Several mechanisms have been proposed to explain such ability, including hysteresis in the Ras pathway, 14 persistence of nuclear factor of activated T-cells (NFAT) in the nucleus 15 and gradual increase in c-fos levels that can act as a stimulation counter.”
BackgroundGharbi, S., Ávila‐Flores, A., Soutar, D., Orive, A., Koretzky, G. A., Albar, J. P., & Mérida, I. (2013) · Journal of Cell Science · doi:10.1242/jcs.118513 · Cited by 16
Modulation of TCR responsiveness by the Grb2-family adaptor, Gads
Lugassy, J., Corso, J., Beach, D., Petrik, T., Oellerich, T., Urlaub, H., & Yablonski, D. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.10.005 · Cited by 16
Universality of biochemical feedback and its application to immune cells
Erez, A., Byrd, T. A., VOGEL, R. M., Altan-Bonnet, G. Y., & Mugler, A. (2019) · Physical review. E · doi:10.1103/physreve.99.022422 · Cited by 16
Perspectives for Computer Modeling in the Study of T Cell ActivationPreprint
Coward, J., Germain, R. N., & Altan-Bonnet, G. Y. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a005538 · Cited by 15
“In the case of the TCR and B cell receptor (BCR) signaling machinery, Das et al (2009) showed that this positive feedback resulted in bistability.”
BackgroundMethodInfluentialKremer, K. N., Kumar, A., & Hedin, K. E. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100206 · Cited by 15
“Once localized, RasGRP1 activates Ras isoforms directly and also indirectly via another RasGEF, SOS (17).”
BackgroundA fractional‐order model for chronic lymphocytic leukemia and immune system interactions
Fadaei, Y., Ahmadi, A., Fekri, K., Masoumi, R., & Radunskaya, A. (2020) · Mathematical Methods in the Applied Sciences · doi:10.1002/mma.6743 · Cited by 15
Digital response in T cells: to be or not to be
Wertek, F., & Xu, C. (2014) · Cell Research · doi:10.1038/cr.2014.5 · Cited by 15
A Circuit Model of Hysteresis and Creep
Biggio, M., Oliveri, A., Stellino, F., Parodi, M., & Storace, M. (2015) · IEEE Transactions on Circuits and Systems - II - Express Briefs · doi:10.1109/tcsii.2014.2385412 · Cited by 16
Order by chance: origins and benefits of stochasticity in immune cell fate control
Abadie, K., Pease, N. A., Wither, M. J., & Kueh, H. Y. (2019) · Current Opinion in Systems Biology · doi:10.1016/j.coisb.2019.10.013 · Cited by 14
Proprotein convertase FURIN regulates T cell receptor-induced transactivation
Ortutay, Z., Oksanen, A., Aittomäki, S., Ortutay, C., & Pesu, M. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.2a0514-257rr · Cited by 15
“ERK is activated by the GTPase Ras, whose activation, in turn, is dependent on RasGRP1 and son of sevenless [35–37].”
BackgroundGolec, D. P., Dower, N. A., Stone, J. C., & Baldwin, T. A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0053300 · Cited by 13
“However, there is evidence suggesting Sos1 and RasGRP1 cooperate in a feedforward loop to coordinate Ras/ ERK activation [20,21].”
BackgroundNakamura, Y., Hibino, K., Yanagida, T., & Sako, Y. (2016) · Biophysics and Physicobiology · doi:10.2142/biophysico.13.0_1 · Cited by 15
Wen, Z. H., Yun, G., Hebert, A. S., Kong, G., Ranheim, E. A., Finn, R., Rajagoplan, A., Li, S., Zhou, Y., Yu, M., et al. (2021) · Blood · doi:10.1182/blood.2020009082 · Cited by 14
Self-citationBurban, D. J., Haglund, E., Capraro, D. T., & Jennings, P. A. (2015) · Journal of Physics Condensed Matter · doi:10.1088/0953-8984/27/35/354108 · Cited by 14
Ultrasensitivity in the Cofilin Signaling Module: A Mechanism for Tuning T Cell Responses
Ramirez-Munoz, R., Castro-Sánchez, P., & Roda‐Navarro, P. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00059 · Cited by 13
“In order to further demonstrate irreversibility, it will be needed to design experiments for the complete deprivation of peptide antigenic stimulation by, for example, combining antigen washing and pharmacological inhibition of early TCR signals as previously done (31).”
BackgroundMethodComputer vision reveals hidden variables underlying NF-κB activation in single cells
Patel, P., Drayman, N., Liu, P., Bilgic, M., & Tay, S. (2021) · Science Advances · doi:10.1126/sciadv.abg4135 · Cited by 12
Lee, A. A., Kim, N. H., Alvarez, S. A., Ren, H., DeGrandchamp, J. B., Lew, L. J. N., & Groves, J. T. (2024) · Science Advances · doi:10.1126/sciadv.adi0707 · Cited by 11
“Such high densities of Ras have been reportedly observed in Ras clusters in cells ( 13 , 17 ) but are distinctly higher than the average Ras density in the plasma membrane ( ~ 400 molecules/ μ m 2 ) ( 21 ).”
BackgroundInfluentialHeterogeneity assessment of functional T cell avidity
Ioannidou, K., Baumgaertner, P., Gannon, P. O., Speiser, M., Allard, M., Hebeisen, M., Rufer, N., & Speiser, D. E. (2017) · Scientific Reports · doi:10.1038/srep44320 · Cited by 12
A Biased Competition Theory of Cytotoxic T Lymphocyte Interaction with Tumor Nodules
Christophe, C., Müller, S., Rodrigues, M., Petit, A.-E., Cattiaux, P., Dupré, L., Gadat, S., & Valitutti, S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0120053 · Cited by 12
“The capacity of individual T cells to provide all-or-nothing responses has been thoroughly documented both at the molecular and at the cellular level [27, 28] and has been illustrated by mathematical modeling of TCR-associated signaling pathways [29].”
BackgroundCritical slowing down in biochemical networks with feedback
Byrd, T. A., Erez, A., VOGEL, R. M., Peterson, C., Vennettilli, M., Altan-Bonnet, G. Y., & Mugler, A. (2019) · Physical review. E · doi:10.1103/physreve.100.022415 · Cited by 12
Mathematical Investigation of How Oncogenic Ras Mutants Promote Ras Signaling
Stites, E. C., & Ravichandran, K. S. (2012) · Methods in molecular biology · doi:10.1007/978-1-61779-833-7_5 · Cited by 12
Aull, K. H., Tanner, E. J., Thomson, M., & Weinberger, L. S. (2017) · Biophysical Journal · doi:10.1016/j.bpj.2017.05.002 · Cited by 11
Understanding natural killer cell regulation by mathematical approaches
Watzl, C., Sternberg‐Simon, M., Urlaub, D., & Mehr, R. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00359 · Cited by 11
“The understanding of T cell receptor signaling has been greatly aided by mathematical approaches (for examples, see Feinerman et al., 2008; Das et al., 2009).”
MethodAllosteric autoactivation of SOS and its kinetic mechanism
Hoang, H. M., Umutesi, H. G., & Heo, J. (2019) · Small GTPases · doi:10.1080/21541248.2019.1601954 · Cited by 11
“dynamic conditions within a local confined membrane region?[24] Finally, it is unclear whether the occurrence of the predicted steady-state SOS hysteresis [23] accurately accounts for the positive feedback loop action of active”
BackgroundMethodInfluentialPositive feedback can lead to dynamic nanometer-scale clustering on cell membranes
Wehrens, M., ten Wolde, P. R., & Mugler, A. (2014) · The Journal of Chemical Physics · doi:10.1063/1.4901888 · Cited by 11
Dynamical properties of a two-gene network with hysteresis
Shu, Q., & Sanfelice, R. G. (2014) · Information and Computation · doi:10.1016/j.ic.2014.01.015 · Cited by 11
Chakraborty, A. K., Das, J., Zikherman, J., Yang, M., Govern, C. C., Ho, M., Weiss, A., & Roose, J. P. (2009) · PubMed Central · Cited by 11
Self-citationProofreading and single-molecule sensitivity in T cell receptor signaling by condensate nucleation
White, W. L., Yirdaw, H. K., Ben‐Sasson, A. J., Groves, J. T., Baker, D. A., & Kueh, H. Y. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2422787122 · Cited by 10
Modeling of cytometry data in logarithmic space: When is a bimodal distribution not bimodal?
Erez, A., VOGEL, R. M., Mugler, A., Belmonte, A. L., & Altan-Bonnet, G. Y. (2018) · Cytometry Part A · doi:10.1002/cyto.a.23333 · Cited by 11
“used to infer the fixed points of a dynamic stochastic biochemical network (1,7,9) and other in silico methods (18); (2)”
Regulation of the Small GTPase Ras and Its Relevance to Human Disease
Kulhanek, K. R., Roose, J. P., & Rubio, I. (2021) · Methods in molecular biology · doi:10.1007/978-1-0716-1190-6_2 · Cited by 10
Self-citationHigh-Content Analysis with Cellular and Tissue Systems Biology
Gough, A., Lezon, T. R., Faeder, J. R., Chennubhotla, C., Murphy, R. F., Critchley-Thorne, R. J., & Taylor, D. L. (2015) · Elsevier eBooks · doi:10.1016/b978-1-4557-4066-6.00025-1 · Cited by 10
How T Cells Do the “Search for the Needle in the Haystack”
Baumgart, F., Schneider, M. C., & Schütz, G. J. (2019) · Frontiers in Physics · doi:10.3389/fphy.2019.00011 · Cited by 10
Pitavastatin Is a Highly Potent Inhibitor of T-Cell Proliferation
Voss, L., Guttek, K., Reddig, A., Reinhold, A., Voß, M., Simeoni, L., Schraven, B. L., & Reinhold, D. (2021) · Pharmaceuticals · doi:10.3390/ph14080727 · Cited by 12
“The expression of the early activation marker CD69 is induced by TCR engagement and dependent on Ras activation [42], while CD25 expression is predominantly dependent on NFAT activation [43].”
BackgroundOsei-Sarfo, K., Martello, L. A., Ibrahim, S., & Pellicer, À. (2011) · Oncogene · doi:10.1038/onc.2011.93 · Cited by 10
Mechanistic modeling to investigate signaling by oncogenic Ras mutants
Stites, E. C., & Ravichandran, K. S. (2011) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.156 · Cited by 10
Whitacre, J. M., Lin, J., & Harding, A. S. (2012) · Frontiers in Genetics · doi:10.3389/fgene.2012.00005 · Cited by 10
“Interestingly, T cell activation has been shown to be digital in nature: a T cell can only exist in an “Off” (resting) state or an “On” (activated) state (Altan-Bonnet and Germain, 2005; Daniels et al., 2006; Chakraborty et al., 2009; Das et al., 2009; Lin et al., 2009; Prasad et al., 2009).”
Backgroundc-Raf participates in adaptive immune response of Nile tilapia via regulating lymphocyte activation
Wei, X., Zhao, T., Ai, K., Zhang, Y., Li, H., & Yang, J. (2018) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2018.11.072 · Cited by 10
Chang, Y.-T., Manivannan, P., Doosti, A., Lapinski, P. E., Chen, D., Roose, J. P., & King, P. D. (2023) · The Journal of Immunology · doi:10.4049/jimmunol.2300138 · Cited by 9
Self-citationAggregation-fragmentation model of robust concentration gradient formation
Saunders, T. E. (2015) · Physical Review E · doi:10.1103/physreve.91.022704 · Cited by 9
Kullback-Leibler divergence-based optimal compression of Preisach operator in hysteresis modeling
Zhang, J., Merced, E., Sepúlveda, N., & Tan, X. (2013) · Proceedings of the ... American Control Conference/Proceedings of the American Control Conference · doi:10.1109/acc.2013.6579819 · Cited by 9
“Hysteresis is a nonlinear effect that occurs in a wide range of areas, such as biology [1], economics [2], ferromagnetic materials [3] and various smart materials [4]–[7].”
BackgroundZorn, C. N., Simonowski, A., & Huber, M. (2018) · Scientific Reports · doi:10.1038/s41598-018-33769-1 · Cited by 10
López, J. M. (2010) · Communicative & Integrative Biology · doi:10.4161/cib.3.2.10365 · Cited by 9
“Recently, it has been described that Ras activation in lymphoid cells is characterized by digital signaling and hysteresis as a consequence of a positive feedback loop.(16) In principle, it could be possible to develop algorithms to predict outputs from specific inputs (signals) if we know all the pathways involved an…”
BackgroundStites, E. C. (2014) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/005397 · Cited by 10
“Models of Ras signaling more specifically have provided a solid theoretical understanding for many processes in Ras biology, ranging from how membrane localization affects Ras activation [35], to Ras mediated positive feedback on its direct upstream regulator [36], to the function of Ras signaling from membrane micro-…”
BackgroundSimpson, C., Ferrari, N., Calvo, F., & Bakal, C. (2018) · SSRN Electronic Journal · doi:10.2139/ssrn.3188455 · Cited by 9
Peeking Into the Black Box of T Cell Receptor Signaling
Weiss, A. (2023) · Annual Review of Immunology · doi:10.1146/annurev-immunol-090222-112028 · Cited by 9
Self-citationDramatic reduction of dimensionality in large biochemical networks owing to strong pair correlations
Dworkin, M., Mukherjee, S., Jayaprakash, C., & Das, J. (2012) · Journal of The Royal Society Interface · doi:10.1098/rsif.2011.0896 · Cited by 8
Self-citationQuantal concept of T-cell activation: adhesion domains as immunological synapses
Sackmann, E. (2011) · New Journal of Physics · doi:10.1088/1367-2630/13/6/065013 · Cited by 8
“After phosphorylation by ZAP-70, LAT recruits several actuators (such as SPL-76 and PLC-γ ), which trigger two parallel signalling pathways (see [14–16] and figure 4 for the function).”
BackgroundMethodInfluentialInvolvement of H-Ras in the adaptive immunity of Nile tilapia by regulating lymphocyte activation
Wei, X., Zhao, T., Zhang, Y., Ai, K., Li, H., & Yang, J. (2019) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2019.04.003 · Cited by 8
“In the MAPK cascade, activated Ras causes Raf activation, and ultimately leads Erk entering nuclear to promote gene expression [14].”
BackgroundSH3-domain mutations selectively disrupt Csk homodimerization or PTPN22 binding
Brian, B. F., Sjaastad, F. V., & Freedman, T. S. (2022) · Scientific Reports · doi:10.1038/s41598-022-09589-9 · Cited by 8
T cell microvilli simulations show operation near packing limit and impact on antigen recognition
Morgan, J., Pettmann, J., Dushek, O., & Lindsay, A. E. (2022) · Biophysical Journal · doi:10.1016/j.bpj.2022.09.030 · Cited by 8
Modeling the T cell immune response: a fascinating challenge
Morel, P. A., Faeder, J. R., Hawse, W. F., & Miškov-Živanov, N. (2014) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-014-9376-y · Cited by 8
“This has led to several models based on feedback loops and leading to digital responses necessary for full activation based on ERK [94] or Ras activation [95].”
PASCAR: a multiscale framework to explore the design space of constitutive and inducible CAR T cells
Rajakaruna, H., Desai, M., & Das, J. (2023) · Life Science Alliance · doi:10.26508/lsa.202302171 · Cited by 7
Self-citationYin, R., Melton, S., Huseby, E. S., Mehran Kardar, A., & Chakraborty, A. K. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2318599121 · Cited by 7
“We chose a sharp threshold of activation because in individual T cells the membrane-proximal signaling network exhibits a digital, all-or-nothing response [85, 86, 87].”
BackgroundSelf-citationIL ‐2 amplifies quantitative TCR signalling inputs to drive Th1 and Th2 differentiation
Al‐Aghbar, M. A., Guarch, M. E., & van Panhuys, N. (2024) · Immunology · doi:10.1111/imm.13821 · Cited by 7
“Several previous studies have attributed the digital signalling that results in the bimodal response of thymocytes [32], CD4 + [21, 33] and CD8 + [34] T cells to the activation of an ERK-dependent pathway that functions directly downstream of the TCR. Additionally, the degree of TCR stimulation…”
The MAPK/ERK channel capacity exceeds 6 bit/hour
Nałęcz‐Jawecki, P., Gagliardi, P. A., Kochańczyk, M., Dessauges, C., Pertz, O. C., & Lipniacki, T. (2023) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1011155 · Cited by 7
Detection of biological switches using the method of Gröebner bases
Arkun, Y. (2019) · BMC Bioinformatics · doi:10.1186/s12859-019-3155-0 · Cited by 7
A Model for How Signal Duration Can Determine Distinct Outcomes of Gene Transcription Programs
Fowler, K. D., Kuchroo, V. K., & Chakraborty, A. K. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033018 · Cited by 6
“A number of studies have investigated the effects of positive feedback loops on decision making [24,29].”
Self-citationZhang, X., Qin, N., Ji, F., Su, H., Shang, H., Chen, H., Huang, D., Li, Q., Ren, J., Liu, W., et al. (2025) · 癌症：英文版 · doi:10.1002/cac2.70070 · Cited by 6
“Additionally, SOS proteins can form a positive feedback loop with RAS, contributing to sustained MAPK/ERK signaling activation [56, 57].”
Fan, S., Kang, B., Li, S., Li, W., Chen, C., Chen, J., Deng, L., Chen, D., & Zhou, J. (2024) · Cell Cycle · doi:10.1080/15384101.2024.2366009 · Cited by 6
“Therefore, knocking out RASGRP1 alone is not sufficient to block negative selection [43,44,46].”
BackgroundZou, H., Chen, Y., Zhu, X., Zhao, X., Cao, J., Chen, Y., Zhang, Z., Zhu, Y., Li, Q., & Li, M. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117105 · Cited by 6
Artomov, M., Mehran Kardar, A., & Chakraborty, A. K. (2010) · The Journal of Chemical Physics · doi:10.1063/1.3482813 · Cited by 6
Self-citationFlavors of EGFR-Ras signals impacting intestinal homeostasis
Depeille, P., & Roose, J. P. (2015) · Cell Cycle · doi:10.1080/15384101.2015.1084203 · Cited by 6
Self-citationPatel, A., Kutuzov, M. A., Dustin, M. L., van der Merwe, P. A., & Dushek, O. (2024) · Immunotherapy Advances · doi:10.1093/immadv/ltae004 · Cited by 6
“The ability of co-stimulation receptors to increase cytokine production by a population of cells may result from increasing the fraction of activated T cells and/or increasing the amount of cytokine produced by each T cell [38–40].”
Data-driven quantification of the robustness and sensitivity of cell signaling networks
Mukherjee, S., Seok, S.-C., Vieland, V. J., & Das, J. (2013) · Physical Biology · doi:10.1088/1478-3975/10/6/066002 · Cited by 5
Self-citationRamos, J., Lynch, S., Jones, D. A., & Degens, H. (2017) · International Journal of Bifurcation and Chaos · doi:10.1142/s0218127417300038 · Cited by 6
Gangopadhyay, K., Roy, A., Chandradasan, A. C., Roy, S., Debnath, O., SenGupta, S., Chowdhury, S., Das, D., & Das, R. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102376 · Cited by 5
“It may be noted that our model does not have any feedback regulation (43, 44) and is based on allosteric interaction between the two SH2 domains (33).”
BackgroundCampanello, L., Traver, M. K., Shroff, H., Schaefer, B. C., & Losert, W. (2021) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1007986 · Cited by 6
Vujovic, F., Shepherd, C. E., Witting, P. K., Hunter, N., & Farahani, R. H. (2023) · Antioxidants · doi:10.3390/antiox12101873 · Cited by 5
“This generates a positive feedback cycle which triggers a sharp amplification of Ras signalling, transforming the analogue signalling output of Ras to a digital binary output [31] (Figure 2).”
BackgroundPositive feedback in Ras activation by full-length SOS arises from autoinhibition release mechanism
Ren, H., Lee, A. A., Lew, L. J. N., DeGrandchamp, J. B., & Groves, J. T. (2024) · Biophysical Journal · doi:10.1016/j.bpj.2024.07.014 · Cited by 5
“The higher binding affinity for RasGTP relative to RasGDP at the SOS allosteric site as well as a presumption of nucleotide-specific enhancement of catalytic activity have generally been accepted as the mechanisms of positive feedback (4,18–21).”
Mlynarczyk, P. J., Pullen, R. H., & Abel, S. M. (2016) · The Journal of Chemical Physics · doi:10.1063/1.4939219 · Cited by 4
Mukherjee, S., Stewart, D. E., Stewart, W., Lanier, L. L., & Das, J. (2017) · Royal Society Open Science · doi:10.1098/rsos.170811 · Cited by 4
“We used an experimentally validated signalling network for Ras activation in T lymphocytes (electronic supplementary material, figure S6) [24].”
BackgroundMethodSelf-citationOn the hysteresis of financial crises in the US: Evidence from S&P 500
Bentes, S. R. (2020) · Physica A Statistical Mechanics and its Applications · doi:10.1016/j.physa.2020.125583 · Cited by 5
Mathematical Modelling of T Cell Activation
Trendel, N., & Dushek, O. (2021) · Springer eBooks · doi:10.1007/978-3-030-57204-4_13 · Cited by 4
T-cell activation and tolerance
Peterson, E. J., Maltzman, J. S., & Koretzky, G. A. (2013) · Elsevier eBooks · doi:10.1016/b978-0-7234-3691-1.00036-2 · Cited by 5
Chemical kinetic mechanistic models to investigate cancer biology and impact cancer medicine
Stites, E. C. (2013) · Physical Biology · doi:10.1088/1478-3975/10/2/026004 · Cited by 5
Biochemical heterogeneity and developmental varieties in T-cell leukemia
Chakraborty, A. K., & Roose, J. P. (2013) · Cell Cycle · doi:10.4161/cc.24858 · Cited by 5
Self-citationBalit, N., Cermakian, N., & Khadra, A. (2024) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2024.111852 · Cited by 4
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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