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leads to hysteresis in the dose-response curve, which can enable a capacity to sustain Ras activation as stimuli are withdrawn and exhibit "memory" of past encounters with antigen.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.
“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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“In T lymphocytes, this positive feedback is key to establish a bistable Ras response that contributes to the establishment of memory cells, which maintain the ability to be rapidly reactivated by the specific antigens they have encountered before.(410) The biological relevance of positive feedback includes the generat…”
BackgroundRas Conformational Ensembles, Allostery, and Signaling
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“The positive feedback loop between Ras and SOS has also been shown to underlie a 'digital' response to T-cell receptor activation, in which the MAP kinase pathway is either on or of”
BackgroundAn orthosteric inhibitor of the Ras-Sos interaction
Patgiri, A., Yadav, K. K., Arora, P. S., & Bar‐Sagi, D. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.612 · Cited by 294 · see citing works
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InfluentialCD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery
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“Furthermore, triple Vav-deficient B cells have an intact MAPK pathway but are completely impaired in Ca signaling (76, 77), and more recent studies suggest that Sos is important in BCR-mediated activation of Ras under conditions of suboptimal BCR stimulation (88, 89).”
ResultUbiquitination of K-Ras Enhances Activation and Facilitates Binding to Select Downstream Effectors
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Phenotypic models of T cell activation
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“, 2011), is most likely due to intracellular feedback mechanisms (Altan-Bonnet and Germain, 2005; Chan et al., 2004; Das et al., 2009; Stefanová et al., 2003).”
BackgroundRas activation by SOS: Allosteric regulation by altered fluctuation dynamics
Iversen, L., Tu, H.-L., Lin, W.-C., Christensen, S. M., Abel, S. M., Iwig, J., Wu, H.-J., Gureasko, J., Rhodes, C., Petit, R. S., et al. (2014) · Science · doi:10.1126/science.1250373 · Cited by 154 · see citing works
Self-citationMarangoni, F., Murooka, T. T., Manzo, T., Kim, E. Y., Carrizosa, E., Elpek, N. M., & Mempel, T. R. (2013) · Immunity · doi:10.1016/j.immuni.2012.09.012 · Cited by 164 · see citing works
“Furthermore, to examine whether slow nuclear export of NFAT was paralleled by an equally slow decrease of intracellular Ca, which would suggest continued TCR signaling, we activated HA-CTL with the lectin Concanavalin A (ConA) that crosslinks various cell surface receptors including the TCR but can be antagonized with…”
InfluentialCD45 functions as a signaling gatekeeper in T cells
Courtney, A. H., Shvets, A. A., Lu, W., Griffante, G., Mollenauer, M., Horkova, V., Lo, W.-L., Yu, S., Stepanek, O., Chakraborty, A. K., et al. (2019) · Science Signaling · doi:10.1126/scisignal.aaw8151 · Cited by 161 · see citing works
“We previously reported that Ras/SOS/ERK pathway behavior in T cells can be recapitulated computationally (41).”
BackgroundSelf-citationH-Ras forms dimers on membrane surfaces via a protein–protein interface
Lin, W., Iversen, L., Tu, H., Rhodes, C., Christensen, S. M., Iwig, J. S., Hansen, S. D., Huang, W. Y. C., & Groves, J. T. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1321155111 · Cited by 156 · see citing works
“Reported average plasma membrane densities of H-Ras in vivo vary from tens (33) to over hundreds (34) of molecules per square micrometer.”
BackgroundResponse and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras
Lauchle, J., Kim, D. S., Le, D., Akagi, K., Crone, M., Krisman, K., Warner, K., Bonifas, J. M., Li, Q., Coakley, K. M., et al. (2009) · Nature · doi:10.1038/nature08279 · Cited by 150 · see citing works
Self-citationFerrell, J. E., Pomerening, J. R., Kim, S. Y., Trunnell, N. B., Xiong, W., Huang, C. F., & Machleder, E. M. (2009) · FEBS Letters · doi:10.1016/j.febslet.2009.10.068 · Cited by 145 · see citing works
Ras activation revisited: role of GEF and GAP systems
Hennig, A., Markwart, R., Esparza-Franco, M. A., Ladds, G., & Rubio, I. (2015) · Biological Chemistry · doi:10.1515/hsz-2014-0257 · Cited by 141 · see citing works
“Similarly, current models of antigen-dependent Ras activation in T cells invoke the action of both Sos and RasGRP1 downstream of the activated TCR (Das et al., 2009; Jun et al., 2013) but have so far ignored the fact that one or both GEFs must be active prior to antigen encounter driving the high flux through the Ras-…”
BackgroundInfluentialHenrickson, S. E., Perro, M., Loughhead, S. M., Senman, B. C., Stutte, S., Quigley, M. M., Alexe, G., Iannacone, M., Flynn, M. P., Omid, S., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.08.034 · Cited by 138 · see citing works
“The mechanism for in vivo integration of serial activation signals is unknown, but in vitro work has implicated the Ras family of GTPases (Das et al., 2009) and the Akt pathway (Kim et al.”
BackgroundHuang, W. Y. C., Yan, Q., Lin, W., Chung, J. K., Hansen, S. D., Christensen, S. M., Tu, H., Kuriyan, J., & Groves, J. T. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1602602113 · Cited by 138 · see citing works
“Positive feedback from allosteric activation of SOS has been identified as a key element of this digitization (42).”
BackgroundUnderstanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update
Icard, P., Coquerel, A., Wu, Z., Gligorov, J., Fuks, D., Fournel, L., Lincet, H., & Simula, L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126587 · Cited by 139 · see citing works
“Indeed, F-1,6-BP can bind to Son-of-Sevenless-homolog-1 (SoS1) [67], which catalyses Ras activation [68].”
BackgroundDeconstruction of the Ras switching cycle through saturation mutagenesis
Bandaru, P., Shah, N. H., Bhattacharyya, M., Barton, J. P., Kondo, Y., Cofsky, J. C., Gee, C. L., Chakraborty, A. K., Kortemme, T., Ranganathan, R., et al. (2017) · eLife · doi:10.7554/elife.27810 · Cited by 117 · see citing works
“GTP to SOS converts SOS to a highly processive enzyme at the membrane, and this positive feedback loop in Ras activation is necessary for the generation of a sharp response in signaling by the T cell receptor (Gureasko et al., 2008; Das et al., 2009; Iversen et al., 2014).”
BackgroundSelf-citationChylek, L. A., Harris, L. A., Tung, C., Faeder, J. R., Lopez, C. F., & Hlavacek, W. S. (2013) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1245 · Cited by 131 · see citing works
Enhanced Effector Responses in Activated CD8+ T Cells Deficient in Diacylglycerol Kinases
Riese, M. J., Wang, L. S., Moon, E. K., Joshi, R. P., Ranganathan, A., June, C. H., Koretzky, G. A., & Albelda, S. Μ. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-3874 · Cited by 126 · see citing works
“Under a currently posited model of TCR signaling, the interplay of 2 Ras-activating proteins, the guanine nucleotide-exchange factors SOS and RasGRP1, determine whether the threshold for Ras activation ismet within a T cell after TCR engagement, an event required for T-cell activation (34).”
Signalling complexes and clusters: functional advantages and methodological hurdles
Cebecauer, M., Spitaler, M., Sergé, A., & Magee, A. I. (2010) · Journal of Cell Science · doi:10.1242/jcs.061739 · Cited by 126 · see citing works
“Computational analyses show that this positive feedback, which is responsible for the bistable response of the Ras pathway, favours an increase in cluster number or size (Das et al., 2009b).”
BackgroundInfluentialA new look at T cell receptor signaling to nuclear factor-κB
Paul, S., & Schaefer, B. C. (2013) · Trends in Immunology · doi:10.1016/j.it.2013.02.002 · Cited by 126 · see citing works
STIM1, PKC-δ and RasGRP set a threshold for proapoptotic Erk signaling during B cell development
Limnander, A., Depeille, P., Freedman, T. S., Liou, J., Leitges, M., Kurosaki, T., Roose, J. P., & Weiss, A. (2011) · Nature Immunology · doi:10.1038/ni.2016 · Cited by 125 · see citing works
“RasGrp and SOS are Ras guanine nucleotide exchange factors (RasGEFs) involved in RasGTP production upstream of Erk activation in lymphocytes 25, 29–33 .”
Self-citationRegulation and Function of the RasGRP Family of Ras Activators in Blood Cells
Stone, J. C. (2011) · Genes & Cancer · doi:10.1177/1947601911408082 · Cited by 118 · see citing works
“However, in DT40 cells at least, it is the suboptimal signaling that depends on both RasGRP and Sos.(106) Obviously, the proposal is untenable if Sos cannot be more directly implicated in TCR signaling.”
InfluentialPhenotypic model for early T-cell activation displaying sensitivity, specificity, and antagonism
François, P., Voisinne, G., Siggia, E. D., Altan-Bonnet, G. Y., & Vergassola, M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1300752110 · Cited by 113 · see citing works
“(27), and they both amplify and digitize (via ERK and SOS feedbacks) the signal.”
BackgroundRegulation of T Helper Cell Fate by TCR Signal Strength
Bhattacharyya, N. D., & Feng, C. G. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00624 · Cited by 114 · see citing works
“NFAT and ERK/AP-1 predominantly drive the expression of surface markers associated with CD4 T cell activation, such as CD25 (93, 94) and CD69, respectively (89, 95).”
BackgroundInfluentialRas and extracellular signal-regulated kinase signaling in thymocytes and T cells
Kortum, R. L., Rouquette‐Jazdanian, A. K., & Samelson, L. E. (2013) · Trends in Immunology · doi:10.1016/j.it.2013.02.004 · Cited by 115 · see citing works
“Correlation of these observations with the biochemical and modeling data describing the engagement of a RasGRP1–Ras–Sos–Ras positive feedback loop following strong, but not weak, TCR stimulation [25] has led to a hypothesis whereby weak TCR stimulation by low-potency ligands signals to Ras via RasGRP1 alone to support…”
BackgroundResultThe Duration of T Cell Stimulation Is a Critical Determinant of Cell Fate and Plasticity
Miškov-Živanov, N., Turner, M. S., Kane, L., Morel, P. A., & Faeder, J. R. (2013) · Science Signaling · doi:10.1126/scisignal.2004217 · Cited by 113 · see citing works
Sparta, B., Pargett, M., Minguet, M., Distor, K., Bell, G. R. R., & Albeck, J. G. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.662247 · Cited by 113 · see citing works
“This feedback loop has previously been implicated in driving digital ERK activation in lymphocytes using fixed cell measurements to assay the initial stimulus response (40).”
MethodSignaling in Lymphocyte ActivationPreprint
Cantrell, D. A. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a018788 · Cited by 105 · see citing works
Gureasko, J. M., Kuchment, O., Makino, D. L., Sondermann, H., Bar‐Sagi, D., & Kuriyan, J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0913915107 · Cited by 105 · see citing works
“Kubiseski TJ, Chook YM, Parris WE, Rozakis-Adcock M, Pawson T (1997) High affinity binding of the pleckstrin homology domain of mSos1 to phosphatidylinositol (4,5)-”
BackgroundExtracellular matrix density promotes EMT by weakening cell–cell adhesions
Kumar, S., Das, A., & Sen, S. (2014) · Molecular BioSystems · doi:10.1039/c3mb70431a · Cited by 101 · see citing works
Mitogen‐activated protein kinase signalling and ERK1/2 bistability in asthma
Alam, R., & Gorska, M. M. (2010) · Clinical & Experimental Allergy · doi:10.1111/j.1365-2222.2010.03658.x · Cited by 103 · see citing works
T‐cell receptor affinity in thymic development
Moran, A. E., & Hogquist, K. A. (2011) · Immunology · doi:10.1111/j.1365-2567.2011.03547.x · Cited by 103 · see citing works
Qian, H. (2012) · Annual Review of Biophysics · doi:10.1146/annurev-biophys-050511-102240 · Cited by 96 · see citing works
Wang, B., Mao, Y., Diorio, C. J., Pasyk, M., Wu, R., Bienenstock, J., & Kunze, W. (2010) · The FASEB Journal · doi:10.1096/fj.09-153841 · Cited by 98 · see citing works
“Dose-response hysteresis has also been described in other peripheral systems, for example, autonomic cardiac reflexes (77) or Ras activation of lymphocytes (78).”
BackgroundLight-based tuning of ligand half-life supports kinetic proofreading model of T cell signaling
Tischer, D., & Weiner, O. D. (2019) · eLife · doi:10.7554/elife.42498 · Cited by 93 · see citing works
Evolving concepts of specificity in immune reactions
Eisen, H. N., & Chakraborty, A. K. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1012051108 · Cited by 92 · see citing works
“For a typical T cell in a normal repertoire, the need for multiplicity of TCRpeptide interactions may account for specificity, because weakening even one interaction may make a significant percentage change to the binding free energy, and this could abrogate recognition because strong nonlinearities in the T-cell sign…”
BackgroundSelf-citationOgura, Y., Wen, F.-L., Sami, M. M., Shibata, T., & Hayashi, S. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.06.004 · Cited by 91 · see citing works
Non‐catalytic tyrosine‐phosphorylated receptors
Dushek, O., Goyette, J., & van der Merwe, P. A. (2012) · Immunological Reviews · doi:10.1111/imr.12008 · Cited by 90 · see citing works
Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1
Iwig, J. S., Vercoulen, Y., Das, R., Barros, T. F., Limnander, A., Che, Y., Pelton, J. G., Wemmer, D. E., Roose, J. P., & Kuriyan, J. (2013) · eLife · doi:10.7554/elife.00813 · Cited by 89 · see citing works
“The action of RasGRP1 in initiating the positive feedback loop of SOS leads to ultrasensitive ERK activation in Jurkat T cells and has been postulated to define the sharp boundary between positively and negatively selecting ligands during thymocyte development (Das et al., 2009; Prasad et al., 2009).”
BackgroundSelf-citationConley, J. M., Gallagher, M. P., & Berg, L. J. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00076 · Cited by 87 · see citing works
“CD69 was also observed to have this digital response and its expression was highly dependent on the MAPK pathway (13, 14).”
Antigen Potency and Maximal Efficacy Reveal a Mechanism of Efficient T Cell Activation
Dushek, O., Aleksic, M., Wheeler, R. J., Zhang, H., Cordoba, S., Peng, Y., Chen, J., Cerundolo, V., Dong, T., Coombs, D., et al. (2011) · Science Signaling · doi:10.1126/scisignal.2001430 · Cited by 87 · see citing works
“This has been well documented, for example, by the all-or-none phosphorylation state of downstream signaling molecules, such as the extracellular signal–regulated kinases (ERKs) (37, 38).”
BackgroundLinear Integration of ERK Activity Predominates over Persistence Detection in Fra-1 Regulation
Gillies, T. E., Pargett, M., Minguet, M., Davies, A. E., & Albeck, J. G. (2017) · Cell Systems · doi:10.1016/j.cels.2017.10.019 · Cited by 83 · see citing works
“It has remained ambiguous whether ERK responses are digital/bimodal (Altan-Bonnet and Germain, 2005; Das et al., 2009; Ferrell and Machleder, 1998) or analog (O’Shaughnessy et al.”
BackgroundIL-7– and IL-15–Mediated TCR Sensitization Enables T Cell Responses to Self-Antigens
Deshpande, P., Cavanagh, M., Saux, S. L., Singh, K., Weyand, C. M., & Goronzy, J. J. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1201620 · Cited by 83 · see citing works
“Such a feedback loop in ERK signaling has been postulated by Chakraborty and colleagues (28) and Das and colleagues (62).”
BackgroundBirtwistle, M. R., Rauch, J., Kiyatkin, A. B., Aksamitiene, E., Dobrzyński, M., Hoek, J. B., Kölch, W., Ogunnaike, B. A., & Kholodenko, B. Ν. (2012) · BMC Systems Biology · doi:10.1186/1752-0509-6-109 · Cited by 83 · see citing works
“Although the most direct interpretation of these RasGTP responses (where the population mean changes as a function of time and EGF dose, Figure 2A) is a unimodal RasGTP distribution, a recent study suggested that in T lymphocytes, a positive feedback between RasGTP and its activator guanine exchange factor Son of Seve…”
BackgroundRasGRP1 opposes proliferative EGFR–SOS1–Ras signals and restricts intestinal epithelial cell growth
Depeille, P., Henricks, L. M., van de Ven, R. A. H., Lemmens, E., Wang, C.-Y., Matli, M., Werb, Z., Haigis, K. M., Donner, D., Warren, R., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3175 · Cited by 80 · see citing works
Self-citationMérida, I., Andrada, E., Gharbi, S., & Ávila‐Flores, A. (2015) · Science Signaling · doi:10.1126/scisignal.aaa0974 · Cited by 80 · see citing works
“This difference contrasts with a mathematical model that characterizes the RasGRP1 and SOS pathways as analog and digital determinants, respectively, in the regulation of Ras activation in T cells (46).”
ResultThe Interdependent Activation of Son-of-Sevenless and RasPreprint
Bandaru, P., Kondo, Y., & Kuriyan, J. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031534 · Cited by 78 · see citing works
“Conversely, high levels of receptor stimulation led to a predominant population of cells containing a high amount of Ras•GTP (Das et al. 2009).”
BackgroundInfluentialMechanistic principles of RAF kinase signaling
Udell, C. M., Rajakulendran, T., Sicheri, F., & Therrien, M. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0520-6 · Cited by 74 · see citing works
“remain bound at the plasma membrane even after the stimulus is removed [62, 63].”
BackgroundAffinity and dose of TCR engagement yield proportional enhancer and gene activity in CD4+ T cells
Allison, K. A., Sajti, E., Collier, J. G., Gosselin, D., Troutman, T. D., Stone, E. L., Hedrick, S. Μ., & Glass, C. K. (2016) · eLife · doi:10.7554/elife.10134 · Cited by 74 · see citing works
“At least one of the feedback loops leading to digital TCR signaling, the son of sevenless (SOS) positive feedback loop, exists upstream of ERK, and it has been shown in thymocytes that pERK signaling is digital (Das et al., 2009; Daniels et al., 2006; Prasad et al., 2009).”
BackgroundInfluentialJun, J. E., Rubio, I., & Roose, J. P. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00239 · Cited by 71 · see citing works
“and Ras’ RAF-MEK-ERK effector pathway (65, 66).”
BackgroundInfluentialSelf-citationInhibitors of Ras–SOS Interactions
Lu, S., Jang, H., Zhang, J., & Nussinov, R. (2016) · ChemMedChem · doi:10.1002/cmdc.201500481 · Cited by 72 · see citing works
Joshi, R. P., Schmidt, A. M., Das, J., Pytel, D., Riese, M. J., Lester, M., Diehl, J. A., Behrens, E. M., Kambayashi, T., & Koretzky, G. A. (2013) · Science Signaling · doi:10.1126/scisignal.2004373 · Cited by 71 · see citing works
“” Further details regarding the simulation can be found in previous studies (21, 27).”
BackgroundMethodSelf-citationDynamics and control of the ERK signaling pathway: Sensitivity, bistability, and oscillations
Arkun, Y., & Yasemi, M. (2018) · PLoS ONE · doi:10.1371/journal.pone.0195513 · Cited by 71 · see citing works
Singh, P. K., Kashyap, A., & Silakari, O. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.10.002 · Cited by 70 · see citing works
Origin of the sharp boundary that discriminates positive and negative selection of thymocytes
Prasad, A., Zikherman, J., Das, J., Roose, J. P., Weiss, A., & Chakraborty, A. K. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805981105 · Cited by 70 · see citing works
“cpla2 is absent in mature lymphocytes, and this may be why our recent results show that feedback regulation of SOS underlies a digital response in mature T cells (27).”
BackgroundResultSelf-citationUltrafast distant wound response is essential for whole-body regeneration
Fan, Y., Chai, C., Li, P., Zou, X., Ferrell, J. E., & Wang, B. (2023) · Cell · doi:10.1016/j.cell.2023.06.019 · Cited by 68 · see citing works
“In addition, Roose, Weiss, Chakraborty and co-workers have shown that active Ras can allosterically activate its upstream activator Sos, resulting in positive feedback and bistability in Ras activation in some cells.(49) This could lead to trigger waves of Ras activation.”
BackgroundTargeted Sos1 deletion reveals its critical role in early T-cell development
Kortum, R. L., Sommers, C. L., Alexander, C. P., Pinski, J. M., Li, W., Grinberg, A., Lee, J., Love, P. E., & Samelson, L. E. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1104295108 · Cited by 68 · see citing works
“Furthermore, recent studies have proposed a positive feedback loop between RasGRP1 and Sos that is engaged during Ras activation (31, 42).”
Cutting Edge: TCR Ligation Triggers Digital Activation of NF-κB
Kingeter, L. M., Paul, S., Maynard, S. K., Cartwright, N. G., & Schaefer, B. C. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1001051 · Cited by 66 · see citing works
“Although current models of TCR triggering of the Ras-ERK pathway (3, 5) do not explicitly include a mechanism for initiation of NF-kB signaling, it seems logical that the mechanisms of digital activation of ERK and NF-kB signaling would be identical or mechanistically linked to prevent the circumstances under which ER…”
InfluentialA Perspective on the Role of Computational Models in Immunology
Chakraborty, A. K. (2017) · Annual Review of Immunology · doi:10.1146/annurev-immunol-041015-055325 · Cited by 66 · see citing works
Self-citationDaley, S. R., Coakley, K. M., Hu, D. Y., Randall, K. L., Jenne, C. N., Limnander, A., Myers, D. R., Polakos, N. K., Enders, A., Roots, C. M., et al. (2013) · eLife · doi:10.7554/elife.01020 · Cited by 65 · see citing works
“, 2007) and Rasgrp1 serves a critical role in priming SOS1 via Rasgrp1-produced RasGTP (Das et al., 2009).”
BackgroundSelf-citationDynamic regulation of CD28 conformation and signaling by charged lipids and ions
Yang, W., Pan, W., Chen, S., Trendel, N., Jiang, S., Xiao, F., Xue, M., Wu, W., Peng, Z., Li, X., et al. (2017) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3489 · Cited by 66 · see citing works
Digital signaling network drives the assembly of the AIM2-ASC inflammasome
Matyszewski, M., Morrone, S. R., & Sohn, J. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1712860115 · Cited by 67 · see citing works
Diacylglycerol Kinases (DGKs): Novel Targets for Improving T Cell Activity in Cancer
Riese, M. J., Moon, E. K., Johnson, B. D., & Albelda, S. Μ. (2016) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2016.00108 · Cited by 65 · see citing works
“…cell anti-tumor activity in tumors with low-grade antigens, since DAG-mediated activation of RasGRP1 regulates the threshold for T cell activation (Das et al., 2009), and earlier studies implicated a role for Ras in Jurkat T cell activation mediated by low grade TCR stimulus (Perez de Castro et…”
BackgroundSchmidt, C., Berger, T., Groettrup, M., & Basler, M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02386 · Cited by 65 · see citing works
Discrete LAT condensates encode antigen information from single pMHC:TCR binding events
McAffee, D. B., O’Dair, M. K., Lin, J. J., Low-Nam, S. T., Wilhelm, K. B., Kim, S., Morita, S., & Groves, J. T. (2022) · Nature Communications · doi:10.1038/s41467-022-35093-9 · Cited by 65 · see citing works
“Certain output parameters of the T cell activation response, including NFAT and Erk activation as well as cytokine production, exhibit essentially binary behavior at the single cell level (Das et al., 2009; Huang et al., 2013; Podtschaske et al., 2007).”
BackgroundRiese, M. J., Grewal, J., Das, J., Zou, T., Patil, V., Chakraborty, A. K., & Koretzky, G. A. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.171884 · Cited by 64 · see citing works
Self-citationComputational modeling of mammalian signaling networks
Hughey, J., Lee, T. K., & Covert, M. W. (2009) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.52 · Cited by 63 · see citing works
“74,99 The method is straightforward to implement but becomes computationally expensive as the number of molecules increases.”
MethodOne-way membrane trafficking of SOS in receptor-triggered Ras activation
Christensen, S. M., Tu, H., Jun, J. E., Alvarez, S. A., Triplet, M. G., Iwig, J. S., Yadav, K. K., Bar‐Sagi, D., Roose, J. P., & Groves, J. T. (2016) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3275 · Cited by 61 · see citing works
Self-citationA Density-Dependent Switch Drives Stochastic Clustering and Polarization of Signaling Molecules
Jilkine, A., Angenent, S., Wu, L. F., & Altschuler, S. J. (2011) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002271 · Cited by 62 · see citing works
“This transition may require careful regulation, particularly when an ‘‘on’’ state initiates large-scale cellular changes, such as observed in migration, cell division, or immune responses [2,3,4,5,6].”
BackgroundTang, S., Chen, T., Zhou, Y., Zhu, X., Yang, M., Xie, B., Li, N., Cao, X., & Wang, J. (2014) · Nature Communications · doi:10.1038/ncomms5657 · Cited by 60 · see citing works
Self-citationFunctional Redundancy of Sos1 and Sos2 for Lymphopoiesis and Organismal Homeostasis and Survival
Baltanás, F. C., Pérez‐Andrés, M., Ginel-Picardo, A., Díaz, D., Jimeno, D., Liceras-Boillos, P., Kortum, R. L., Samelson, L. E., Órfão, A., & Santos, E. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01026-13 · Cited by 60 · see citing works
Antigen and checkpoint receptor engagement recalibrates T cell receptor signal strength
Elliot, T. A. E., Jennings, E. K., Lecky, D. A. J., Thawait, N., Flores‐Langarica, A., Copland, A., Maslowski, K. M., Wraith, D. C., & Bending, D. (2021) · Immunity · doi:10.1016/j.immuni.2021.08.020 · Cited by 60 · see citing works
“Similar results are reported for extracellular signal-regulated kinase (ERK) activation (Altan-Bonnet and Ger-main, 2005; Das et al., 2009).”
Tkach, K. E., Barik, D., Voisinne, G., Malandro, N., Hathorn, M. M., Cotari, J. W., VOGEL, R. M., Merghoub, T., Wolchok, J. D., Krichevsky, O., et al. (2014) · eLife · doi:10.7554/elife.01944 · Cited by 60 · see citing works
“Furthermore, early antigen discrimination is all-or-none (Das et al., 2009), with limited *For correspondence: altanbog@mskcc.org”
BackgroundMethodInfluentialLee, Y. K., Low-Nam, S. T., Chung, J. K., Hansen, S. D., Lam, H. Y. M., Alvarez, S. A., & Groves, J. T. (2017) · Nature Communications · doi:10.1038/ncomms15061 · Cited by 60 · see citing works
“Ras (cid:2) GTP is a more potent allosteric activator of SOS than Ras (cid:2) GDP, thereby creating a positive feedback loop in which SOS is activated by its own product 8,31 .”
Jang, I. K., Zhang, J., Chiang, Y. J., Kole, H. K., Cronshaw, D. G., Zou, Y.-R., & Gu, H. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0905039107 · Cited by 60 · see citing works
“A recent study further shows that Sos regulatesRas activation in an “onor off”manner possibly via Grb2, whereas Ras-GRPmay gradually tune Ras activity in cultured T cells, suggesting that Ras activation can be “digital or analog” (24).”
BackgroundRelaxation oscillations and hierarchy of feedbacks in MAPK signaling
Kochańczyk, M., Kocieniewski, P., Kozłowska, E., Jaruszewicz-Błońska, J., Sparta, B., Pargett, M., Albeck, J. G., Hlavacek, W. S., & Lipniacki, T. (2017) · Scientific Reports · doi:10.1038/srep38244 · Cited by 59 · see citing works
Sheffels, E., Sealover, N. E., Wang, C., Kim, D., Vazirani, I. A., Lee, E., Terrell, E. M., Morrison, D. K., Luo, J., & Kortum, R. L. (2018) · Science Signaling · doi:10.1126/scisignal.aar8371 · Cited by 59 · see citing works
Molecular mechanisms of T cell sensitivity to antigen
Siller‐Farfán, J. A., & Dushek, O. (2018) · Immunological Reviews · doi:10.1111/imr.12690 · Cited by 56 · see citing works
“As in other signal transduction cascades, phosphorylation by ZAP-70 of downsteam targets initiates signalling that involves cascades and feedbacks that can amplify a small number of activated molecules at the TCR into a large number that can lead to T cell activation (82, 83).”
BackgroundStructural understanding of T cell receptor triggering
Xu, X., Li, H., & Xu, C. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-0367-1 · Cited by 57 · see citing works
Pairing computation with experimentation: a powerful coupling for understanding T cell signalling
Chakraborty, A. K., & Das, J. (2009) · Nature reviews. Immunology · doi:10.1038/nri2688 · Cited by 55 · see citing works
“In turn, results of such calculations can help to inform the design of experiments that will sensitively discriminate between viable hypotheses that are predicted to describe an observation of unknown origin equally wel”
BackgroundSelf-citationHierarchical control of enzymatic actuators using DNA-based switchable memories
Meijer, L. H. H., Joesaar, A., Steur, E., Engelen, W., van Santen, R. A., Merkx, M., & de Greef, T. F. A. (2017) · Nature Communications · doi:10.1038/s41467-017-01127-w · Cited by 56 · see citing works
Visualizing how T cells collect activation signals in vivo
Moreau, H. D., & Bousso, P. (2013) · Current Opinion in Immunology · doi:10.1016/j.coi.2013.10.013 · Cited by 55 · see citing works
“This short-term memory allows T cells to ‘sum up’ signals over a few minutes [57].”
Extracellular signal-regulated kinase (ERK) pathway control of CD8+ T cell differentiation
Damasio, M. P. S., Marchingo, J. M., Spinelli, L., Hukelmann, J. L., Cantrell, D. A., & Howden, A. J. M. (2020) · Biochemical Journal · doi:10.1042/bcj20200661 · Cited by 55 · see citing works
Translocation dynamics of sorting nexin 27 in activated T cells
Rincón, E., de Guinoa, J. S., Gharbi, S., Sorzano, C. Ó. S., Carrasco, Y. R., & Mérida, I. (2011) · Journal of Cell Science · doi:10.1242/jcs.072447 · Cited by 54 · see citing works
“The interplay between these two RasGEF proteins has been the basis for theoretical models that explain how lymphocytes can adopt specific responses to antigens with different affinities to the TCR (Das et al., 2009).”
BackgroundGanti, R., Lo, W., McAffee, D. B., Groves, J. T., Weiss, A., & Chakraborty, A. K. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2008303117 · Cited by 53 · see citing works
Self-citation
- 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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