SOS GEFs in health and disease
Open accessAbstract
SOS1 and SOS2 are the most universal and widely expressed family of guanine exchange factors (GEFs) capable or activating RAS or RAC1 proteins in metazoan cells. SOS proteins contain a sequence of modular domains that are responsible for different intramolecular and intermolecular interactions modulating mechanisms of self-inhibition, allosteric activation and intracellular homeostasis. Despite their homology, analyses of SOS1/2-KO mice demonstrate functional prevalence of SOS1 over SOS2 in cellular processes including proliferation, migration, inflammation or maintenance of intracellular redox homeostasis, although some functional redundancy cannot be excluded, particularly at the organismal level. Specific SOS1 gain-of-function mutations have been identified in inherited RASopathies and various sporadic human cancers. SOS1 depletion reduces tumorigenesis mediated by RAS or RAC1 in mouse models and is associated with increased intracellular oxidative stress and mitochondrial dysfunction. Since WT RAS is essential for development of RAS-mutant tumors, the SOS GEFs may be considered as relevant biomarkers or therapy targets in RAS-dependent cancers. Inhibitors blocking SOS expression, intrinsic GEF activity, or productive SOS protein-protein interactions with cellular regulators and/or RAS/RAC targets have been recently developed and shown preclinical and clinical effectiveness blocking aberrant RAS signaling in RAS-driven and RTK-driven tumors.
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
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?
SOS1 is a guanine nucleotide exchange factor that activates the RAS signaling cascade.
“SOS1 showed a significant sex interaction with CAA and is a guanine nucleotide exchange factor that activates the RAS signaling cascade. 64”
From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [64]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Oncogenic Signaling Pathways in The Cancer Genome Atlas
Sanchez-Vega, F., Mina, M., Armenia, J., Chatila, W. K., Luna, A., La, K. C., Dimitriadoy, S., Liu, D. L., Kantheti, H. S., Saghafinia, S., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.035 · Cited by 3,201 · see citing works
Discovery and saturation analysis of cancer genes across 21 tumour types
Lawrence, M. S., Stojanov, P., Mermel, C. H., Robinson, J. T., Garraway, L. A., Golub, T. R., Meyerson, M., Gabriel, S. B., Lander, E. S., & Getz, G. (2014) · Nature · doi:10.1038/nature12912 · Cited by 3,096 · see citing works
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions
Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A., & Shokat, K. M. (2013) · Nature · doi:10.1038/nature12796 · Cited by 2,557 · see citing works
The Clinical KRAS(G12C) Inhibitor AMG 510 Drives Anti-Tumour Immunity
Canon, J., Rex, K., Saiki, A. Y., Mohr, C., Cooke, K., Bagal, D., Gaida, K., Holt, T., Knutson, C. G., Koppada, N., et al. (2019) · Nature · doi:10.1038/s41586-019-1694-1 · Cited by 2,277 · see citing works
Drugging the undruggable RAS: Mission Possible?
Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J., & Der, C. J. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4389 · Cited by 1,997 · see citing works
RAS Proteins and Their Regulators in Human Disease
Simanshu, D. K., Nissley, D. V., & McCormick, F. (2017) · Cell · doi:10.1016/j.cell.2017.06.009 · Cited by 1,943 · see citing works
Ras oncogenes: split personalities
Karnoub, A. E., & Weinberg, R. A. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2438 · Cited by 1,467 · see citing works
Hallin, J., Engstrom, L. D., Hargis, L., Calinisan, A., Aranda, R., Briere, D. M., Sudhakar, N., Bowcut, V., Baer, B. R., Ballard, J. A., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-1167 · Cited by 1,304 · see citing works
Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor
Janes, M. R., Zhang, J., Li, L.-S., Hansen, R., Peters, U., Guo, X., Chen, Y., Babbar, A., Firdaus, S. J., Darjania, L., et al. (2018) · Cell · doi:10.1016/j.cell.2018.01.006 · Cited by 1,172 · see citing works
Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state
Patricelli, M. P., Janes, M. R., Li, L.-S., Hansen, R., Peters, U., Kessler, L. V., Chen, Y., Kucharski, J. M., Feng, J., Ely, T., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1105 · Cited by 759 · see citing works
Fell, J. B., Fischer, J. P., Baer, B. R., Blake, J. F., Bouhana, K., Briere, D. M., Brown, K. D., Burgess, L. E., Burns, A. C., Burkard, M. R., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b02052 · Cited by 653 · see citing works
Drugging an undruggable pocket on KRAS
Kessler, D., Gmachl, M., Mantoulidis, A., Martin, L. J., Zoephel, A., Mayer, M., Gollner, A., Covini, D., Fischer, S., Gerstberger, T., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1904529116 · Cited by 449 · see citing works
Nichols, R. J., Haderk, F., Stahlhut, C., Schulze, C. J., Hemmati, G., Wildes, D., Tzitzilonis, C., Mordec, K., Marquez, A., Romero, J., et al. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0169-1 · Cited by 415 · see citing works
Hillig, R. C., Sautier, B., Schroeder, J., Moosmayer, D., Hilpmann, A., Stegmann, C. M., Werbeck, N. D., Briem, H., Boemer, U., Weiske, J., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1812963116 · Cited by 388 · see citing works
A model for RAS mutation patterns in cancers: finding the sweet spot
Li, S., Balmain, A., & Counter, C. M. (2018) · Nature Reviews Cancer · doi:10.1038/s41568-018-0076-6 · Cited by 384 · see citing works
Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase
Ruess, D. A., Heynen, G. J., Ciecielski, K. J., Ai, J., Berninger, A., Kabacaoglu, D., Görgülü, K., Dantes, Z., Wörmann, S. M., Diakopoulos, K. N., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0024-8 · Cited by 370 · see citing works
Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival
Drosten, M., Dhawahir, A., Sum, E. Y. M., Urosevic, J., Lechuga, C. G., Esteban, L. M., Castellano, E., Guerra, C., Santos, E., & Barbacid, M. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.7 · Cited by 347 · see citing works
Self-citationSlevin, M., Kumar, S., & Gaffney, J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m109443200 · Cited by 346 · see citing works
SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo
Mainardi, S., Mulero-Sánchez, A., Prahallad, A., Germano, G., Bosma, A., Krimpenfort, P., Lieftink, C., Steinberg, J. D., de Wit, N., Gonçalves-Ribeiro, S., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0023-9 · Cited by 320 · see citing works
The EGF Receptor Provides an Essential Survival Signal for SOS-Dependent Skin Tumor Development
Sibilia, M., Fleischmann, A., Behrens, A., Stingl, L., Carroll, J., Watt, F. M., Schlessinger, J., & Wagner, E. F. (2000) · Cell · doi:10.1016/s0092-8674(00)00026-x · Cited by 304 · see citing works
Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition
Wong, G. S., Zhou, J., Liu, J. B., Wu, Z., Xu, X., Li, T., Xu, D., Schumacher, S. E., Puschhof, J., McFarland, J., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0022-x · Cited by 266 · see citing works
Young, A., Lou, D., & McCormick, F. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0231 · Cited by 211 · see citing works
Oh-hora, M., Johmura, S., Hashimoto, A., Hikida, M., & Kurosaki, T. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20031547 · Cited by 113 · see citing works
RAS, wanted dead or alive: Advances in targeting RAS mutant cancers
Stalnecker, C. A., & Der, C. J. (2020) · Science Signaling · doi:10.1126/scisignal.aay6013 · Cited by 90 · see citing works
RasGRP1 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
Inhibitors 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
Theard, P. L., Sheffels, E., Sealover, N. E., Linke, A. J., Pratico, D. J., & Kortum, R. L. (2020) · eLife · doi:10.7554/elife.58204 · Cited by 69 · see citing works
The small molecule BI-2852 induces a nonfunctional dimer of KRAS
Tran, T. H., Alexander, P., Dharmaiah, S., Agamasu, C., Nissley, D. V., McCormick, F., Esposito, D., Simanshu, D. K., Stephen, A. G., & Balius, T. E. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1918164117 · Cited by 65 · see citing works
Efforts to Develop KRAS Inhibitors
Holderfield, M. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031864 · Cited by 43 · see citing works
Flagged first, then by citations
Research works printed but not linked: 16
- D. Bowtell, P. Fu, M. Simon, P. Senior, Identification of murine homologues of the Drosophila son of sevenless gene: potential activators of ras, Proc. Natl. Acad. Sci.
- R.L. Kortum, C.L. Sommers, C.P. Alexander, J.M. Pinski, W. Li, A. Grinberg, J. Lee, P.E. Love, L.E. Samelson, Targeted Sos1 deletion reveals its critical role in early T- cell development, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 12407-12412.
- S. Nickerson, S.T. Joy, P.S. Arora, D. Bar-Sagi, An orthosteric inhibitor of the RAS? SOS Interaction, Enzym, 2013, pp. 25-39.
- M.H. Hofmann, M. Gmachl, J. Ramharter, F. Savarese, D. Gerlach, J.R. Marszalek, M.P. Sanderson, D. Kessler, F. Trapani, H. Arnhof, K. Rumpel, D.-A. Botesteanu, P. Ettmayer, T. Gerstberger, C. Kofink, T. Wunberg, A. Zoephel, S.-C. Fu, J.L. Teh, J. Bottcher, et al., BI-3406, a potent and selective SOS1::KRAS interaction in- hibitor, is effective in KRAS-driven cancers through combined MEK inhibition, Cancer Discov. (2020), https://doi.org/10.1158/2159-8290 CD-20-0142. · DOI
- T. Shi, M. Niepel, J.E. McDermott, Y. Gao, C.D. Nicora, W.B. Chrisler, L.M. Markillie, V.A. Petyuk, R.D. Smith, K.D. Rodland, P.K. Sorger, W.J. Qian, H.S. Wiley, Conservation of protein abundance patterns reveals the regulatory architecture of the EGFR-MAPK pathway, Sci. Signal. 9 (2016).
- J. Gureasko, O. Kuchment, D.L. Makino, H. Sondermann, D. Bar-Sagi, J. Kuriyan, Role of the histone domain in the autoinhibition and activation of the Ras acti- vator Son of Sevenless, Proc. Natl. Acad. Sci. U. S. A. 107 (2010) 3430-3435.
- H. Sondermann, B. Nagar, D. Bar-Sagi, J. Kuriyan, Computational docking and solution x-ray scattering predict a membrane-interacting role for the histone do- main of the Ras activator son of sevenless, Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 16632-16637.
- K.K. Yadav, D. Bar-Sagi, Allosteric gating of Son of sevenless activity by the his- tone domain, Proc. Natl. Acad. Sci. U. S. A. 107 (2010) 3436-3440.
- T.-Y. Lu, J. Doherty, M.R. Freeman, DRK/DOS/SOS converge with Crk/Mbc/dCed- 12 to activate Rac1 during glial engulfment of axonal debris, Proc. Natl. Acad. Sci.
- Y. Kumei, H. Shimokawa, K. Ohya, H. Katano, H. Akiyama, M. Hirano, S. Morita, Small GTPase Ras and Rho expression in rat osteoblasts during spaceflight, Annals of the New York Academy of Sciences, Blackwell Publishing Inc., 2007, pp. 292-299.
- Ö. Babur, A. Melrose, J. Cunliffe, J. Klimek, J. Pang, A.-L. Sepp, J. Zilberman- Rudenko, S. Tassi Yunga, T. Zheng, I. Parra-Izquierdo, J. Minnier, O. McCarty, E. Demir, A. Reddy, P. Wilmarth, L.L. David, J.E. Aslan, Phosphoproteomic quantitation and causal analysis reveal pathways in GPVI/ITAM-mediated platelet activation programs, Blood (2020), https://doi.org/10.1182/blood.2020005496. · DOI
- S. De, J.K.T. Dermawan, G.R. Stark, EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells, Proc. Natl. Acad. Sci. U. S. A. 111 (2014) 11721-11726.
- C. Lissewski, V. Chune, F. Pantaleoni, A. De Luca, Y. Capri, J. Brinkmann, F. Lepri, P. Daniele, E. Leenders, L. Mazzanti, E. Scarano, F.C. Radio, K. Kutsche, A. Kuechler, M. Gérard, K. Ranguin, M. Legendre, Y. Vial, I. van der Burgt, T. Rinne, et al., Variants of SOS2 are a rare cause of Noonan syndrome with particular predisposition for lymphatic complications, Eur. J. Hum. Genet. (2020), https://doi.org/10.1038/s41431-020-00708-6. · DOI
- E.S. Leshchiner, A. Parkhitko, G.H. Bird, J. Luccarelli, J.A. Bellairs, S. Escudero, K. Opoku-Nsiah, M. Godes, N. Perrimon, L.D. Walensky, Direct inhibition of on- cogenic KRAS by hydrocarbon-stapled SOS1 helices, Proc. Natl. Acad. Sci. U. S. A. 112 (2015) 1761-1766.
- H.J. Hocker, K.-J. Cho, C.-Y.K. Chen, N. Rambahal, S.R. Sagineedu, K. Shaari, J. Stanslas, J.F. Hancock, A.A. Gorfe, Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function, Proc. Natl. Acad. Sci.
- T. Maurer, L.S. Garrenton, A. Oh, K. Pitts, D.J. Anderson, N.J. Skelton, B.P. Fauber, B. Pan, S. Malek, D. Stokoe, M.J.C. Ludlam, K.K. Bowman, J. Wu, A.M. Giannetti, M.A. Starovasnik, I. Mellman, P.K. Jackson, J. Rudolph, W. Wang, G. Fang, Small- molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity, Proc. Natl. Acad. Sci. U. S. A. 109 (2012) 5299-5304.
Cited by
Sorted by citations
Zhou, C., Li, C., Luo, L., Li, X., Jia, K., He, N., Mao, S., Wang, W., Shao, C., Liu, X., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.06.001 · Cited by 102 · see citing works
Zhou, C., Fan, Z., Zhou, Z., Li, Y., Cui, R., Liu, C., Zhou, G., Diao, X., Jiang, H., Zheng, M., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01774 · Cited by 94 · see citing works
Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes
Mei, Z., Liu, J., Bennett, D. A., Seyfried, N., Wingo, A. P., & Wingo, T. S. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70206 · Cited by 11 · see citing works
- Authors
- Baltanás, F. C., Zarich, N., Rojas-Cabañeros, J. M., & Santos, E.
- Affiliations
- Universidad de Salamanca (ES)
- Instituto de Salud Carlos III (ES)
- Corresponding author
- Santos, Eugenio
- Venue
- Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
- Publisher
- Elsevier BV
- Published
- 2020-12
- Volume
- 1874
- Issue
- 2
- Pages
- 188445
- ISSN
- 0304-419X (ISSN-L)
- OpenAlex
- W3092229078
- Cited by
- 100
- References
- 29
- Citations by year
- 2026: 9 · 2025: 20 · 2024: 25 · 2023: 15 · 2022: 14 · 2021: 17
- FWCI
- 1.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Reviews on Cancer (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-nd)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by-nc-nd)
- Deposito de Investigacion Universidad de Sevilla (University of Seville) (submittedVersion, cc-by-nc-nd)
- Funders
- Fundación Científica Asociación Española Contra el Cáncer
- Junta de Castilla y León
- Instituto de Salud Carlos III
- Fundación Ramón Areces
- Ministerio de Economía y Competitividad
- 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 › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- SOS1, SOS2, guanine nucleotide exchange factor, Ras signaling, Rac1, RASopathies, RAS-driven cancers, oxidative stress, mitochondrial dysfunction, biomarkers, therapy targets, protein-protein interaction
- MeSH terms
- Allosteric Regulation, Animals, Homeostasis, Humans, Mutation, Neoplasms, ras Proteins, Son of Sevenless Proteins, rac1 GTP-Binding Protein, Mice
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
