The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index.
GTP-Dependent K-Ras Dimerization
Open accessAbstract
Ras proteins recruit and activate effectors, including Raf, that transmit receptor-initiated signals. Monomeric Ras can bind Raf; however, activation of Raf requires its dimerization. It has been suspected that dimeric Ras may promote dimerization and activation of Raf. Here, we show that the GTP-bound catalytic domain of K-Ras4B, a highly oncogenic splice variant of the K-Ras isoform, forms stable homodimers. We observe two major dimer interfaces. The first, highly populated β-sheet dimer interface is at the Switch I and effector binding regions, overlapping the binding surfaces of Raf, PI3K, RalGDS, and additional effectors. This interface has to be inhibitory to such effectors. The second, helical interface also overlaps the binding sites of some effectors. This interface may promote activation of Raf. Our data reveal how Ras self-association can regulate effector binding and activity, and suggest that disruption of the helical dimer interface by drugs may abate Raf signaling in cancer.
Overview
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
Verification
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?
In the citing paper
“The KRAS dimerization is a GTP-dependent process [67].”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
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 · cited 1×
“K-Ras, which is frequently mutated in human cancer (Lawrence et al., 2014), is the most potent activator of Raf among Ras isoforms (Prior et al., 2012).”
BackgroundA Comprehensive Survey of Ras Mutations in Cancer
Prior, I. A., Lewis, P. D., & Mattos, C. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-2612 · Cited by 2,063 · cited 2×
“K-Ras, which is frequently mutated in human cancer (Lawrence et al., 2014), is the most potent activator of Raf among Ras isoforms (Prior et al., 2012).”
BackgroundRas oncogenes: split personalities
Karnoub, A. E., & Weinberg, R. A. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2438 · Cited by 1,467
Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions
Kölch, W. (2000) · Biochemical Journal · doi:10.1042/bj3510289 · Cited by 1,443
Hancock, J. F., Paterson, H., & Marshall, C. J. (1990) · Cell · doi:10.1016/0092-8674(90)90294-o · Cited by 1,042
Molecular Interaction Studies Using Microscale Thermophoresis
Jerabek‐Willemsen, M., Wienken, C. J., Braun, D., Baaske, P., & Duhr, S. (2011) · Assay and Drug Development Technologies · doi:10.1089/adt.2011.0380 · Cited by 820
Stephen, A. G., Esposito, D., Bagni, R. K., & McCormick, F. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.02.017 · Cited by 795
RAS Interaction with PI3K: More Than Just Another Effector Pathway
Castellano, E., & Downward, J. (2011) · Genes & Cancer · doi:10.1177/1947601911408079 · Cited by 762
Principles of Protein−Protein Interactions: What are the Preferred Ways For Proteins To Interact?
Keskin, O., Gursoy, A., Ma, B., & Nussinov, R. (2008) · Chemical Reviews · doi:10.1021/cr040409x · Cited by 697
Self-citationThe RCSB Protein Data Bank: views of structural biology for basic and applied research and education
Rose, P. W., Prlić, A., Bi, C., Bluhm, W. F., Christie, C. H., Dutta, S., Green, R. K., Goodsell, D. S., Westbrook, J., Woo, J., et al. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku1214 · Cited by 519
A dimerization-dependent mechanism drives RAF catalytic activation
Rajakulendran, T., Sahmi, M., Lefrançois, M., Sicheri, F., & Therrien, M. (2009) · Nature · doi:10.1038/nature08314 · Cited by 505
A dimeric 14-3-3 protein is an essential cofactor for Raf kinase activity
Tzivion, G., Luo, Z., & Avruch, J. (1998) · Nature · doi:10.1038/27938 · Cited by 482
Plowman, S. J., Muncke, C., Parton, R. G., & Hancock, J. F. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0504114102 · Cited by 468
Signaling Interplay in Ras Superfamily Function
Mitin, N., Rossman, K. L., & Der, C. J. (2005) · Current Biology · doi:10.1016/j.cub.2005.07.010 · Cited by 402
Renewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis?
Repasky, G. A., Chenette, E. J., & Der, C. J. (2004) · Trends in Cell Biology · doi:10.1016/j.tcb.2004.09.014 · Cited by 299
Architecture of Eph receptor clusters
Himanen, J. P., Yermekbayeva, L., Janes, P. W., Walker, J. R., Xu, K. Y., Atapattu, L., Rajashankar, K. R., Mensinga, A., Lackmann, M., Nikolov, D. B., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1004148107 · Cited by 269
A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK
Brennan, D. F., Dar, A. C., Hertz, N. T., Chao, W. C. H., Burlingame, A. L., Shokat, K. M., & Barford, D. (2011) · Nature · doi:10.1038/nature09860 · Cited by 264
Tunçbağ, N., Gürsoy, A., Nussinov, R., & Keskin, Ö. (2011) · Nature Protocols · doi:10.1038/nprot.2011.367 · Cited by 264
Self-citationAllosteric Effects of the Oncogenic RasQ61L Mutant on Raf-RBD
Fetics, S., Guterres, H., Kearney, B. M., Buhrman, G., Ma, B., Nussinov, R., & Mattos, C. (2015) · Structure · doi:10.1016/j.str.2014.12.017 · Cited by 225
Self-citationRas membrane orientation and nanodomain localization generate isoform diversity
Abankwa, D., Gorfe, A. A., Inder, K. L., & Hancock, J. F. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903907107 · Cited by 223
PRISM: protein interactions by structural matching
Ogmen, U., Keskin, Ö., Aytuna, A. S., Nussinov, R., & Gürsoy, A. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki585 · Cited by 207
Self-citationHotPoint: hot spot prediction server for protein interfaces
Tunçbağ, N., Keskin, Ö., & Gürsoy, A. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq323 · Cited by 206
Keskin, Ö., Tsai, C., Wolfson, H. J., & Nussinov, R. (2004) · Protein Science · doi:10.1110/ps.03484604 · Cited by 197
Self-citationAytuna, A. S., Gürsoy, A., & Keskin, Ö. (2005) · Computer applications in the biosciences · doi:10.1093/bioinformatics/bti443 · Cited by 188
FiberDock: Flexible induced‐fit backbone refinement in molecular docking
Mashiach, E., Nussinov, R., & Wolfson, H. J. (2009) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.22668 · Cited by 187
Self-citationInhibitors that stabilize a closed RAF kinase domain conformation induce dimerization
Lavoie, H., Thevakumaran, N., Gavory, G., Li, J. J., Padeganeh, A., Guiral, S., Duchaine, J., Mao, D. Y. L., Bouvier, M., Sicheri, F., et al. (2013) · Nature Chemical Biology · doi:10.1038/nchembio.1257 · Cited by 181
Nan, X., Collisson, E. A., Lewis, S., Huang, J., Tamgüney, T., Liphardt, J., McCormick, F. P., Gray, J. W., & Chu, S. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1318188110 · Cited by 162
Requirement for Interaction of PI3-Kinase p110α with RAS in Lung Tumor Maintenance
Castellano, E., Sheridan, C., Thin, M. Z., Nye, E., Spencer-Dene, B., Diefenbacher, M., Moore, C., Kumar, M., Murillo, M., Grönroos, E., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.09.012 · Cited by 161
H-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
Formation of the Ras Dimer Is Essential for Raf-1 Activation
Inouye, K., Mizutani, S., Koide, H., & Kaziro, Y. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.6.3737 · Cited by 154
Spoerner, M., Hozsa, C., Poetzl, J. A., Reiss, K., Ganser, P., Geyer, M., & Kalbitzer, H. R. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.145235 · Cited by 148
N-Ras Forms Dimers at POPC Membranes
Güldenhaupt, J., Rudack, T., Bachler, P. S., Mann, D., Triola, G., Waldmann, H., Kötting, C., & Gerwert, K. B. (2012) · Biophysical Journal · doi:10.1016/j.bpj.2012.08.043 · Cited by 148
Protein interface classification by evolutionary analysis
Duarte, J. M., Srebniak, A., Schärer, M. A., & Capitani, G. (2012) · BMC Bioinformatics · doi:10.1186/1471-2105-13-334 · Cited by 141
Tsai, C., Lin, S. L., Wolfson, H. J., & Nussinov, R. (1996) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409239609106582 · Cited by 117
Self-citationMechanisms of Membrane Binding of Small GTPase K-Ras4B Farnesylated Hypervariable Region
Jang, H., Abraham, S. J., Chavan, T., Hitchinson, B., Khavrutskii, L., Tarasova, N. I., Nussinov, R., & Gaponenko, V. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.620724 · Cited by 112
Self-citationStructurally encoded intraclass differences in EphA clusters drive distinct cell responses
Seiradake, E., Schaupp, A., del Toro, D., Kaufmann, R., Mitakidis, N., Harlos, K., Aricescu, A. R., Klein, R., & Jones, E. Y. (2013) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2617 · Cited by 108
The importance of Raf dimerization in cell signaling
Freeman, A. K., Ritt, D. A., & Morrison, D. K. (2013) · Small GTPases · doi:10.4161/sgtp.26117 · Cited by 95
Raf Inhibitors Target Ras Spatiotemporal Dynamics
Cho, K.-J., Kasai, R. S., Park, J.-H., Chigurupati, S., Heidorn, S. J., van der Hoeven, D., Plowman, S. J., Kusumi, A., Marais, R., & Hancock, J. F. (2012) · Current Biology · doi:10.1016/j.cub.2012.03.067 · Cited by 68
US National Cancer Institute's new Ras project targets an old foe
Thompson, H. (2013) · Nature Medicine · doi:10.1038/nm0813-949 · Cited by 65
Aramini, J. M., Hamilton, K., Ma, L.-C., Swapna, G. V. T., Leonard, P. G., Ladbury, J. E., Krug, R. M., & Montelione, G. T. (2014) · Structure · doi:10.1016/j.str.2014.01.010 · Cited by 57
Human Proteome-scale Structural Modeling of E2–E3 Interactions Exploiting Interface Motifs
Kar, G., Keskin, Ö., Nussinov, R., & Gürsoy, A. (2011) · Journal of Proteome Research · doi:10.1021/pr2009143 · Cited by 55
Self-citationThe spatial structure of cell signaling systems
Nussinov, R. (2013) · Physical Biology · doi:10.1088/1478-3975/10/4/045004 · Cited by 49
Self-citationTsai, C., & Nussinov, R. (2014) · Physical Chemistry Chemical Physics · doi:10.1039/c3cp54253j · Cited by 47
Self-citationTunçbağ, N., Keskin, Ö., Nussinov, R., & Gürsoy, A. (2011) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.24022 · Cited by 46
Self-citationNussinov, R., Ma, B., & Tsai, C. (2013) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2012.12.014 · Cited by 45
Self-citationEnriching the human apoptosis pathway by predicting the structures of protein–protein complexes
Acuner, S. E., Keskin, Ö., Nussinov, R., & Gürsoy, A. (2012) · Journal of Structural Biology · doi:10.1016/j.jsb.2012.02.002 · Cited by 33
Self-citationA molecular rheostat at the interface of cancer and diabetes
Osman, M. A., Sarkar, F. H., & Rodriguez-Boulan, E. J. (2013) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2013.04.005 · Cited by 28
Paleskava, A., Konevega, A. L., & Rodnina, M. V. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.366120 · Cited by 28
Chavan, T., Abraham, S. J., & Gaponenko, V. (2013) · Molecules · doi:10.3390/molecules18067103 · Cited by 25
Self-citationDimerization Opens New Avenues into Ras Signaling Research
Santos, E. (2014) · Science Signaling · doi:10.1126/scisignal.2005318 · Cited by 23
Expression, purification, and characterization of soluble K-Ras4B for structural analysis
Abraham, S. J., Muhamed, I., Nolet, R., Yeung, F., & Gaponenko, V. (2010) · Protein Expression and Purification · doi:10.1016/j.pep.2010.05.015 · Cited by 21
Self-citationNitric oxide activates Rap1 and Ral in a Ras-independent manner
Mittar, D., Sehajpal, P. K., & Lander, H. M. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.07.107 · Cited by 15
Cited by
Sorted by citations
RAS-targeted therapies: is the undruggable drugged?
Moore, A. R., Rosenberg, S. C., McCormick, F., & Malek, S. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0068-6 · Cited by 1,103
Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development
Salo‐Ahen, O. M. H., Alanko, I., Bhadane, R. N., Bonvin, A. M. J. J., Honorato, R. V., Hossain, S., Juffer, A. H., Kabedev, A., Lahtela-Kakkonen, M. K., Larsen, A. S., et al. (2020) · Processes · doi:10.3390/pr9010071 · Cited by 732
Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design
Ostrem, J. M. L., & Shokat, K. M. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.139 · Cited by 641
Ras Conformational Ensembles, Allostery, and Signaling
Lu, S., Jang, H., Muratcioglu, S., Gursoy, A., Keskin, O., Nussinov, R., & Zhang, J. (2016) · Chemical Reviews · doi:10.1021/acs.chemrev.5b00542 · Cited by 355
Self-citationInhibition of RAS function through targeting an allosteric regulatory site
Spencer-Smith, R., Koide, A., Zhou, Y., Eguchi, R. R., Sha, F., Gajwani, P., Santana, D., Gupta, A., Jacobs, M., Herrero-Garcia, E., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2231 · Cited by 283
Metadata
- Authors
- Muratcioglu, S., Chavan, T. S., Freed, B. C., Jang, H., Khavrutskii, L., Freed, R. N., Dyba, M. A., Stefanisko, K., Tarasov, S. G., Gursoy, A., Keskin, O., Tarasova, N. I., Gaponenko, V., & Nussinov, R.
- Affiliations
- University of Illinois Chicago (US)
- National Cancer Institute (US)
- Frederick National Laboratory for Cancer Research (US)
- Tel Aviv University (IL)
- Corresponding author
- Gaponenko, Vadim
- Nussinov, Ruth
- ORCID
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 23
- Issue
- 7
- Pages
- 1325-1335
- ISSN
- 0969-2126 (ISSN-L)
- PMC
- PMC4497850
- OpenAlex
- W1535997186
- Cited by
- 202
- References
- 52
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 12 · 2023: 15 · 2022: 17 · 2021: 23 · 2020: 27 · 2019: 21 · 2018: 22 · 2017: 15 · 2016: 30 · 2015: 12
- FWCI
- 10.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Structure (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (HHSN261200800001C)
- National Heart, Lung, and Blood Institute (R21HL118588)
- National Cancer Institute (HHSN261200800001E), R01CA135341)
- 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 › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- K-Ras4B, GTP-bound Ras, Raf activation, RAF dimerization, dimer interface, switch I, effector binding, phosphatidylinositol 3-kinase, RalGDS, Ras effectors, cancer drug targets
- MeSH terms
- Guanosine Triphosphate, Humans, Kinetics, Protein Binding, Proto-Oncogene Proteins p21(ras), Catalytic Domain, Protein Interaction Domains and Motifs, Protein Multimerization
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
