Integrated RAS signaling defined by parallel NMR detection of effectors and regulators
Abstract
The RAS GTPase directs cell proliferation and survival by selectively relaying signals amid a dynamic network of regulatory enzymes and protein interactions. Oncogenic mutation of RAS alters cell growth by deleteriously controlling output to RAS-binding effectors. Mechanisms underlying multieffector interactions for both wild-type and oncogenic RAS are poorly understood owing to challenges in quantifying outputs to multiple pathways in parallel. Using highly selective NMR probes for wild-type and oncogenic (G12V) RAS, we develop a systematic approach that quantitatively measures RAS output in composite mixtures of GEF, GAP and effector RAS-binding domains (RBDs). We derive effector signaling hierarchies and establish how oscillating concentrations generate effector 'switching'. The G12V mutation highly perturbs this system, specifically altering interactions with RAL GTPase-specific GEFs and RAF kinases. We further reveal that RAS-RBD complexes show extensive feedback to full-length regulatory proteins. Our approach quantifies output from signaling hubs, here providing an integrated view of the RAS network.
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Additional biochemical, structural, and signaling distinctions have been identified between different mutant KRAS alleles, including between those at the same amino acid position.
“Additional biochemical, structural, and signaling distinctions have been identified between different mutant alleles, including between those at the same amino acid position4,8,13–20.”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [19]
Wild-type RAS isoforms have weak intrinsic GTPase activity and can self-inactivate, while RAS-GAPs stimulate this activity dramatically, increasing it fivefold over the intrinsic rate.
“Wild-type RAS isoforms have intrinsic, albeit weak, hydrolytic (GTPase) activity and can, therefore, self-inactivate; however, RAS-GAPs stimulate this activity dramatically11–14. Indeed, the GAPs increase RAS GTPase activity fivefold relative to the intrinsic rate12.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [14]
RAS mutants were once thought to be locked in the GTP-bound on state and undruggable, but detailed structural and biochemical analyses have revealed differences among RAS mutants in GTPase activity, GDP-GTP exchange and effector binding.
“RAS mutants were once viewed as being ‘locked’ in the GTP-bound ‘on’ state, impervious to GAP-stimulated or intrinsic GTP hydrolysis, and hence undruggable. However, detailed structural and biochemical analyses of various RAS mutants associated with cancer and ‘RASopathies’”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [14]
Smith and Ikura proposed that discrepancies in effector protein binding profiles of the mutants are due to altered switch dynamics.
“Smith and Ikura [10] proposed that the discrepancies in the effector protein binding profiles of the mutants are due to altered switch dynamics.”
RAS G12X mutants give rise to differences in preferred signaling pathway in terms of effector protein binding.
“Importantly, not only RAS G12X mutants exhibit a discrepancy in GTP hydrolysis, but they also give rise to differences in the preferred signaling pathway (in terms of effector protein binding) [9,10].”
An NMR study revealed different binding preferences for mutant HRAS G12V compared to wild-type HRAS with various effector proteins, with HRAS G12V showing reduced interactions with Raf and enhanced binding with RalGDS.
“Here, HRAS G12V showed reduced interactions with Raf and enhanced binding with RalGDS.”
The difference in mutant dynamics, such as G12V's inability to reach metastable states I and V, may reflect differences observed in RAS effector protein binding.
“We consider that the difference in the mutant dynamics, for instance the G12V dynamics with its inability to reach the metastable states I and V (Fig 5), may reflect the differences observed in the RAS effector protein binding [8,10].”
Cites
NMRPipe: A multidimensional spectral processing system based on UNIX pipes
Delaglio, F., Grzesiek, S., Vuister, G. W., Zhu, G., Pfeifer, J., & Bax, A. (1995) · Journal of Biomolecular NMR · doi:10.1007/bf00197809 · Cited by 15,994 · see citing works
Boussif, O., Lezoualc’h, F., Zanta, M. A., Djavaheri‐Mergny, M., Scherman, D., DEMENEIX, B. A., & Behr, J. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.16.7297 · Cited by 6,256 · see citing works
The Guanine Nucleotide-Binding Switch in Three Dimensions
Vetter, I. R., & Wittinghofer, A. (2001) · Science · doi:10.1126/science.1062023 · Cited by 1,875 · see citing works
The Ras-RasGAP Complex: Structural Basis for GTPase Activation and Its Loss in Oncogenic Ras Mutants
Scheffzek, K., Ahmadian, M. R., Kabsch, W., Wiesmüller, L., Lautwein, A., Schmitz, F., & Wittinghofer, A. (1997) · Science · doi:10.1126/science.277.5324.333 · Cited by 1,543 · 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
Using NMRView to Visualize and Analyze the NMR Spectra of Macromolecules
Johnson, B. A. (2004) · Humana Press eBooks · doi:10.1385/1-59259-809-9:313 · Cited by 1,032 · see citing works
Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1
Zhang, X., Settleman, J. E., Kyriakis, J. M., Takeuchi-Suzuki, E., Elledge, S. J., Marshall, M. S., Bruder, J. T., Rapp, U. R., & Avruch, J. (1993) · Nature · doi:10.1038/364308a0 · Cited by 859 · see citing works
Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro
Warne, P. H., Vician, P. R., & Downward, J. (1993) · Nature · doi:10.1038/364352a0 · Cited by 729 · see citing works
Regulation of Raf-1 by direct feedback phosphorylation.
Dougherty, M., Müller, J., Ritt, D. A., Zhou, M., Zhou, X.-Z., Copeland, T., Conrads, T., Veenstra, T., Lu, K., & Morrison, D. (2005) · Molecules and Cells · doi:10.1016/j.molcel.2004.11.055 · Cited by 663 · see citing works
Nassar, N. N., Horn, G., Herrmann, C., Scherer, A., McCormick, F. P., & Wittinghofer, A. (1995) · Nature · doi:10.1038/375554a0 · Cited by 631 · see citing works
Crystal Structure and Functional Analysis of Ras Binding to Its Effector Phosphoinositide 3-Kinase γ
Pacold, M. E., Suire, S., Perišić, O., Lara‐González, S., Davis, C. T., Walker, E. H., Hawkins, P. T., Stephens, L., Eccleston, J. F., & Williams, R. L. (2000) · Cell · doi:10.1016/s0092-8674(00)00196-3 · Cited by 603 · see citing works
Margarit, S. M., Sondermann, H., Hall, B. E., Nagar, B., Hoelz, A., Pirruccello, M., Bar‐Sagi, D., & Kuriyan, J. (2003) · Cell · doi:10.1016/s0092-8674(03)00149-1 · Cited by 486 · see citing works
Bivona, T. G., Quatela, S. E., Bodemann, B. O., Ahearn, I. M., Soskis, M. J., Mor, A., Miura, J., Wiener, H. H., Wright, L. P., Saba, S. G., et al. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.012 · Cited by 467 · see citing works
Distinct requirements for Ras oncogenesis in human versus mouse cellsPreprint
Hamad, N. M., Elconin, J. H., Karnoub, A. E., Bai, W., Rich, J. N., Abraham, R. T., Der, C. J., & Counter, C. M. (2002) · Genes & Development · doi:10.17615/zkd7-3774 · Cited by 430 · see citing works
Plasma membrane nanoswitches generate high-fidelity Ras signal transduction
Tian, T., Harding, A. S., Inder, K. L., Plowman, S. J., Parton, R. G., & Hancock, J. F. (2007) · Nature Cell Biology · doi:10.1038/ncb1615 · Cited by 407 · see citing works
Rodriguez-Viciana, P., Sabatier, C., & McCormick, F. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.11.4943-4954.2004 · Cited by 327 · see citing works
Dynamic properties of the Ras switch I region and its importance for binding to effectors
Spoerner, M., Herrmann, C., Vetter, I. R., Kalbitzer, H. R., & Wittinghofer, A. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.081441398 · Cited by 324 · see citing works
Structural Analysis of Autoinhibition in the Ras Activator Son of Sevenless
Sondermann, H., Soisson, S. M., Boykevisch, S., Yang, S., Bar‐Sagi, D., & Kuriyan, J. (2004) · Cell · doi:10.1016/j.cell.2004.10.005 · Cited by 315 · see citing works
Gideon, P., John, J., Frech, M., Lautwein, A., Clark, R., Scheffler, J. E., & Wittinghofer, A. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.5.2050 · Cited by 287 · see citing works
NMR-based functional profiling of RASopathies and oncogenic RAS mutations
Smith, M. J., Neel, B. G., & Ikura, M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1218173110 · Cited by 257 · see citing works
Self-citationMembrane-dependent signal integration by the Ras activator Son of sevenless
Gureasko, J. M., Galush, W. J., Boykevisch, S., Sondermann, H., Bar‐Sagi, D., Groves, J. T., & Kuriyan, J. (2008) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1418 · Cited by 257 · see citing works
Structural basis for the interaction of Ras with RaIGDS
Huang, L., Hofer, F., Martin, G. S., & Kim, S. (1998) · Nature Structural Biology · doi:10.1038/nsb0698-422 · Cited by 248 · see citing works
Geyer, M., Schweins, T., Herrmann, C., Prisner, T. F., Wittinghofer, A., & Kalbitzer, H. R. (1996) · Biochemistry · doi:10.1021/bi952858k · Cited by 227 · see citing works
Differential modification of Ras proteins by ubiquitination.
Jura, N., Scotto–Lavino, E., Sobczyk, A., & Bar-Sagi, D. (2006) · Molecules and Cells · doi:10.1016/j.molcel.2006.02.011 · Cited by 219 · see citing works
RalGDS is required for tumor formation in a model of skin carcinogenesis
González-Garcı́a, A., Pritchard, C. A., Paterson, H. F., Mavria, G., Stamp, G., & Marshall, C. J. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.01.029 · Cited by 181 · see citing works
Ras–effector interactions: after one decade
Herrmann, C. (2003) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(02)00007-6 · Cited by 179 · see citing works
Recognizing and Defining True Ras Binding Domains I: Biochemical Analysis
Wohlgemuth, S., Kiel, C., Kraemer, A., Serrano, L. G., Wittinghofer, F., & Herrmann, C. (2005) · Journal of Molecular Biology · doi:10.1016/j.jmb.2005.02.048 · Cited by 177 · see citing works
A Ras-induced conformational switch in the Ras activator Son of sevenless
Freedman, T. S., Sondermann, H., Friedland, G. D., Kortemme, T., Bar‐Sagi, D., Marqusee, S., & Kuriyan, J. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0608127103 · Cited by 160 · see citing works
EGF induced SOS phosphorylation in PC12 cells involves P90 RSK-2
Douville, E. M. J., & Downward, J. (1997) · Oncogene · doi:10.1038/sj.onc.1201214 · Cited by 159 · see citing works
Subcellular Localization Determines MAP Kinase Signal Output
Harding, A. S., Tian, T., Westbury, E., Frische, E. W., & Hancock, J. F. (2005) · Current Biology · doi:10.1016/j.cub.2005.04.020 · Cited by 153 · see citing works
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 · see citing works
Oncogenic K-Ras requires activation for enhanced activity
Huang, H., Daniluk, J., Liu, Y., Chu, J., Li, Z., Ji, B., & Logsdon, C. D. (2013) · Oncogene · doi:10.1038/onc.2012.619 · Cited by 139 · see citing works
Roberts, P. J., Usary, J., Darr, D. B., Dillon, P. M., Pfefferle, A. D., Whittle, M. C., Duncan, J. S., Johnson, S. M., Combest, A. J., Jin, J. J., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-0563 · Cited by 138 · see citing works
Takashima, A., & Faller, D. V. (2013) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2013.764990 · Cited by 135 · see citing works
Sydor, J. R., Engelhard, M., Wittinghofer, A., Goody, R. S., & Herrmann, C. (1998) · Biochemistry · doi:10.1021/bi980764f · Cited by 128 · see citing works
Regulation of Ras Signaling Dynamics by Sos-Mediated Positive Feedback
Boykevisch, S., Zhao, C., Sondermann, H., Philippidou, P., Halegoua, S., Kuriyan, J., & Bar‐Sagi, D. (2006) · Current Biology · doi:10.1016/j.cub.2006.09.033 · Cited by 125 · see citing works
Kiel, C., Selzer, T., Shaul, Y. D., Schreiber, G., & Herrmann, C. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401160101 · Cited by 111 · 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
Eccleston, J. F., Moore, K. J. M., Morgan, L. K., Skinner, R. H., & Lowe, P. N. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)74211-2 · Cited by 104 · see citing works
A Detailed Thermodynamic Analysis of Ras/Effector Complex Interfaces
Kiel, C., Serrano, L. G., & Herrmann, C. (2004) · Journal of Molecular Biology · doi:10.1016/j.jmb.2004.05.050 · Cited by 91 · see citing works
Effector Recognition by the Small GTP-binding Proteins Ras and Ral
BAUER, B. E., Mirey, G., Vetter, I. R., Ranea, J. A. G., Valencia, A., Wittinghofer, A., Camonis, J., & Cool, R. H. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.25.17763 · Cited by 82 · see citing works
Depetris, R. S., Wu, J., & Hubbard, S. R. (2009) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1642 · Cited by 72 · see citing works
Rudolph, M. G., Linnemann, T., Grünewald, P., Wittinghofer, A., Vetter, I. R., & Herrmann, C. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m011600200 · Cited by 71 · see citing works
Spoerner, M., Wittinghofer, A., & Kalbitzer, H. R. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.11.020 · Cited by 70 · see citing works
Mitogenic signaling of Ras is regulated by differential interaction with Raf isozymes
Weber, C. K., Slupsky, J. R., Herrmann, C., Schuler, M., Rapp, U. R., & Block, C. (2000) · Oncogene · doi:10.1038/sj.onc.1203261 · Cited by 70 · see citing works
Ras Effector Switching Promotes Divergent Cell Fates in C. elegans Vulval Patterning
Zand, T. P., Reiner, D. J., & Der, C. J. (2011) · Developmental Cell · doi:10.1016/j.devcel.2010.12.004 · Cited by 69 · see citing works
K-RAS Mutant Pancreatic Tumors Show Higher Sensitivity to MEK than to PI3K Inhibition In Vivo
Hofmann, I., Weiss, A., Elain, G., Schwaederle, M. C., Sterker, D., Romanet, V., Schmelzle, T., Lai, A., Brachmann, S. M., Bentires‐Alj, M., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044146 · Cited by 69 · see citing works
Dissection of RAS downstream pathways in melanomagenesis: a role for Ral in transformation
Mishra, P. J., Ha, L., Rieker, J., Sviderskaya, E. V., Bennett, D. C., Oberst, M. D., Kelly, K., & Merlino, G. T. (2010) · Oncogene · doi:10.1038/onc.2009.521 · Cited by 68 · see citing works
Vigil, D., Martin, T. D., Williams, F. J., Yeh, J. J., Campbell, S. L., & Der, C. J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.116756 · Cited by 65 · see citing works
Scheffler, J. E., Waugh, D. S., Bekesi, E., Kiefer, S. E., LoSardo, J. E., Neri, A., Prinzo, K., Tsao, K. L., Wegrzynski, B. B., & Emerson, S. D. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)31795-7 · Cited by 58 · see citing works
Targeting signal transduction in pancreatic cancer treatment
Yeh, J. J., & Der, C. J. (2007) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.11.5.673 · Cited by 56 · see citing works
The Activation of RalGDS Can Be Achieved Independently of Its Ras Binding Domain
Linnemann, T., Kiel, C., Herter, P., & Herrmann, C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m110800200 · Cited by 48 · see citing works
A Genome-wide Ras-Effector Interaction Network
Kiel, C., Foglierini, M., Kuemmerer, N., Beltrão, P., & Serrano, L. G. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.05.015 · Cited by 36 · see citing works
Ader, C., Spoerner, M., Kalbitzer, H. R., & Brunner, E. (2007) · The Journal of Physical Chemistry B · doi:10.1021/jp067792p · Cited by 5 · see citing works
Oncogenic Ras requires activation for pathological levels of activity
Huang, H., Daniluk, J., Liu, Y., Ji, B., & Logsdon, C. D. (2013) · Pancreatology · doi:10.1016/j.pan.2012.12.172 · Cited by 2 · see citing works
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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 693 · see citing works
The current state of the art and future trends in RAS-targeted cancer therapies
Punekar, S. R., Velcheti, V., Neel, B. G., & Wong, K.-K. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00671-9 · Cited by 549 · see citing works
KRAS Alleles: The Devil Is in the Detail
Haigis, K. M. (2017) · Trends in Cancer · doi:10.1016/j.trecan.2017.08.006 · Cited by 373 · see citing works
“Mutant forms of KRAS differ from WT and from other mutants, for example, in their affinity for RAF and other effectors [16, 64].”
BackgroundResultRas 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 · see citing works
The current understanding of KRAS protein structure and dynamics
Pantsar, T. (2019) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2019.12.004 · Cited by 288 · see citing works
“teins, diminished or enhanced binding, a clear on/off binding changes are not observed [4,110].”
BackgroundSHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling
Fedele, C., Li, S., Teng, K. W., Foster, C. J. R., Peng, D., Ran, H., Mita, P., Geer, M. J., Hattori, T., Koide, A., et al. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20201414 · Cited by 265 · see citing works
“” More recent analyses revealed subtle but key differences between RAS mutants in intrinsic and residual GAP-catalyzed GTPase activity, intrinsic and SOS-stimulated exchange, and effector binding (Bandaru et al., 2017; Gremer et al., 2011; Hunter et al., 2015; Johnson et al., 2017; Mazhab-Jafari et al., 2015; Smith an…”
BackgroundAtypical KRASG12R Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer
Hobbs, G. A., Baker, N. M., Miermont, A. M., Thurman, R. D., Pierobon, M., Tran, T. H., Anderson, A. O., Waters, A. M., Diehl, J. N., Papke, B., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-1006 · Cited by 231 · see citing works
The origins and genetic interactions of KRAS mutations are allele- and tissue-specific
Cook, J. H., Melloni, G. E. M., Gulhan, D. C., Park, P. J., & Haigis, K. M. (2021) · Nature Communications · doi:10.1038/s41467-021-22125-z · Cited by 208 · see citing works
Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view
Lu, S., Jang, H., Gu, S., Zhang, J., & Nussinov, R. (2016) · Chemical Society Reviews · doi:10.1039/c5cs00911a · Cited by 188 · see citing works
RAS mutations in human cancers: Roles in precision medicine
Murugan, A. K., Grieco, M., & Tsuchida, N. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.06.007 · Cited by 146 · see citing works
Johnson, C. W., Reid, D., Parker, J. A., Salter, S., Knihtila, R., Kuzmic, P., & Mattos, C. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.778886 · Cited by 133 · see citing works
“This scenario is consistent with the observation that binding of Raf-RBD to Ras fully inhibits GAP activity (28) and that GAP is generally a poor competitor of Ras– effector interactions (28, 29).”
Deconstruction 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
“We note that since Raf-RBD and GAP have an overlapping interface, mutations in Switch I also impede GAP binding (Scheffzek et al., 1997; Smith and Ikura, 2014).”
BackgroundClassification of KRAS -Activating Mutations and the Implications for Therapeutic Intervention
Johnson, C. W., Burkhart, D. L., & Haigis, K. M. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0035 · Cited by 130 · see citing works
Tyrosyl phosphorylation of KRAS stalls GTPase cycle via alteration of switch I and II conformation
Kano, Y., Gebregiworgis, T., Marshall, C. B., Radulovich, N., Poon, B. P. K., St-Germain, J., Cook, J. D., Valencia-Sama, I., Grant, B. M. M., Herrera, S. G., et al. (2019) · Nature Communications · doi:10.1038/s41467-018-08115-8 · Cited by 103 · see citing works
Self-citationDetermining the ERK-regulated phosphoproteome driving KRAS-mutant cancer
Klomp, J. E., Diehl, J. N., Klomp, J. A., Edwards, A. C., Yang, R., Morales, A. J., Taylor, K. E., Drizyte-Miller, K., Bryant, K. L., Schaefer, A., et al. (2024) · Science · doi:10.1126/science.adk0850 · Cited by 83 · see citing works
“This result is also consistent with the ~200-fold-greater affinity of RAS-GTP for RAF versus phosphatidylinositol 3-kinase a (PI3K a ) ( 17 , 18 ) and with a system-wide proteomic assessment of RAS association with 56 effectors showing that RAS-RAF is the predominant RAS-effector complex ( 19 ).”
ResultFang, Z., Marshall, C. B., Nishikawa, T., Gossert, A. D., Jansen, J. M., Jahnke, W., & Ikura, M. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2018.07.009 · Cited by 86 · see citing works
Self-citationAdvances in NMR Methods To Map Allosteric Sites: From Models to Translation
Boulton, S., & Melacini, G. (2016) · Chemical Reviews · doi:10.1021/acs.chemrev.5b00718 · Cited by 89 · see citing works
Pantsar, T., Rissanen, S., Dauch, D., Laitinen, T., Vattulainen, I., & Poso, A. (2018) · PLOS Computational Biology · doi:10.1371/journal.pcbi.1006458 · Cited by 85 · see citing works
“Furthermore, an NMR study revealed different binding preferences for mutant HRAS G12V compared to wild-type HRAS, with various effector proteins [10].”
BackgroundInfluentialHigh-affinity interaction of the K-Ras4B hypervariable region with the RAS active site
Chavan, T. S., Jang, H., Khavrutskii, L., Abraham, S. J., Banerjee, A., Freed, B. C., Johannessen, L., Tarasov, S. G., Gaponenko, V., Nussinov, R., et al. (2015) · Biophysical Journal · doi:10.1016/j.bpj.2015.09.034 · Cited by 79 · see citing works
Direct Attack on RAS: Intramolecular Communication and Mutation-Specific Effects
Marcus, K., & Mattos, C. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2148 · Cited by 75 · see citing works
“This is a difficult problem to overcome, as the mutations themselves severely perturb the active site and impair the ability of GAPs to enhance GTP hydrolysis even upon binding RAS (50, 71).”
BackgroundReal-time NMR monitoring of biological activities in complex physiological environments
Smith, M. J., Marshall, C. B., Theillet, F., Binolfi, A., Selenko, P., & Ikura, M. (2015) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2015.02.003 · Cited by 73 · see citing works
Self-citationPI3K: A Crucial Piece in the RAS Signaling PuzzlePreprint
Krygowska, A. A., & Castellano, E. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031450 · Cited by 71 · see citing works
“This preference changes with oncogenic mutations such as G12V, explaining how small changes in RAS affinity could substantially modify the outcome of integrated RAS signaling networks (Marshall et al. 2012a; Smith and Ikura 2014).”
BackgroundVatansever, S., Erman, B., & Gumus, Z. H. (2020) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2020.04.003 · Cited by 67 · see citing works
Parker, J. A., & Mattos, C. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031427 · Cited by 60 · see citing works
“Specifically, this level of regulation may be important in the context of Raf binding, which can outcompete GAP binding because of its nanomolar affinity for Ras-GTP (Smith and Ikura 2014).”
BackgroundFunctional and biological heterogeneity of KRAS Q61 mutations
Huynh, M. V., Hobbs, G. A., Schaefer, A., Pierobon, M., Carey, L. M., Diehl, J. N., DeLiberty, J. M., Thurman, R. D., Cooke, A. R., Goodwin, C. M., et al. (2022) · Science Signaling · doi:10.1126/scisignal.abn2694 · Cited by 47 · see citing works
“Bacterial expression vectors encoding KRAS-GTP effector interacting domains included BRAF-RBD (residues 149 to 232, pET28a), CRAF-RBD (residues 54 to 131, pQlinkH), RGL2RA (residues 647 to 736, pGEX3T-2) (51), and PLC-RA (residues 2113 to 2221, pTriEx4) (52).”
Akimoto, M., McNicholl, E. T., Ramkissoon, A., Moleschi, K., Taylor, S. S., & Melacini, G. (2015) · PLoS Biology · doi:10.1371/journal.pbio.1002305 · Cited by 43 · see citing works
Killoran, R. C., & Smith, M. J. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.008653 · Cited by 41 · see citing works
“Future combination of multiplexed GTPases with multiple competing effectors (58) will facilitate study of evermore complex in vitro systems that retain a capacity to deliver atomic-level, quantitative data for composite protein– protein interactions.”
BackgroundSelf-citationInsight into the mechanism of allosteric activation of PI3Kα by oncoprotein K-Ras4B
Li, X., Dai, J., Ni, D., He, X., Zhang, H., Zhang, J., Fu, Q., Liu, Y., & Lu, S. (2019) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2019.12.020 · Cited by 38 · see citing works
A New View of Activating Mutations in Cancer
Nussinov, R., Tsai, C., & Jang, H. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-2125 · Cited by 35 · see citing works
Structure, signaling and the drug discovery of the Ras oncogene protein
Han, C. W., Jeong, M. S., & Jang, S. B. (2017) · BMB Reports · doi:10.5483/bmbrep.2017.50.7.062 · Cited by 35 · see citing works
“Ras binds many effectors, which regulate signals over various cellular pathways (18).”
BackgroundAramini, J. M., Vorobiev, S. M., Tuberty, L., Janjua, H., Campbell, E., Seetharaman, J., Su, M., Huang, Y. J., Acton, T., Xiao, R., et al. (2015) · Structure · doi:10.1016/j.str.2015.06.003 · Cited by 33 · see citing works
“The reciprocal NMR studies of effector binding to RAS and its oncogenic mutants, where RAS is isotopically enriched, established a hierarchy of effector binding to HRAS inwhich BRAFRBDdisplayed the highest-affinity binding, and provide an elegant approach for directly monitoring the complex RAS signaling network (Smit…”
BackgroundDirect K-Ras Inhibitors to Treat Cancers: Progress, New Insights, and Approaches to Treat Resistance
Nussinov, R., & Jang, H. (2023) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-022823-113946 · Cited by 32 · see citing works
Functional and structural insights into RAS effector proteins
Mozzarelli, A. M., Simanshu, D. K., & Castel, P. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.06.027 · Cited by 31 · see citing works
RASSF5: An MST activator and tumor suppressor in vivo but opposite in vitro
Liao, T.-J., Tsai, C., Jang, H., Fushman, D., & Nussinov, R. (2016) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2016.09.001 · Cited by 31 · see citing works
Moleschi, K., Akimoto, M., & Melacini, G. (2015) · Journal of the American Chemical Society · doi:10.1021/jacs.5b06557 · Cited by 30 · see citing works
Shen, M., Qi, R., Ren, J., Lv, D., & Yang, H. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2021.780655 · Cited by 29 · see citing works
“that co-occur with genomic changes that affect tumor biology and response to systemic therapy (92, 104, 105, 119).”
BackgroundInhibition of Nonfunctional Ras
Nussinov, R., Jang, H., Gürsoy, A., Keskin, Ö., & Gaponenko, V. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2020.12.012 · Cited by 29 · see citing works
“Strong oncogenic mutations block GAP catalytic activity, retaining the active GTP-bound state, thus promoting downstream signaling and cell proliferation as in the case of G12DK-Ras4Bmutant (Adjei, 2001; Schubbert et al., 2007; Smith and Ikura, 2014; Smith et al., 2013; Vigil et al., 2010).”
BackgroundEvolution of AF6-RAS association and its implications in mixed-lineage leukemia
Smith, M. J., Ottoni, E., Ishiyama, N., Goudreault, M., Haman, A., Meyer, C., Tucholska, M., Gasmi-Seabrook, G. M. C., Menezes, S., Laister, R. C., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01326-5 · Cited by 28 · see citing works
Self-citationThe spatiotemporal regulation of RAS signalling
Herrero, A., Matallanas, D., & Kölch, W. (2016) · Biochemical Society Transactions · doi:10.1042/bst20160127 · Cited by 26 · see citing works
VanSchouwen, B., Akimoto, M., Sayadi, M., Fogolari, F., & Melacini, G. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.651877 · Cited by 25 · see citing works
Liu, Z., Wang, M., Wang, H., Fang, L., & Gou, S. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112269 · Cited by 25 · see citing works
RAS‐targeted cancer therapy: Advances in drugging specific mutations
Liu, C., Ye, D., Yang, H., Chen, X., Su, Z., Li, X., Ding, M., & Liu, Y. (2023) · MedComm · doi:10.1002/mco2.285 · Cited by 24 · see citing works
Evolution of direct RAS inhibitors: from undruggable target to clinical breakthroughs
Wang, X., Wu, J., Xiao, A., Wang, J., & Tian, J. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02364-0 · Cited by 24 · see citing works
“Under normal circumstances, RAS activation is transient, and GTPase-activating proteins (GAPs), such as Neurofibromin (NF1), accelerate the hydrolysis of GTP to GDP, inactivating RAS and thus tightly regulating its signaling [9–12].”
Coyle, S. M., & Lim, W. A. (2016) · eLife · doi:10.7554/elife.12435 · Cited by 22 · see citing works
“GTP (Smith and Ikura, 2014).”
BackgroundInfluentialRegulation of GTPase function by autophosphorylation
Johnson, C. W., Seo, H., Terrell, E. M., Yang, M.-H., KleinJan, F., Gebregiworgis, T., Gasmi-Seabrook, G. M. C., Geffken, E. A., Lakhani, J., Song, K., et al. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.02.011 · Cited by 21 · see citing works
Self-citationNikolaev, Y., Ripin, N., Soste, M., Picotti, P., Iber, D., & Allain, F. H.-T. (2019) · Nature Methods · doi:10.1038/s41592-019-0495-7 · Cited by 20 · see citing works
Quirion, L., Robert, A., Boulais, J., Huang, S., Astrain, G. B., Strakhova, R., Jo, C. H., Kherdjemil, Y., Faubert, D., Thibault, M.-P., et al. (2024) · Journal of Cell Science · doi:10.1242/jcs.262140 · Cited by 19 · see citing works
Self-citationNew 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 20 · see citing works
Fang, Z., Marshall, C. B., Yin, J. C., Mazhab‐Jafari, M. T., Gasmi-Seabrook, G. M. C., Smith, M. J., Nishikawa, T., Xu, Y., Neel, B. G., & Ikura, M. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.714196 · Cited by 18 · see citing works
“A construct encoding residues 150 –233 of the RBD of BRAF was cloned into pGEX-4T2 to express a GST-BRAF-RBD fusion protein, which was purified as previously described (33).”
BackgroundMethodSelf-citationAnalysis of Ras-effector interaction competition in large intestine and colorectal cancer context
Gaspar, V. I., Catozzi, S., Ternet, C., Luthert, P. J., & Kiel, C. (2020) · Small GTPases · doi:10.1080/21541248.2020.1724596 · Cited by 18 · see citing works
“isothermal titration calorimetry or surface plasmon resonance) (Table S3) (reviewed in [37], and obtained from [13,14,38–40]).”
BackgroundMolt, R. W., Pellegrini, E., & Jin, Y. (2019) · Chemistry - A European Journal · doi:10.1002/chem.201901627 · Cited by 15 · see citing works
Allosteric site variants affect GTP hydrolysis on Ras
Johnson, C. W., Fetics, S., Davis, K. P., Rodrigues, J. A., & Mattos, C. (2023) · Protein Science · doi:10.1002/pro.4767 · Cited by 15 · see citing works
“…protein cannot compete with Ras effectors, including RAF, under physiological-like conditions (Smith & Ikura, 2014), and it is well documented that RAF blocks GAP activity by binding to RAS (Moodie et al., 1995; Scheffler et al., 1994; Smith & Ikura, 2014; Warne et al., 1993; Zhang et al., 1993).”
BackgroundRAS GTPase signalling to alternative effector pathways
Singh, S., & Smith, M. J. (2020) · Biochemical Society Transactions · doi:10.1042/bst20200506 · Cited by 15 · see citing works
Self-citationNMR in integrated biophysical drug discovery for RAS: past, present, and future
Marshall, C. B., KleinJan, F., Gebregiworgis, T., Lee, K., Fang, Z., Eves, B. J., Liu, N. F., Gasmi-Seabrook, G. M. C., Enomoto, M., & Ikura, M. (2020) · Journal of Biomolecular NMR · doi:10.1007/s10858-020-00338-6 · Cited by 15 · see citing works
Self-citationSpecific inhibition of oncogenic RAS using cell-permeable RAS-binding domains
Nomura, T. K., Heishima, K., Sugito, N., Sugawara, R., Ueda, H., Akao, Y., & Honda, R. P. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.04.013 · Cited by 14 · see citing works
Targeting Ras with protein engineering
Tomazini, A., & Shifman, J. M. (2023) · Oncotarget · doi:10.18632/oncotarget.28469 · Cited by 13 · see citing works
Defining bone fide effectors of RAS GTPases
Smith, M. J. (2023) · BioEssays · doi:10.1002/bies.202300088 · Cited by 12 · see citing works
“We have previously mined the human proteome for RBD domains by sequence homology, identifying 50 putative effectors[34,35] that are”
BackgroundMethodSelf-citationThe small GTPase MRAS is a broken switch
Astrain, G. B., Strakhova, R., Jo, C. H., Teszner, E., Killoran, R. C., & Smith, M. J. (2025) · Nature Communications · doi:10.1038/s41467-025-55967-y · Cited by 10 · see citing works
Self-citationMerlin cooperates with neurofibromin and Spred1 to suppress the Ras–Erk pathway
Cui, Y., Ma, L., Schacke, S., Yin, J. C., Hsueh, Y., Jin, H., & Morrison, H. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa263 · Cited by 10 · see citing works
Structures of RGL1 RAS-Association Domain in Complex with KRAS and the Oncogenic G12V Mutant
Eves, B. J., Gebregiworgis, T., Gasmi-Seabrook, G. M. C., Kuntz, D. A., Privé, G. G., Marshall, C. B., & Ikura, M. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167527 · Cited by 10 · see citing works
Self-citationBrother’s Keeper: Wild-Type Mutant K-Ras Dimers Limit Oncogenesis
Lin, Y.-J., & Haigis, K. M. (2018) · Cell · doi:10.1016/j.cell.2018.01.019 · Cited by 8 · see citing works
Reconstitution and characterization of BRAF in complex with 14‐3‐3 and KRAS4B on nanodiscs
Liu, N. F., Enomoto, M., Marshall, C. B., & Ikura, M. (2024) · Protein Science · doi:10.1002/pro.5016 · Cited by 6 · see citing works
Self-citationRas Isoforms from Lab Benches to Lives—What Are We Missing and How Far Are We?
Nair, A., Kubatzky, K. F., & Saha, B. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126508 · Cited by 6 · see citing works
Structural insights into the complex of oncogenic KRas4B G12V and Rgl2, a RalA/B activator
Tariq, M., Ikeya, T., Togashi, N., Fairall, L., Kamei, S., Mayooramurugan, S., Abbott, L. R., Hasan, A., Bueno-Alejo, C. J., Sukegawa, S., et al. (2023) · Life Science Alliance · doi:10.26508/lsa.202302080 · Cited by 6 · see citing works
“…structural and molecular modelling studies indicate that oncogenic RAS mutations affect the interaction kinetics with the effector molecules and may trigger a biased overactivation of a set of effectors (Hunter et al., 2015; Mazhab-Jafari et al., 2015; Pantsar et al., 2018; Smith and Ikura, 2014).”
BackgroundResultInfluentialMutant KRAS-Associated Proteome Is Mainly Controlled by Exogenous Factors
Carvalho, P. D., Martins, F., Carvalho, J., Oliveira, M. J., & Velho, S. (2022) · Cells · doi:10.3390/cells11131988 · Cited by 5 · see citing works
Zhang, Q., Geng, Y., Chen, H., Ni, J., Guan, L., Zhai, D., Wang, Y., Xu, S., Niu, M., Zheng, L., et al. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c02435 · Cited by 4 · see citing works
Singh, A., Erijman, A., Noronha, A., Kumar, H., Peleg, Y., Yarden, Y., & Shifman, J. M. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101353 · Cited by 4 · see citing works
Aboalroub, A. A. (2025) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-025-01869-1 · Cited by 2 · see citing works
“Building on this initial research, their follow-up 2014 study introduced a new NMR method that could track the interactions of RAS with both its effector and regulatory proteins at the same time in real-time [124].”
Profiling Complex RAS-Effector Interactions Using NMR Spectroscopy
Strakhova, R., & Smith, M. J. (2024) · Methods in molecular biology · doi:10.1007/978-1-0716-3822-4_14 · Cited by 2 · see citing works
Self-citationStructure and Function of the mTOR Activator Rheb
Marshall, C. B., Mazhab‐Jafari, M. T., Stambolic, V., & Ikura, M. (2014) · Springer eBooks · doi:10.1007/978-3-7091-1806-1_13 · Cited by 2 · see citing works
“This new methodology has also been successfully applied to RAS (Smith and Ikura 2014; Smith et al. 2013) and RhoA (Gasmi-Seabrook et al.”
MethodSelf-citationRavera, E., Carlon, A., & Parigi, G. (2014) · Journal of Biomolecular NMR · doi:10.1007/s10858-014-9846-y · Cited by 2 · see citing works
“In the original description (Smith and Ikura 2014), the ratios between the bound forms of the hub protein to each of the two competitors were averaged to give a direct measure of the average affinity of each partner in any mix.”
BackgroundResultInfluentialMartins, F., Machado, A. L., Ribeiro, A., Oliveira, S. M., Carvalho, J., Matthiesen, R., Backman, V., & Velho, S. (2024) · Research Square · doi:10.21203/rs.3.rs-3752760/v2 · Cited by 2 · see citing works
Gray, J. P., Bildik, G., Kim, H.-N., Sutton, M. N., Wang, J., Osuji, A. O., Batistatou, N., Yang, H., Mao, W., Tan, Z., et al. (2025) · iScience · doi:10.1016/j.isci.2025.113686 · Cited by 1 · see citing works
Self-citationThe competitive world of RAS biology
Luchinat, C., Parigi, G., & Ravera, E. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1461 · Cited by 1 · see citing works
NMR Detection Methods for Profiling RAS Nucleotide Cycling
Killoran, R. C., & Smith, M. J. (2021) · Methods in molecular biology · doi:10.1007/978-1-0716-1190-6_9 · Cited by 1 · see citing works
Self-citationStructure-based Drug Design Using NMR
Jeeves, M., Quill, L., & Overduin, M. (2015) · Encyclopedia of Magnetic Resonance · doi:10.1002/9780470034590.emrstm1430 · Cited by 1 · see citing works
Qian, X., Pantsar, T., Papageorge1, A. G., Tripathi, B. K., Sánchez‐Solana, B., Durkin, M. E., Gao, Y., Esposito, D., Waybright, T. J., Stephen, A. G., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-1521657/v1 · Cited by 1 · see citing works
Reverse engineering GTPase programming languages with reconstituted signaling networks
Coyle, S. M. (2016) · Small GTPases · doi:10.1080/21541248.2016.1178367
“H-Ras can communicate signals to many different competing downstream targets such as Raf, PI3 Kinase, RalGDS, as well as many others.(10,11) Remarkably, we found that in multi-effector networks, different effectors could interpret an input to the signaling network with completely different output dynamics.”
BackgroundHambleton, P. J., & Barbieri, M. A. (2020) · Biocell · doi:10.32604/biocell.2020.011407
“In a study of integrative Ras signaling, Smith and Ikura (2014) used NMR probes to determine a preferential Ras binding hierarchy among equal concentrations of various Ras effector proteins.”
BackgroundInfluentialThe most oncogenic Ras isoform
Parker, J. A. (2017) · doi:10.17760/d20240308
Martins, F., Machado, A. L., Ribeiro, A., Oliveira, S. M., Carvalho, J., Matthiesen, R., & Velho, S. (2023) · Research Square · doi:10.21203/rs.3.rs-3752760/v1
Lecian, O. M. (2023) · IgMin Research · doi:10.61927/igmin133
“The di ff erent binding pro fi les can be compared within [15,18].”
BackgroundMartins, F., Machado, A. L., Ribeiro, A., Oliveira, S. M., Carvalho, J., Matthiesen, R., Backman, V., & Velho, S. (2024) · Research Square · doi:10.21203/rs.3.rs-3752760/v3
Cooperativity between Ras pathway mutations in colonic tumorigenesisPreprint
Johnson, C. W., Idelevich, A., Shui, B., Tisdale, A. W., O’Donoghue, E., Cook, J., Hull, S., Yang, M. H., Sheth, S., Terrell, E. M., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.05.673994
Inducible activation of small GTPases reveals direct effector recruitment and signalling dynamicsPreprint
Singh, S., Goudreault, M., & Smith, M. J. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.26.734842
Self-citationSwitch dynamics and activity of GTP-bound HRAS affected by R97 mutations at allosteric helix α3
Li, Y., Wang, J., 沈建忠, Longlong, R. E. N., & Chen, J. (2026) · Physical Chemistry Chemical Physics · doi:10.1039/d6cp03485c
- Authors
- Smith, M. J., & Ikura, M.
- Affiliations
- University Health Network (CA)
- Corresponding author
- Ikura, Mitsuhiko
- Venue
- Nature Chemical Biology
- Published
- 2014-01-19
- Volume
- 10
- Issue
- 3
- Pages
- 223-230
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W2064086713
- Cited by
- 87
- References
- 55
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 7 · 2023: 9 · 2022: 9 · 2021: 6 · 2020: 9 · 2019: 8 · 2018: 4 · 2017: 8 · 2016: 8 · 2015: 8 · 2014: 3
- FWCI
- 3.69
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- 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
- Ras signaling, Ras-binding domain, Raf kinase, Ras GTPase, feedback regulation, signaling hubs
- MeSH terms
- Allosteric Regulation, Humans, Magnetic Resonance Spectroscopy, Signal Transduction, Protein Structure, Tertiary, ras Proteins, Proto-Oncogene Proteins c-raf, GTPase-Activating Proteins
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