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Signaling Specificity by Ras Family GTPases Is Determined by the Full Spectrum of Effectors They Regulate
Open accessAbstract
Ras family GTPases (RFGs) regulate signaling pathways that control multiple biological processes. How signaling specificity among the closely related family members is achieved is poorly understood. We have taken a proteomics approach to signaling by RFGs, and we have analyzed interactions of a panel of RFGs with a comprehensive group of known and potential effectors. We have found remarkable differences in the ability of RFGs to regulate the various isoforms of known effector families. We have also identified several proteins as novel effectors of RFGs with differential binding specificities to the various RFGs. We propose that specificity among RFGs is achieved by the differential regulation of combinations of effector families as well as by the selective regulation of different isoforms within an effector family. An understanding of this new level of complexity in the signaling pathways regulated by RFGs is necessary to understand how they carry out their many cellular functions. It will also likely have critical implications in the treatment of human diseases such as cancer.
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“While MRAS shares approximately 50% sequence identity with other RAS isoforms and can interact with some of the common RAS effectors and regulators, such as RAF, PI3K, RalGDS and SOS38,50,51”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [50]
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InfluentialRenewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis?
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“The diversification of Ras and Notch family members may allow individual isoforms to experience unique modes of regulation or to signal through unique targets (O’Neill and Kolch 2004; Rodriguez-Viciana et al. 2004).”
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BackgroundInfluentialRare Codons Regulate KRas Oncogenesis
Lampson, B. L., Pershing, N. L., Prinz, J. A., Lacsina, J. R., Marzluff, W. F., Nicchitta, C. V., MacAlpine, D. M., & Counter, C. M. (2012) · Current Biology · doi:10.1016/j.cub.2012.11.031 · Cited by 149
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The RASSF1A Tumor Suppressor Activates Bax via MOAP-1
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“Mammalian Lpd and RIAM interact with H-, K-, N-, and R-Ras [41], so a Ras-PI3K pathway could provide another mechanism for activation of MIG-10.”
BackgroundRASSF tumor suppressor gene family: Biological functions and regulation
Volodko, N. V., Gordon, M., Salla, M., Ghazaleh, H. A., & Baksh, S. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.02.041 · Cited by 135
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“The ras(E37G) mutation has been long regarded as specific for RalGDS binding and activation (Cambell and Der, 2004), but recent advances in our knowledge of ras effectors suggest other proteins can bind and potentially be activated by this ras mutant (Rodriguez-Viciana et al., 2004).”
BackgroundThe RalGEF-Ral Effector Signaling Network: The Road Less Traveled for Anti-Ras Drug Discovery
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“In one study, p110α was found to become activated by most Ras isoforms, whereas p110δ became activated selectively by R-Ras and Tc21; p110β did not become activated by Ras at all [43].”
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Delgado, P., Cubelos, B., Calleja, E., Martínez, N., Ciprés, A., Mérida, I., Bellas, C., Bustelo, X. R., & Alarcón, B. (2009) · Nature Immunology · doi:10.1038/ni.1749 · Cited by 128
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BackgroundRole of RAS in the Regulation of PI 3-Kinase
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“Previous studies have shown interaction between several RASSF members and different Ras proteins 15,29–31 , leading to the hypothesis that Ras association localizes RASSFs and the MST kinases to the cell membrane, thus bringing the MST kinase domains into close proximity for trans-activating…”
Alveolar rhabdomyosarcoma–associated PAX3-FOXO1 promotes tumorigenesis via Hippo pathway suppression
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“It is thought that each p110 has a distinct binding capacity to Ras or shows a binding preference for specific Ras isoforms (27, 28).”
BackgroundSpatio-temporal segregation of Ras signals: one ship, three anchors, many harbors
Rocks, O., Lorentzen, A., & Bastiaens, P. I. H. (2006) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2006.06.007 · Cited by 127
“The apparent complexity of Ras function is associated with the multitude of Ras-activating stimuli and regulatory proteins, the ongoing identification of new effector proteins and thus putative downstream signaling pathways, tissue-specific signaling components and overlapping signaling properties of other Ras-related…”
BackgroundMetastasis: tumor cells becoming MENAcing
Gertler, F. B., & Condeelis, J. S. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.10.001 · Cited by 121
“Lamellipodin (Lpd), an adaptor protein containing RA and PH domains that bind Ras and PI(3,4)P2, respectively, harbors six EVH1-binding sites and plays an important role in recruiting Ena/VASP to lamellipodia [70, 71].”
BackgroundLi, Y., Asuri, S., Rebhun, J. F., Castro, A. F., Paranavitana, N. C., & Quilliam, L. A. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508165200 · Cited by 123
RASSF4/AD037 Is a Potential Ras Effector/Tumor Suppressor of the RASSF Family
Eckfeld, K., Hesson, L. B., Vos, M. D., Bièche, I., Latif, F., & Clark, G. J. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-2065 · Cited by 120
“To date, RASSF1 (12, 13), Nore1 [RASSF5 (14, 15)], and RASSF2 (16) have been shown to directly interact with Ras proteins with the characteristics of effectors.”
BackgroundLi, H., & Marshall, A. J. (2015) · Cellular Signalling · doi:10.1016/j.cellsig.2015.05.013 · Cited by 117
RIT1 oncoproteins escape LZTR1-mediated proteolysis
Castel, P., Cheng, A. S., Cuevas-Navarro, A., Everman, D. B., Papageorge, A. G., Simanshu, D. K., Tankka, A. T., Galeas, J., Urisman, A., & McCormick, F. P. (2019) · Science · doi:10.1126/science.aav1444 · Cited by 114
Self-citationRal small GTPase signaling and oncogenesis: More than just 15minutes of fame
Gentry, L. R., Martin, T. D., Reiner, D. J., & Der, C. J. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.09.004 · Cited by 116
“Similar to Ras, the intrinsic GDP-GTP exchange and GTP hydrolysis activities of Ral GTPases are very weak, with each activity accelerated by Ral-selective guanine nucleotide exchange factors (RalGEFs) and GTPase activating proteins (RalGAPs), respectively (Fig.”
BackgroundInfluentialHuman Sin1 contains Ras-binding and pleckstrin homology domains and suppresses Ras signalling
Schroder, W. A., Buck, M., Cloonan, N., Hancock, J. F., Suhrbier, A., Sculley, T. B., & Bushell, G. R. (2007) · Cellular Signalling · doi:10.1016/j.cellsig.2007.01.013 · Cited by 106
Phosphoinositide 3-kinases as drug targets in cancer
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“activation of type I PI3Ks (with the possible exception of PI3Kb [10 ]) and, in some cases, it is clear that PI3Ks, and not the MEK/ERK pathway, are the most important mediators of the transforming activity of oncogenic Ras [11].”
BackgroundCancer Targets in the Ras PathwayPreprint
Rodriguez‐Viciana, P., Tetsu, O., ODA, K., Okada, J., Rauen, K. A., & McCormick, F. P. (2005) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2005.70.044 · Cited by 105
“Other Ras effectors identified from two-hybrid screens and other approaches include AF-6, RIN, PLCε, Nore1/Rassf5, IMP, and many others that await characterization (Rodriguez-Viciana et al. 2004).”
BackgroundInfluentialSelf-citationTwo distinct functions for PI3-kinases in macropinocytosis
Hoeller, O., Bolourani, P., Clark, J. P., Stephens, L., Hawkins, P. T., Weiner, O. D., Weeks, G., & Kay, R. R. (2013) · Journal of Cell Science · doi:10.1242/jcs.134015 · Cited by 102
“other PI3-kinase isoforms (Rodriguez-Viciana et al., 2004).”
Young, L. C., Hartig, N., Boned del Río, I., Sari, S., Ringham-Terry, B., Wainwright, J. R., Jones, G. G., McCormick, F., & Rodriguez-Viciana, P. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1720352115 · Cited by 98
“P40, D41 MRAS (21-93) DGGVGKSALTIQFFQKIFVPDYDPTIEDSYLKHTEIDNQWAILDVLDTAGQEEFSAMREQYMRTGDGFLIVYS RRAS (37-109) G------------I-SY--SD---------T-ICSV-GIP-R--I---------G--------A-H-----FA TC21 (22-92) G------------I-SY--TD---------T-QCVI-DRA-R--I---------G--------T-E-----FS H/N/KRAS (11-83) A-----------LI-NH--DE---------R…”
BackgroundSelf-citationKiel, C., Wohlgemuth, S., Rousseau, F., Schymkowitz, J. W. H., Ferkinghoff‐Borg, J., Wittinghofer, F., & Serrano, L. (2005) · Journal of Molecular Biology · doi:10.1016/j.jmb.2005.02.046 · Cited by 102
The molecular genetics of RASopathies : An update on novel disease genes and new disorders
Tartaglia, M., Aoki, Y., & Gelb, B. D. (2022) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.32012 · Cited by 103
Ras is an indispensable coregulator of the class I B phosphoinositide 3-kinase p87/p110γ
Kurig, B., Shymanets, A., Bohnacker, T., Prajwal, P., Brock, C., Ahmadian, M. R., Schaefer, M., Gohla, A., Harteneck, C., Wymann, M. P., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0905506106 · Cited by 95
Distinct roles of class IA PI3K isoforms in primary and immortalised macrophages
Papakonstanti, E., Zwaenepoel, O., Bilancio, A., Burns, E. M., Nock, G., Houseman, B., Shokat, K., Ridley, A., & Vanhaesebroeck, B. (2008) · Journal of Cell Science · doi:10.1242/jcs.032763 · Cited by 116
“PI3Ks are considered important new pharmacological targets in inflammation and cancer (Hennessy et al., 2005; Rommel et al., 2007; Ward and Finan, 2003; Wymann et al., 2003).”
Integrated RAS signaling defined by parallel NMR detection of effectors and regulators
Smith, M. J., & Ikura, M. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1435 · Cited by 87
Sherwood, V., Recino, A., Jeffries, A. C., Ward, A., & Chalmers, A. D. (2009) · Biochemical Journal · doi:10.1042/bj20091318 · Cited by 94
Urano, J., Comiso, M. J., Guo, L., Aspuria, P.-J. P., Deniskin, R., Tabancay, A. P., Kato‐Stankiewicz, J., & Tamanoi, F. (2005) · Molecular Microbiology · doi:10.1111/j.1365-2958.2005.04877.x · Cited by 94
“GTPase assay was carried out by binding [α-32P]GTP to 4 µg of purified proteins.”
BackgroundInfluentialMiglietta, G., Cogoi, S., Marinello, J., Capranico, G., Tikhomirov, A. S., Shchekotikhin, A. E., & Xodo, L. E. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00622 · Cited by 94
Adhikari, H., & Counter, C. M. (2018) · Nature Communications · doi:10.1038/s41467-018-05692-6 · Cited by 90
Jiang, X., Chen, S., Asara, J. M., & Balk, S. P. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.085696 · Cited by 93
Hester, S., Wolf, D. C., Nesnow, S., & Thai, S. (2006) · Toxicologic Pathology · doi:10.1080/01926230601047824 · Cited by 91
“Extracellular signals that activate Ras proteins can act through different receptors such as, tyrosine kinase receptors (platelet derived growth factor receptor and epidermal growth factor receptor), cytokine receptors (IL-2, 4, 6, and 9 receptors), T-cell receptors, and subunits of heterotrimeric G proteins ( Rodrigu…”
BackgroundLock, F. E., Underhill-Day, N., Dunwell, T. L., Matallanas, D., Cooper, W. N., Hesson, L. B., Recino, A., Ward, A., Pavlova, T. V., Zabarovsky, E. R., et al. (2010) · Oncogene · doi:10.1038/onc.2010.192 · Cited by 89
RalGDS family members couple Ras to Ral signalling and that's not all
Ferro, E., & Trabalzini, L. (2010) · Cellular Signalling · doi:10.1016/j.cellsig.2010.05.010 · Cited by 87
SIRT6 regulates Ras-related protein R-Ras2 by lysine defatty-acylation
Zhang, X., Spiegelman, N. A., Nelson, O. D., Jing, H., & Lin, H. (2017) · eLife · doi:10.7554/elife.25158 · Cited by 86
“We overexpressed FLAG-tagged R-Ras2 WT and 4KR in Sirt6 WT and KO MEFs, immunoprecipitated R-Ras2 and examined p110a, one isoform of the catalytic subunit of PI3K, which has been reported to interact with R-Ras2 (Rodriguez-Viciana et al., 2004).”
MethodSiempelkamp, B. D., Rathinaswamy, M. K., Jenkins, M. L., & Burke, J. E. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.789263 · Cited by 86
“The robust activation of PI3K by HRas-coupled vesicles was unexpected, as previous reports in HEK293T cells had suggested that HRas does not lead to activation of p110 (29).”
BackgroundResultYang, Q., Lang, C., Wu, Z., Dai, Y., He, S., Guo, W., Huang, S., Du, H., Ren, D., & Peng, X. (2019) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-019-1374-x · Cited by 86
Myricetin is a potent chemopreventive phytochemical in skin carcinogenesis
Kang, N. J., Jung, S. K., Lee, K. W., & Lee, H. J. (2011) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2011.06122.x · Cited by 81
The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases
Qu, L., Pan, C., He, S., Lang, B., Gao, G.-D., Wang, X., & Wang, Y. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00121 · Cited by 84
Bolourani, P., Spiegelman, G. B., & Weeks, G. (2006) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-11-1019 · Cited by 79
The Key Role of Calmodulin in KRAS-Driven Adenocarcinomas
Nussinov, R., Muratcioğlu, S., Tsai, C., Jang, H., Gürsoy, A., & Keskin, Ö. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-15-0165 · Cited by 78
“The only knownprotein that fits this description is calmodulin (95, 102).”
BackgroundLi, W., Zhu, T., & Guan, K. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405730200 · Cited by 77
RetractedDesbuquois, B., Carré, N., & Burnol, A. (2012) · FEBS Journal · doi:10.1111/febs.12080 · Cited by 79
Nadler, Y., González, A. M., Camp, R. L., Rimm, D. L., Kluger, H. M., & Kluger, Y. (2009) · Annals of Oncology · doi:10.1093/annonc/mdp346 · Cited by 77
“The recruitment of Grb7 to protein complexes containing activated Ras proteins indicates that Grb7 expression may also modulate Ras signaling [19].”
Pauls, S. D., Lafarge, S. T., Landego, I., Zhang, T., & Marshall, A. J. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00224 · Cited by 78
“Binding of the catalytic subunit to certain Ras family GTPases at the membrane also contributes to activation (Rodriguez-Viciana et al., 1994, 2004; Jimenez et al., 2002).”
BackgroundMueller, A., Bachmann, E., Linnig, M., Khillimberger, K., Schimanski, C. C., Galle, P. R., & Moehler, M. H. (2012) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-012-1869-z · Cited by 77
“The two mutations in PI3KCA and KRAS can, however, occur together [20], whilst RAS can also cross talk to the AKT pathway by activating PI3K [13].”
BackgroundA Structure is Worth a Thousand Words: New Insights for RAS and RAF Regulation
Simanshu, D. K., & Morrison, D. K. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1494 · Cited by 70
“The RAS superfamily consists of the RAS, RHO, RAB, ARF, and RAN subfamilies, and although members of the RAS subfamily such as MRAS, RRAS, RRAS2, RAL, RHEB, RAP1, RIT, and RIN can bind RAF, they only weakly promote RAF activation (79).”
BackgroundCrystal Structure of M-Ras Reveals a GTP-bound “Off” State Conformation of Ras Family Small GTPases
Ye, M., Shima, F., Muraoka, S., Liao, J., Okamoto, H., Yamamoto, M., Tamura, A., Yagi, N., Ueki, T., & Kataoka, T. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m505503200 · Cited by 73
PI3K: 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 79
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
“In mammalian cells Ras is thought to be the exclusive small GTPase activator of RalGEFs, but in Drosophila the Rap family of Ras-related small GTPases has been implicated in RalGEF activation (Mirey et al., 2003; Rodriguez-Viciana et al., 2004).”
Depetris, R. S., Wu, J., & Hubbard, S. R. (2009) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1642 · Cited by 72
“Ras binding to Grb10 and Grb14 Previous pull-down experiments using cell lysates demonstrated that Grb7 (Grb10 and Grb14 were not tested) binds to activated Ras (N-Ras, K-Ras and H-Ras) and much more weakly to activated Rap1 and Rap2 (ref”
Mathematical Models of Specificity in Cell Signaling
Bardwell, L., Zou, X., Nie, Q. H., & Komarova, N. L. (2007) · Biophysical Journal · doi:10.1529/biophysj.106.090084 · Cited by 72
“Another type of combinatorial signaling occurs when a pathway branches into two subpathways (one that contains shared components and one that doesn’t) that are reintegrated at a point further downstream, so that the response to a given signal is determined by the combination of subpathways activated by that signal (Fi…”
BackgroundIsoprenoids and Alzheimer's disease: A complex relationship
Cole, S. L., & Vassar, R. J. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.11.007 · Cited by 71
“The Ras GTPase superfamily is composed of over a 150 members, subdivided into five major branches, namely the small Arf/Sar and Ran families, and the larger Ras, Rho and Rab GTPase families (Rodriguez-Viciana et al., 2004; reviewed in Takai et al., 2001).”
BackgroundInfluential
Metadata
- Authors
- Rodriguez-Viciana, P., Sabatier, C., & McCormick, F.
- Affiliations
- Cancer Research Institute and Comprehensive Cancer Center, University of California
- University of California, San Francisco (US)
- Corresponding author
- McCormick, Frank
- ORCID
- McCormick, Frank
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2004-06
- Volume
- 24
- Issue
- 11
- Pages
- 4943-4954
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC416418
- OpenAlex
- W2165023373
- Cited by
- 327
- References
- 81
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 16 · 2023: 5 · 2022: 7 · 2021: 12 · 2020: 5 · 2019: 8 · 2018: 18 · 2017: 10 · 2016: 12 · 2015: 12 · 2014: 13 · 2013: 22 · 2012: 24
- FWCI
- 7.36
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- Ras family GTPases, signaling specificity, effector proteins, protein-protein interaction, signaling pathways, cancer
- MeSH terms
- Humans, Substrate Specificity, Protein Structure, Tertiary, ras Proteins, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-raf, Protein Isoforms, GTP Phosphohydrolases
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