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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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Citations
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Items 101–200 of 327
The RAS-Effector Interface: Isoform-Specific Differences in the Effector Binding Regions
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“Integrins also induce PI3K activity, which at least for β1-integrins occurs through p110α [89,90]. p110α and p110γ can interact with several RAS proteins, including H-, N-, K-, R-RAS and TC21, while p110δ interacts with R-RAS and TC21 [91].”
BackgroundMechanisms of Ras membrane organization and signaling: Ras on a rocker
Abankwa, D., Gorfe, A. A., & Hancock, J. F. (2008) · Cell Cycle · doi:10.4161/cc.7.17.6596 · Cited by 70
Cai, W., Rudolph, J. L., Harrison, S. M. W., Jin, L., Frantz, A. L., Harrison, D. A., & Andres, D. (2011) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-05-0400 · Cited by 70
“A number of Ras subfamily GTPases are known to direct PI3-kinase-dependent Akt activation (Rodriguez-Viciana et al., 2004; Yuan and Cantley, 2008), with Akt in turn controlling the balance between survival and apoptosis (Engelman et al., 2006).”
BackgroundTwo conformational states of Ras GTPase exhibit differential GTP-binding kinetics
Liao, J., Shima, F., Araki, M., Ye, M., Muraoka, S., Sugimoto, T., Kawamura, M., Yamamoto, N., Tamura, A., & Kataoka, T. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.01.169 · Cited by 68
Imaging Activation of Two Ras Isoforms Simultaneously in a Single Cell
Lorentzen, A., Rocks, O., & Bastiaens, P. I. H. (2005) · ChemBioChem · doi:10.1002/cbic.200400280 · Cited by 68
Death pathways triggered by activated Ras in cancer cells
Jean, H. O. (2010) · Frontiers in bioscience · doi:10.2741/3814 · Cited by 68
“Of the four newer members of the RASSF family, RASSF7-10 (167), only RASSF9 has been shown to bind to Ras proteins (168).”
BackgroundInput from Ras is required for maximal PI(3)K signalling in Drosophila
Orme, M. H., Alrubaie, S., Bradley, G. L., Walker, C. D., & Leevers, S. J. (2006) · Nature Cell Biology · doi:10.1038/ncb1493 · Cited by 74
“In vitro lipid kinase assays showed that Myc–Dp110RBD, Myc–Dp110 and endogenous Dp110 immunoprecipitated from control flies possessed similar intrinsic lipid kinase activity towards phosphatidylinositide, PtdIns(4)P and PtdIns(4,5)P2 (Fig.”
BackgroundInfluentialColorectal cancer and RASSF family—A special emphasis on RASSF1A
Fernandes, M. S., Carneiro, F., Oliveíra, C., & Seruca, R. (2012) · International Journal of Cancer · doi:10.1002/ijc.27696 · Cited by 66
Chu, P.-Y., Huang, L.-Y., Hsu, C., Liang, C.-C., Guan, J., Hung, T., & Shen, T. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.018259 · Cited by 66
PREL1 provides a link from Ras signalling to the actin cytoskeleton via Ena/VASP proteins
Jenzora, A., Behrendt, B., Small, J. V., Wehland, J., & Stradal, T. E. B. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.10.110 · Cited by 66
“PREL1, which includes the RA but not the PH domain, was reported to bind to Ras in pull-down assays [56].”
BackgroundVigil, 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 67
Underhill-Day, N., Hill, V. K., & Latif, F. (2011) · Epigenetics · doi:10.4161/epi.6.3.14108 · Cited by 64
Taming the PI3K team to hold inflammation and cancer at bay
Hirsch, E., Ciraolo, E., Ghigo, A., & Costa, C. (2008) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2008.02.004 · Cited by 63
“There is also strong evidence that Ras plays a key role in activating PI3Kα and PI3Kδ, but not PI3Kβ (Rodriguez-Viciana et al., 2004).”
BackgroundProtein Prenylation and Synaptic Plasticity: Implications for Alzheimer’s Disease
Hottman, D. A., & Li, L. (2014) · Molecular Neurobiology · doi:10.1007/s12035-013-8627-z · Cited by 65
“The Ras GTPase superfamily consists of over 150 known members, divided between five major subfamilies: Ras, Rho, Rab, Arf/Sar, and Ran [15].”
BackgroundRas Is Required for the Cyclic AMP-Dependent Activation of Rap1 via Epac2
Liu, C., Takahashi, M., Li, Y., Song, S., Dillon, T. J., Shinde, U. P., & Stork, P. A. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01060-08 · Cited by 62
“The mechanism by which Epac2 permits Ras to activate Rap1 may be shared by other GEFs that contain functional RA domains (42).”
BackgroundThe Hypervariable Region of K-Ras4B Is Responsible for Its Specific Interactions with Calmodulin
Abraham, S. J., Nolet, R., Calvert, R. J., Anderson, L. M., & Gaponenko, V. (2009) · Biochemistry · doi:10.1021/bi900769j · Cited by 61
“In fact, CaM is the only protein found thus far to bind to K-Ras4B uniquely; the many other known binding partners interact with all four isoforms(12).”
BackgroundMethodHill, V. K., Underhill-Day, N., Krex, D., Robel, K., Sangan, C. B., Summersgill, H. R., Morris, M. R., Gentle, D., Chalmers, A. D., Maher, E. R., et al. (2010) · Oncogene · doi:10.1038/onc.2010.471 · Cited by 61
“RASSF9 has been shown to bind to RAS proteins and is involved in vesicle trafficking (Chen et al., 1998; Rodriguez-Viciana et al., 2004).”
BackgroundOceandy, D., Pickard, A., Prehar, S., Zi, M., Mohamed, T., Stanley, P. J., Baudoin, F., Nadif, R., Tommasi, S., Pfeifer, G. P., et al. (2009) · Circulation · doi:10.1161/circulationaha.109.868554 · Cited by 61
Thatikonda, V., Lyu, H., Jurado, S., Kostyrko, K., Bristow, C. A., Albrecht, C., Alpar, D., Arnhof, H., Bergner, O., Bosch, K., et al. (2024) · Nature Cancer · doi:10.1038/s43018-024-00800-6 · Cited by 76
“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 SOS 38,50,51 , it also uniquely associates with SHOC2 and PPI1C 40 as well as certain RapGEFs 52,53 .”
Interactions of Ras proteins with the plasma membrane and their roles in signaling
Eisenberg, S., & Henis, Y. I. (2007) · Cellular Signalling · doi:10.1016/j.cellsig.2007.07.012 · Cited by 63
Targeting the PI3K Pathway for Cancer Therapy
Sadeghi, N., & Gerber, D. E. (2012) · Future Medicinal Chemistry · doi:10.4155/fmc.12.56 · Cited by 59
“All p110 isoforms contain a Rasbinding domain, which facilitates activation of the catalytic subunit [25–28], although the role of Ras in activation of p110β is controversial [27,29,30].”
BackgroundRodriguez, N., Yang, J., Hasselblatt, K. T., Liu, S., Zhou, Y., Rauh‐Hain, J. A., Ng, S., Choi, P., Fong, W., Agar, N. Y. R., et al. (2012) · EMBO Molecular Medicine · doi:10.1002/emmm.201101094 · Cited by 60
“Characterization of the resulted cell lines was performed as described in Supporting Information Materials and methods.”
R-Ras Regulates Exocytosis by Rgl2/Rlf-mediated Activation of RalA on Endosomes
Takaya, A., Kamio, T., Masuda, M., Mochizuki, N., Sawa, H., Sato, M., Nagashima, K., Mizutani, A., Matsuno, A., Kiyokawa, E., et al. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-08-0765 · Cited by 59
“For example, R-Ras preferentially activates Ral GEFs and PI3K, but it does not activate Raf (Huff et al., 1997; Rodriguez-Viciana et al., 2004).”
BackgroundThe Role of R-Ras Proteins in Normal and Pathologic Migration and Morphologic Change
Weber, S. M., & Carroll, S. L. (2021) · American Journal Of Pathology · doi:10.1016/j.ajpath.2021.05.008 · Cited by 60
“It has also been suggested that M-Ras cooperates with proteins in the classic Ras subfamily to activate the mitogen-activated protein kinase (MAPK) signaling pathway, thereby promoting proliferation and transformation of cells.(2,8,17) R-Ras2, like classic Ras proteins, can strongly activate extracellular signal-regul…”
BackgroundRap1 and Rap2 Antagonistically Control Endothelial Barrier Resistance
Pannekoek, W., Linnemann, J. R., Brouwer, P. M., Bos, J. L., & Rehmann, H. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057903 · Cited by 58
“In this context it is interesting to notice that RapGEFs regulating endothelial junctions, PDZGEF and Epac1, are activating Rap1 and Rap2 [27–29] and that many effectors of Rap1 interact with Rap2 as well [42].”
BackgroundRegulatory subunits of class IA PI3K.
Fruman, D. (2010) · Current Topics in Microbiology and Immunology · doi:10.1007/82_2010_39 · Cited by 69
MRAS: A Close but Understudied Member of the RAS Family
Young, L. C., & Rodriguez-Viciana, P. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a033621 · Cited by 53
Self-citationPAQR10 and PAQR11 mediate Ras signaling in the Golgi apparatus
Jin, T., Ding, Q., Huang, H., Xu, D., Jiang, Y., Zhou, B. Z., Li, Z., Jiang, X., He, J., Liu, W., et al. (2011) · Cell Research · doi:10.1038/cr.2011.161 · Cited by 53
Regulator of G-Protein Signaling 14 (RGS14) Is a Selective H-Ras Effector
Willard, F. S., Willard, M. D., Kimple, A. J., Soundararajan, M., Oestreich, E. A., Li, X., Sowa, N. A., Kimple, R. J., Doyle, D., Der, C. J., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004884 · Cited by 51
“As other Ras family members can interact with RBD-containing proteins [32,33], we conducted a broader analysis of RGS14 selectivity for Ras family GTPases, initially in this in vitro setting with recombinant RGS14 protein.”
BackgroundMolecular Targets for Tumor Radiosensitization
Tofilon, P. J., & Camphausen, K. A. (2009) · Chemical Reviews · doi:10.1021/cr800504x · Cited by 51
Chu, P.-Y., Li, T., Ding, S., Lai, I., & Shen, T. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.c110.114124 · Cited by 51
Shahrzad, S., Quayle, L., Stone, C., Plumb, C., Shirasawa, S., Rak, J. W., & Coomber, B. L. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-0713 · Cited by 51
“It is also understood that in normal cells, this signaling network contains several self-inhibitory feedback mechanisms that prevent protracted and unscheduled activation ( 4 ).”
BackgroundEndris, V., Haußmann, L., Buss, E., Bacon, C., Bartsch, D., & Rappold, G. (2011) · Journal of Cell Science · doi:10.1242/jcs.077081 · Cited by 49
“RodriguezViciana and colleagues reported on the interaction of the lamellipodin RA domain with activated forms of K-Ras, NRas, H-Ras and R-Ras3 using pull-down assays, whereas Krause and co-workers failed to replicate this finding using yeast twohybrid analyses and in vitro assays using purified proteins (Rodriguez-Vi…”
BackgroundOberst, M. D., Beberman, S. J., Liu, Z., Yin, J. J., Ward, Y., & Kelly, K. (2008) · BMC Cancer · doi:10.1186/1471-2407-8-189 · Cited by 50
“The most highly characterized of these are the Raf proteins, PI3K, and the Ral guanidine nucleotide exchange factors (RalGEFs), although Ras does recruit and activate other potentially transforming effectors [11].”
BackgroundRIG1 inhibits the Ras/mitogen-activated protein kinase pathway by suppressing the activation of Ras
Tsai, F., Shyu, R., & Jiang, S. (2005) · Cellular Signalling · doi:10.1016/j.cellsig.2005.05.005 · Cited by 50
Liao, J., Planchon, S. M., Wolfman, J. C., & Wolfman, A. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m600668200 · Cited by 48
“The only Ras binding partner that fits this description is CaM (20,31).”
BackgroundInfluentialLyulcheva, E., Taylor, E., Michael, M., Vehlow, A., Tan, S., Fletcher, A., Krause, M., & Bennett, D. (2008) · Developmental Cell · doi:10.1016/j.devcel.2008.09.020 · Cited by 48
“Second, we used an established cell culture system (Sotiropoulos et al., 1999) to analyze the effect of MRL proteins on SRF activity.”
BackgroundMethodLi, H., & Gorfe, A. A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0071018 · Cited by 46
“Ras proteins are membrane-associated enzymes that mediate a variety of signal transduction pathways [1,2,3,4,5].”
BackgroundGordon, M., & Baksh, S. (2011) · Small GTPases · doi:10.4161/sgtp.2.3.16286 · Cited by 47
Nussinov, R., Zhang, M., Tsai, C., Liao, T.-J., Fushman, D., & Jang, H. (2018) · Biophysical Reviews · doi:10.1007/s12551-018-0461-0 · Cited by 47
“Mutations may also differentially affect Ras target activation (Hamad et al. 2002; Nussinov et al. 2015b; Rodriguez-Viciana et al. 2004; Rodriguez-Viciana et al. 1997; Vandal et al. 2014).”
BackgroundIborra, S., Soto, M., Aroeira, L. S., Castellano, E., Alarcón, B., Alonso, C., Santos, E., & Fernández-Malavé, E. (2011) · Blood · doi:10.1182/blood-2010-10-315770 · Cited by 46
Targeting the RAS upstream and downstream signaling pathway for cancer treatment
Hossain, M. A. (2024) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2024.176727 · Cited by 51
Phosphatidylinositol‐3,4,5‐trisphosphate: Tool of choice for class I PI 3‐kinases
Salamon, R. S., & Backer, J. (2013) · BioEssays · doi:10.1002/bies.201200176 · Cited by 51
“One study did evaluate the effects of distinct Ras isoforms on the four p110 catalytic subunits in cells; p110a, p110d, and p110g were activated by Ras, but only p110d showed selectivity (for the Ras homologs R-Ras and TC21) [90].”
BackgroundA requirement for wild-type Ras isoforms in mutant KRas-driven signalling and transformation
Bentley, C., Jurinka, S. S., Kljavin, N. M., Vartanian, S., Ramani, S. R., Gonzalez, L. C., Yu, K., Modrusan, Z. D., Du, P., Bourgon, R., et al. (2013) · Biochemical Journal · doi:10.1042/bj20121578 · Cited by 45
Miertzschke, M., Stanley, P., Bunney, T. D., Rodrigues‐Lima, F., Hogg, N., & Katan, M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704361200 · Cited by 43
Yaman, E., Gasper, R., Koerner, C., Wittinghofer, A., & Tazebay, U. H. (2009) · FEBS Journal · doi:10.1111/j.1742-4658.2009.07166.x · Cited by 42
Nussinov, R., Tsai, C., Muratcioğlu, S., Jang, H., Gürsoy, A., & Keskin, Ö. (2015) · Expert Review of Proteomics · doi:10.1586/14789450.2015.1100079 · Cited by 42
“[17] As examples, K-Ras was proposed as the only mutant capable of interacting with the p110α subunit of PI3K [147] (variant behavior was observed for K-Ras [148,149]).”
InfluentialKilloran, R. C., & Smith, M. J. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.008653 · Cited by 41
“In the active state, GTPases bind directly to downstream effector proteins via specialized recognition domains, predominantly RAS-binding domains (RBDs) for RAS GTPases and CRIB motifs for RHO GTPases (5, 6).”
BackgroundRole of Ena/VASP Proteins in Homeostasis and Disease
Pula, G., & Krause, M. (2008) · Handbook of experimental pharmacology · doi:10.1007/978-3-540-72843-6_3 · Cited by 41
“Lpd interacts with active Ras, whereas RIAM preferentially binds to active Rap1 (Krause et al. 2004; Lafuente et al. 2004; Rodriguez-Viciana et al. 2004).”
BackgroundWang, T., Liu, H., Chen, Y., Liu, W., Yu, J., & Wu, G. (2009) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/1756-9966-28-160 · Cited by 41
“RASSF1A is a pro-apoptosis protein that has a potential Ras association (RA) domain, which makes the RASSF1A has the theoretical potential to bind to Ras directly in vitro, and form a complex with activated K-Ras when overexpressed in cells[31,32].”
BackgroundPeng, W., Zhi-yin, S., Zhang, Q., Cheng, S.-Q., Wang, S., Wang, X., Kuang, G., Su, X., Tan, J., Huang, Z., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00257 · Cited by 40
O’Keefe, D. D., Prober, D. A., Moyle, P. S., Rickoll, W. L., & Edgar, B. A. (2007) · Developmental Biology · doi:10.1016/j.ydbio.2007.08.003 · Cited by 40
“While the specificities of the activated Ras isoforms are not absolute (Rodriguez-Viciana et al., 2004), we found that the Raf/MAPKspecific, activated form of Ras (Ras) promoted vein cell identity and the sub-apical localization of Shg (Fig.”
BackgroundVasjari, L., Bresan, S., Biskup, C. U., Pai, G. M., & Rubio, I. (2018) · Cell Cycle · doi:10.1080/15384101.2018.1560205 · Cited by 38
“[42] Rodriguez-Viciana P, Sabatier C, McCormick F.”
BackgroundA Novel Role of RASSF9 in Maintaining Epidermal Homeostasis
Lee, C.-M., Yang, P., Chen, L., Chen, C., Wu, S., Cheng, H.-Y., & Chang, Y. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017867 · Cited by 38
“RASSF9 has been reported to associate with Ras proteins [7].”
BackgroundInfluentialR-Ras controls axon branching through afadin in cortical neurons
Iwasawa, N., Negishi, M., & Oinuma, I. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e12-02-0103 · Cited by 38
“RA domains were found in various Ras effectors such as Raf-1 and PI3K, and Ras-family GTPases have been implicated as an upstream regulator of afadin (Rodriguez-Viciana et al., 2004).”
BackgroundA BAT-Centric Approach to the Treatment of Diabetes: Turn on the Brain
Hankir, M. K., Cowley, M. A., & Fenske, W. K. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.003 · Cited by 39
“It has been shown in HEK cells that the downstream target of Epac1, the Ras GTPase Rap1, increases the catalytic activity of the p110-a subunit of PI3K (possibly through a Raf kinase) (Rodriguez-Viciana et al., 2004).”
BackgroundYu, C.-C., Qiu, W., Juang, C. S., MANSUKHANI, M. M., Halmos, B., & Su, G. H. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.10.013 · Cited by 38
“KRAS is a member of the Ras family GTPases that regulates cell growth, differentiation, and survival [35].”
BackgroundOverexpression of wild type RRAS2, without oncogenic mutations, drives chronic lymphocytic leukemia
Hortal, A. M., Oeste, C. L., Cifuentes, C., Alcoceba, M., Fernández‐Pisonero, I., Clavaín, L., Tercero, R., Mendoza, P., Domínguez, V., García‐Flores, M., et al. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01496-x · Cited by 38
“This upregulation of the pathway was somewhat expected, given the ability of R-RAS2 to recruit the catalytic subunit of PI3Kδ and activate the PI3K pathway in normal B cells [50, 51].”
BackgroundThe MRL proteins: Adapting cell adhesion, migration and growth
Coló, G. P., Lafuente, E. M., & Teixidó, J. (2012) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2012.03.001 · Cited by 37
“Using pull-down ssays, a short variant of Lpd was reported to bind active K-Ras, -Ras, H-Ras or R-Ras (Rodriguez-Viciana et al., 2004).”
BackgroundWatanabe‐Takano, H., Takano, K., Keduka, E., & Endo, T. (2009) · Experimental Cell Research · doi:10.1016/j.yexcr.2009.09.028 · Cited by 37
Keller, J. W., Franklin, J. L., Graves‐Deal, R., Friedman, D. B., Whitwell, C. W., & Coffey, R. J. (2006) · Journal of Cellular Physiology · doi:10.1002/jcp.20898 · Cited by 36
Kaul, A., Overmeyer, J. H., & Maltese, W. A. (2006) · Cellular Signalling · doi:10.1016/j.cellsig.2006.11.010 · Cited by 37
“Many additional Ras effectors have now been identified [66].”
BackgroundR-RAS2 overexpression in tumors of the human central nervous system
Gutierrez‐Erlandsson, S., Herrero-Vidal, P., Fernández‐Alfara, M., Hernández-García, S., Gonzalo-Flores, S., Mudarra-Rubio, A., Fresno, M., & Cubelos, B. (2013) · Molecular Cancer · doi:10.1186/1476-4598-12-127 · Cited by 38
“The switch I and II effector domains of R-RAS2 are identical to those of classical RAS [3], indicating that RRAS2 may also act in the pathways activated by classical RAS [14].”
BackgroundA 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
Czyzyk, D. J., Yan, W., Messing, S. A. J., Gillette, W., Tsuji, T., Yamaguchi, M., Furuzono, S., Turner, D. M., Esposito, D., Nissley, D. V., et al. (2025) · Nature Communications · doi:10.1038/s41467-024-55766-x · Cited by 37
“Previous studies have suggested that RAS proteins bind and activate p110 α , p110 γ , and p110 δ , whereas p110 β is activated by RAC1 and CDC42 from the RHO family 1,9,23 .”
InfluentialSelf-citationCooperation between Noncanonical Ras Network Mutations
Stites, E. C., Trampont, P. C., Haney, L. B., Walk, S. F., & Ravichandran, K. S. (2015) · Cell Reports · doi:10.1016/j.celrep.2014.12.035 · Cited by 35
“The level of effector bound to RasGTP is less easily measured directly, in part because of the large number of proteins with a Ras binding domain that bind to the Ras proteins (Rodriguez-Viciana et al., 2004).”
BackgroundComparative analysis of interactions of RASSF1-10
Chan, J. J., Flatters, D., Rodrigues‐Lima, F., Yan, J., Thalassinos, K., & Katan, M. (2013) · Advances in Biological Regulation · doi:10.1016/j.jbior.2012.12.001 · Cited by 35
“Information regarding the RA domain for the N-terminal RASSFs is even scarcer, with only two reports of Ras binding by RASSF7 and RASSF9 (Rodriguez-Viciana et al., 2004; Takahashi et al., 2011).”
BackgroundResultInfluentialPhosphatidylinositol 3-Kinase Isoforms as Novel Drug Targets
Błajecka, K., Borgström, A., & Arcaro, A. (2011) · Current Drug Targets · doi:10.2174/138945011795677773 · Cited by 34
“Ras has also been shown to play a role in activating p110α and p110δ [36].”
BackgroundInactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation
Sung, H., Kanchi, K., Wang, X., Hill, K. S., Messina, J. L., Lee, J., Kim, Y., Dees, N. D., Ding, L., Teer, J. K., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.8127 · Cited by 34
“Although R-Ras shares approximately 55% sequence identity with H-Ras, R-Ras is shown to preferentially activate PI3K and RalGEF, not RAF1 [33], suggesting isoform-specific functions.”
BackgroundAdapter protein connections: The MRL and Grb7 protein families
Holt, L. J., & Daly, R. J. (2005) · Growth Factors · doi:10.1080/08977190500196267 · Cited by 33
“A role for RIAM downstream of Ras GTPases is supported by a study utilizing pulldowns of GST-tagged active GTPases from cells (Rodriguez-Viciana et al. 2004).”
BackgroundMethodInfluentialMendoza, P., Martínez, N., Bovolenta, E. R., Reyes-Garau, D., Hernansanz‐Agustín, P., Delgado, P., Díaz‐Muñoz, M. D., Oeste, C. L., Fernández‐Pisonero, I., Castellano, E., et al. (2018) · Science Signaling · doi:10.1126/scisignal.aal1506 · Cited by 32
“This functional specialization of R-Ras2 is especially critical for hematopoietic cells, because R-Ras2, but not classical Ras proteins, interacts with and activates the p110 catalytic subunit of PI3K (55).”
BackgroundFunctional 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 33
Antigen and cytokine receptor signals guide the development of the naïve mature B cell repertoire
Rowland, S. L., Tuttle, K. D., Torres, R. M., & Pelanda, R. (2012) · Immunologic Research · doi:10.1007/s12026-012-8366-7 · Cited by 31
“Thus, it remains possible that Ras mediates the differentiation of immature B cells into transitional and mature B cells by activating the PI3K pathway as well, a possibility that remains to be explored.”
InfluentialBBO-10203 inhibits tumor growth without inducing hyperglycemia by blocking RAS-PI3Kα interaction.
Simanshu, D., Xu, R., Stice, J., Czyzyk, D., Feng, S.-Y., Denson, J., Riegler, E., Yang, Y., Zhang, C., Donovan, S., et al. (2025) · Science · doi:10.1126/science.adq2004 · Cited by 34
Self-citationRomano, D., Maccario, H., Doherty, C., Quinn, N. P., Kölch, W., & Matallanas, D. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01414-12 · Cited by 31
“For instance, it has been reported that RASSF1A binds preferentially to H-Ras (27, 28) or K-Ras (10).”
BackgroundRodriguez‐Viciana, P., & McCormick, F. P. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.02.012 · Cited by 30
Self-citationBolourani, P., Spiegelman, G. B., & Weeks, G. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m707459200 · Cited by 29
Choose your own path: specificity in Ras GTPasesignaling
Goldfinger, L. E. (2008) · Molecular BioSystems · doi:10.1039/b716887j · Cited by 28
Rassf3 is responsible in part for resistance to mammary tumor development in neu transgenic mice
Chen (1992) · International Journal of Oncology · doi:10.3892/ijo_00000177 · Cited by 28
Han, Y., Yu, C.-C., Fine, S. A., Youssof, A. L., Yang, Y., Yan, J., Karg, D. C., Cheung, E. C., Friedman, R. A., Ying, H., et al. (2021) · Oncogene · doi:10.1038/s41388-021-02040-9 · Cited by 28
“Alternating between the GDPbound and GTP-bound form, it regulates diverse phenotypes such as proliferation, differentiation, senescence, and apoptosis [5].”
BackgroundCuevas-Navarro, A., Wagner, M. E., Van, R., Swain, M., Mo, S., Columbus, J., Allison, M. R., Cheng, A. S., Messing, S. A. J., Turbyville, T. J., et al. (2023) · Science Advances · doi:10.1126/sciadv.adf4766 · Cited by 29
“In certain cell contexts, LZTR1 promotes the degradation of other RAS family GTPases, most notably MRAS (13, 51), and its loss may enhance MRAS-mediated RAF activation in synergy with mutant RIT1 expression (52).”
BackgroundInfluentialSelf-citationSpecific Conformational States of Ras GTPase upon Effector Binding
Baussand, J., & Kleinjung, J. (2012) · Journal of Chemical Theory and Computation · doi:10.1021/ct3007265 · Cited by 28
The RAS GTPase RIT1 compromises mitotic fidelity through spindle assembly checkpoint suppression
Cuevas-Navarro, A., Van, R., Cheng, A. S., Urisman, A., Castel, P., & McCormick, F. P. (2021) · Current Biology · doi:10.1016/j.cub.2021.06.030 · Cited by 30
Self-citationWurtzel, J. G. T., Kumar, P., & Goldfinger, L. E. (2012) · Small GTPases · doi:10.4161/sgtp.21084 · Cited by 27
Classical RAS proteins are not essential for paradoxical ERK activation induced by RAF inhibitors
Lai, L., Fer, N. D., Burgan, W. E., Wall, V. E., Xu, B., Soppet, D. R., Esposito, D., Nissley, D. V., & McCormick, F. P. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2113491119 · Cited by 22
Self-citationBao, H., Wang, W., Sun, H., & Chen, J. (2023) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2023.2195995 · Cited by 27
“Despite its weak interactions with some of the RAS effectors, M-RAS leads to weak activation of the downstream cascades 34,35 .”
BackgroundCalcium Around the Golgi Apparatus: Implications for Intracellular Membrane Trafficking
Micaroni, M. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-94-007-2888-2_18 · Cited by 29
Zhang, H., Chang, Y.-C., Brennan, M. L., & Wu, J. (2013) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjt044 · Cited by 26
“In contrast, RIAM binds to Rap1 specifically and shows little effect in signaling pathways of other Ras superfamily GTPases (Lafuente et al., 2004; Rodriguez-Viciana et al., 2004).”
BackgroundTumor Suppressor RASSF1A Promoter: p53 Binding and Methylation
Tian, Y., Hou, Y., Zhou, X., Cheng, H., & Zhou, R. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017017 · Cited by 25
“When bound to GTP, activated RAS regulates cellular responses through RAS effector proteins and their complex signal transduction cascades, such as those mediated by the Raf serine/threonine kinases, PI3-K and RASSF1A [21,22].”
BackgroundRudolph, J. L., Shi, G., Erdogan, E., Fields, A. P., & Andres, D. (2007) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2007.09.008 · Cited by 25
“Determining the identity of effector protein targets and understanding how their activation leads to alterations in cellular function are important goals in Ras-mediated signal transduction [7–10].”
BackgroundMichael, J. V., Wurtzel, J. G. T., & Goldfinger, L. E. (2016) · Oncogenesis · doi:10.1038/oncsis.2016.36 · Cited by 25
Gong, W., Liu, Y., Zhang, X., & Ma, H. (2012) · Computer Modeling in Engineering & Sciences · doi:10.3970/cmes.2012.083.527 · Cited by 25
Gates, A. Y., Hohenester, S., Anwer, M., & Webster, C. R. (2009) · American Journal of Physiology - Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.90622.2008 · Cited by 26
“The EGFR can activate PI3K via two mechanisms: 1) by binding and activating the p85 regulatory subunit, which in turn could activates the p110 or subunit, and 2) by activating Ras, which has been linked only to activation of the p110 subunit (50).”
BackgroundRASSF9 promotes NSCLC cell proliferation by activating the MEK/ERK axis
Yuan, J. J., Ju, Q., Zhu, J., Jiang, Y., Yang, X., Liu, X., Ma, J., Sun, C., & Shi, J. (2021) · Cell Death Discovery · doi:10.1038/s41420-021-00583-0 · Cited by 24
“RASSF9, a member of the N-terminal RASSF protein, has been shown to bind to Ras protein The RASSF9 and RAS family GTPases pull-down experiments indicate that RASSF9 binds to N-Ras, K-Ras, and R-Ras [34].”
BackgroundCastro, A. F., Campos, T., Babcock, J. T., Armijo, M. E., Martínez‐Conde, A., Pincheira, R., & Quilliam, L. A. (2012) · Journal of Cellular Biochemistry · doi:10.1002/jcb.23458 · Cited by 22
“…several RalGDS family members, a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) [Quilliam et al., 1999; Ehrhardt et al., 2001; Rodriguez-Viciana et al., 2004, 2006], and to uniquely associate with certain Rap GEFs [Rebhun et al., 2000; Gao et al., 2001].”
BackgroundChang, Y.-C., Zhang, H., Brennan, M. L., & Wu, J. (2013) · Protein & Cell · doi:10.1007/s13238-013-2082-5 · Cited by 23
“Binding affi nity of the RA domain in the integrated RA-PH unit to Ras GTPase is weaker compared to that of other independent Ras binding domains (Nassar et al., 1996; Huang et al., 1998; Rodriguez-Viciana et al., 2004).”
ResultWong, K. A., Russo, A., Wang, X., Chen, Y.-J., Lavie, A., & O’Bryan, J. P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045360 · Cited by 23
“Interestingly, a group of these domains including Myr5, Tiam-1, Rain, and PLCe do not bind nucleotide-loaded Ras raising the question of whether additional RBDs may share a similar activity in binding nucleotide-free Ras [41,42,43].”
BackgroundSilver, L. D., Michael, J. V., Goldfinger, L. E., & Gallo, G. (2014) · Developmental Neurobiology · doi:10.1002/dneu.22174 · Cited by 23
“NGF activates multiple pathways, including R-Ras signaling which in turn is a potent driver of PI3K activity (Marte et al., 1997; Rodriguez-Viciana et al., 2004; Iwashita et al., 2007).”
BackgroundTsunoda, T., Ishikura, S., Doi, K., Iwaihara, Y., Hidesima, H., Luo, H., Hirose, Y., & Shirasawa, S. (2015) · PubMed · Cited by 24
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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