The DOI matches its Crossref record; 122 of the 122 references it cites were found in a registry or an index.
RAS oncogenes: the first 30 years
Abstract
From the pioneering work with acute transforming retroviruses to the current post-genomic era, RAS genes have always been at the leading edge of signal transduction and molecular oncology. Yet, a complete understanding of RAS function and dysfunction - mainly in human cancer - is still to come. The knowledge that has accumulated since their discovery 30 years ago has, however, been remarkable, and should pave the way for not only solving the outstanding issues regarding RAS biology, but also for developing efficacious drugs that could have a significant impact on cancer treatment.
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“On the other hand, the KRAS proteins are featureless. They have a nearly spherical structure that lacks a deep hydrophobic pocket and has no obvious binding site [20].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [20]
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“Mutational activation of Ras proteins is seen with high frequency (90%) in pancreatic ductal adenocarcinomas (2).”
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Loss of the miR-21 allele elevates the expression of its target genes and reduces tumorigenesis
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“A family of GDP-GTP exchange factors (GEFs) for the Ral small GTPases (RalGDS, for instance) represents the third family of Ras effectors (27).”
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“KRAS/MAPK Pathway KRAS is a member of the RAS/RAC family that functions to propagate growth signals via downstream effectors such as RAF and PI3K.(46) Activation of KRAS is found in subsets of both GBC and CCs with reported rates that range from 3% to 100% among patients with GBC in the setting of AJPBD.”
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“KRAS is a strong activator of mitogen-activated protein kinase (MAPK) and phosphatydilinositol-3-kinase (PI3K) pathways, which together confer oncogene addiction (5).”
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K-Ras promotes tumorigenicity through suppression of non-canonical Wnt signaling
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“Furthermore, K-Ras deficiency results in embryonic lethality, whereas N- and H-Ras knockout mice develop normally (Johnson et al., 1997; Koera et al., 1997; Malumbres and Barbacid, 2003).”
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NRAS Mutations Are Rare in Colorectal Cancer
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“The RAS proto-oncogenes (HRAS, KRAS, and NRAS) encode a family of GDP/GTP-regulated switches that convey extracellular signals to regulate the growth and survival properties of cells.(1) The 4 enzymes encoded by the 3 RAS genes are highly homologous to one another, sharing a high degree of identity over the first 90%…”
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“Once activated, Ras interacts with and activates several effectors, which, in turn, trigger a multitude of signaling pathways (30).”
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“ras is well known as an oncogene; activating mutations in ras are very frequent in human cancers and can promote a wide variety of tumors in mice (Malumbres and Barbacid 2002).”
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“Thorough reviews describing the discovery of the RAS family have been previously published [19, 22, 23].”
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“In contrast, activation of other downstream effectors of Ras, such as Akt and Ral (Malumbres and Barbacid, 2003) remained either unchanged or undetectable in colonocytes of mice of either genotype, respectively (Figures 2C and 2D).”
BackgroundThe Ras Superfamily of Small GTPases: The Unlocked Secrets
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KRAS G12C inhibition produces a driver-limited state revealing collateral dependencies
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“The most common point mutations affect codon 61 (Q61R and Q61K) and result in the expression of p21RAS oncoproteins with a single substituted amino acid that remain constitutively GTP bound and active (Malumbres and Barbacid, 2003).”
BackgroundRho GTPases in platelet function
Aslan, J. E., & McCarty, O. J. T. (2012) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.12051 · Cited by 194
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Molecular Epidemiology of the Main Druggable Genetic Alterations in Non-Small Cell Lung Cancer
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“KRAS is the most frequent oncogene in cancer [68].”
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The Transcription Factor FOXM1 (Forkhead box M1)
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“Figure 6b shows that in this putative G-tetrad NH(3) and O(4) of thymine form hydrogen bonds with O(6), NH(1) and NH2(2) of adjacent guanines, as indicated by NMR data (50).”
BackgroundZheng, Y., Xia, Y., Hawke, D. H., Hallé, M., Tremblay, M. L., Gao, X., Zhou, X. Z., Aldape, K., Cobb, M. H., Xie, K., et al. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.06.013 · Cited by 174
“The two K-Ras proteins, of which only K-Ras4B is ubiquitously expressed, are formed from alternative splicing of a single transcript differing only at the C terminus (Malumbres and Barbacid, 2003).”
BackgroundInfluentialCurrent Advances in the Treatment of BRAF-Mutant Melanoma
Patel, H. M., Yacoub, N., Mishra, R., White, A., Yuan, L., Alanazi, S., & Garrett, J. T. (2020) · Cancers · doi:10.3390/cancers12020482 · Cited by 184
“Q61 mutations in NRAS keeps it constitutively active in the ‘RAS-GTP’ state [44].”
BackgroundComputational approaches to identify functional genetic variants in cancer genomes
González-Pérez, A., López-Bigas, N., Mustonen, V., Ritchie, G. R. S., Butler, A. P., Dronov, S., Reva, B. A., Sander, C., Flicek, P., Creixell, P., et al. (2013) · Nature Methods · doi:10.1038/nmeth.2562 · Cited by 176
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“Mutations in amino acid residues 12 and 61 in H/K/N-RAS are frequently found in cancer and abolish its RAS GTPase activity, resulting in constitutive activation by keeping it in the GTP-bound active state (Malumbres and Barbacid, 2003).”
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“Extensive sequencing of human tumors has shown that KRAS is the most frequently mutated dominant oncogenic driver in human cancer, with activating mutations in one or another RAS family member being found in about 20% of human tumors (1, 2).”
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“The majority of gain-of-function mutations affect amino acid residues G12, G13, and Q61 [Der et al., 1986; Malumbres and Barbacid, 2003; Seeburg et al., 1984] (www.sanger. ac.uk/genetics/CGP/cosmic/) triggering RAS accumulation in the active, GTP-bound state by impairing intrinsic GTPase activity,…”
BackgroundOncogenic KRAS signalling promotes the Wnt/β-catenin pathway through LRP6 in colorectal cancer
Lemieux, É., Cagnol, S., Beaudry, K., Carrier, J. C., & Rivard, N. (2014) · Oncogene · doi:10.1038/onc.2014.416 · Cited by 164
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“Although NRAS, KRAS, and HRAS share structural and functional similarities, mutations in KRAS are the most frequent RAS mutations in human malignant disease; moreover, in melanoma, the most commonly mutated isoform of RAS mutation typically occur at codons 12, 61, or, less frequently, 13, with 15% of cases harboring p…”
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“Mutations affecting RTK/Ras/MAPK signaling cause many human syndromes and diseases, including cancer (Malumbres and Barbacid, 2002).”
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The improbable targeted therapy: KRAS as an emerging target in non-small cell lung cancer (NSCLC)
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“Oncogenic KRAS missense mutations result in the high-affinity binding of GTP and loss of GTPase activity, thereby leaving KRAS in an ‘‘on’’ state and deregulating various signaling pathways that rely on active RAS (Figure 2B).(16,17) More recent work suggests that another potential mechanism of oncogenic KRAS activati…”
BackgroundMLK3 is required for mitogen activation of B-Raf, ERK and cell proliferation
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Targeting cancer by binding iron: Dissecting cellular signaling pathways
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“Single amino acid mutations place RAS in a constitutively active state promoting tumor growth, angiogenesis, and metastasis (2).”
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Cancer resistance to therapies against the EGFR-RAS-RAF pathway: The role of MEK
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“MEK proteins belong to a family of enzymes that lie upstream to their specific MAPK targets in each of the four MAP kinase signalling pathways and so far 7 MEK enzymes have been identified [1,5].”
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Mutation analysis of the Ras pathway genes NRAS, HRAS, KRAS and BRAF in glioblastomas
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“proteins with GTPase activity that mediate the cellular response to external growth stimuli by signaling via different effector cascades [1, 18].”
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Self-citationHematopoiesis and leukemogenesis in mice expressing oncogenic NrasG12D from the endogenous locus
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“Histopathologic analysis of moribund C57BL/6 mice revealed a preponderance of histiocytic sarcoma, with MPD, MDS, and lymphoproliferation occurring less often.”
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“12 to 1% [138].”
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“The state of nucleotide occupancy is regulated by specific proteins named guanine nucleotides exchange factors (GEFs) and GTPases activating proteins (GAPs) (1,2).”
BackgroundThe Ras Effector RASSF2 Is a Novel Tumor-Suppressor Gene in Human Colorectal Cancer
Akino, K., Toyota, M., Suzuki, H., Mita, H., Sasaki, Y., Ohe-Toyota, M., Issa, J. J., Hinoda, Y., Imai, K., & Tokino, T. (2005) · Gastroenterology · doi:10.1053/j.gastro.2005.03.051 · Cited by 148
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“5,6 In 2009, RNAi experiments revealed that lowering mRNA levels of a transcript encoding the serine/threonine kinase STK33 was selectively toxic to KRAS-dependent cancer cell lines, suggesting that small-molecule inhibitors of STK33 might selectively target KRAS-dependent cancers.”
Human β-Cell Proliferation and Intracellular Signaling: Part 3
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“Typically, binding of a ligand to the relevant tyrosine kinase or GPCR activates the small GTPase, Ras, leading to the formation of Ras-GTP (40,41) (Fig.”
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KRAS Mutation in Colon Cancer: A Marker of Resistance to EGFR-I Therapy
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“The KRAS oncogene encodes the human cellular homolog of the transforming gene Kirsten rat sarcoma-2 virus.(11) The K-ras protein is a self-inactivating signal transducer.”
BackgroundMolecular Pathogenesis of Ovarian Borderline Tumors: New Insights and Old Challenges
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RASSF6 is a novel member of the RASSF family of tumor suppressors
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“Inappropriate activation of Ras proteins promotes a variety of protumorigenic phenotypes including enhanced growth, loss of contact inhibition, reduced requirement for growth factors, enhanced motility and invasion and resistance to apoptosis (Malumbres and Barbacid, 2003).”
ABHD17 regulation of plasma membrane palmitoylation and N-Ras-dependent cancer growth
Remsberg, J. R., Suciu, R. M., Zambetti, N. A., Hanigan, T. W., Firestone, A. J., Sheth, A. I., Long, A. M., Ngo, N., Lum, K. M., Henry, C. L., et al. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00785-8 · Cited by 144
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Frequent alterations of Ras signaling pathway genes in sporadic malignant melanomas
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“In contrast, mice with HRAS or NRAS knockouts are completely viable without any obvious phenotypes [3].”
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“first 85 amino acids of all Ras isoforms being identical and their encompassing the site of interaction with all known Ras effectors (Malumbres and Barbacid, 2002).”
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“Indeed, activating RAS mutations (occurring most often in KRAS, followed by NRAS) are the most common oncogenic mutations observed thus far in human cancer [4].”
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“marrow/peripheral blood, and absence of the t(9;22) BCR-ABL translocation.”
BackgroundRegulation of chemotaxis by the orchestrated activation of Ras, PI3K, and TOR
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“The mammalian Ras family comprises H-Ras, N-Ras, and K-Ras, which are frequently mutated in human cancer and leukemia (Giehl, 2005; Malumbres and Barbacid, 2003; Repasky et al., 2004).”
BackgroundSprouty-2 regulates oncogenic K-ras in lung development and tumorigenesis
Shaw, A. T., Meissner, A., Dowdle, J. A., Crowley, D., Magendantz, M., Ouyang, C., Parisi, T., Rajagopal, J., Blank, L. J., Bronson, R. T., et al. (2007) · Genes & Development · doi:10.1101/gad.1526207 · Cited by 131
“In addition to the canonical Ras effectors—Raf, PI3K, and RalGDS—at least seven other distinct Ras effector pathways have Shaw et al. 702 GENES & DEVELOPMENT been defined (Malumbres and Barbacid 2003).”
Background
Metadata
- Authors
- Malumbres, M., & Barbacid, M.
- Affiliations
- Spanish National Cancer Research Centre (ES)
- Corresponding author
- Malumbres, Marcos
- Barbacid, Mariano
- Venue
- Nature Reviews Cancer
- Published
- 2003-06-01
- Volume
- 3
- Issue
- 6
- Pages
- 459-465
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- OpenAlex
- W2083695927
- Cited by
- 1,902
- References
- 122
- Citations by year
- 2026: 39 · 2025: 77 · 2024: 94 · 2023: 84 · 2022: 89 · 2021: 78 · 2020: 68 · 2019: 74 · 2018: 80 · 2017: 99 · 2016: 91 · 2015: 98 · 2014: 117 · 2013: 120 · 2012: 104
- FWCI
- 3.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature reviews. Cancer (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 › Melanoma and MAPK Pathways
- Keywords
- oncogenic Ras, signal transduction, molecular oncology, RAS inhibitors, cancer therapy
- MeSH terms
- Animals, Humans, Genes, ras, Biomedical Research, History, 20th Century, History, 21st Century
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