A hotspot mutation targeting the R-RAS2 GTPase acts as a potent oncogenic driver in a wide spectrum of tumors

Fernández‐Pisonero, Isabel; Clavaín, Laura; Robles‐Valero, Javier; Lorenzo‐Martín, L. Francisco; Caloto, Rubén; Nieto, Blanca; García-Macías, Carmen; Sánchez-Martı́n, Manuel; Abad, Antonio; Hortal, Alejandro M.; Caballero, Dolores; González, Marcos; Dosil, Mercedes; Alarcón, Balbino; Bustelo, Xosé R.

doi:10.1016/j.celrep.2022.110522

Cited by 10 publications

(23 citation statements)

References 59 publications

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“…Some RRAS2 gain-of-function mutations found in tumors are oncogenic The Q72L, G23V and Dup24-26 RRAS2 mutations, analogous to the Q61L, G12V and Dup13-15 mutations in RAS proteins [22], can activate the transforming function of R-RAS2 in cell culture [2,11,32,33]. We have also recently shown that the Rras2 Q72L mutation acts as a potent oncogenic driver when somatically expressed in mice [18]. Based on this, we tested the transforming activity of a collection of 21 additional RRAS2 mutations that are found in human tumors at very low frequency, according to data from the cBioPortal database.…”

Section: Resultsmentioning

confidence: 99%

“…Endogenous R-RAS2 Q72L is required for tumorigenesis of cancer cells As the somatic expression of the endogenous R-Ras2 Q72L promotes tumor formation in mice [18], we decided to investigate whether the endogenous expression of R-RAS2 Q72L is also important for maintaining the transformed phenotype of already-established human cancer cell lines. As a first approximation, we used the Novartis Drive Data Portal [34] to identify cell lines that are vulnerable to the shRNA-mediated depletion of either the wild-type or oncogenic mutants of R-RAS2.…”

Section: Resultsmentioning

confidence: 99%

“…Results from cell models using ectopically expressed proteins have led to the idea that R-RAS2 and RAS proteins are quite similar according to subcellular localization, transforming activity and signaling criteria [3][4][5][6][7][8][9][10]19]. In contrast to these assumptions, we have recently reported that R-Ras2 Q72L and oncogenic versions of RAS proteins trigger different tumor types when expressed in mice [18,[41][42][43][44][45]. It is unlikely that this is merely due to distinct expression patterns, given that R-Ras2 can be detected in many tissues [2,26].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, RRAS2 mutations have been found at higher frequencies in central nervous system germinomas (in 14.6% of interrogated cases) and KIT + germ cell tumors (in 11.8% of cases) [ 16 , 17 ]. Highlighting the pathogenic importance of the RRAS2 Q72L mutation, we have recently used an inducible knock-in mouse strain to show that somatic expression of the encoded mutant protein drives the rapid development of many tumor types [ 18 ]. RRAS2 missense mutations, including Q72L, have been also identified in Noonan syndrome [ 19 , 20 ], a rare developmental disease frequently associated with the deregulation of RAS signaling elements [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

“…Evidence obtained with mouse models also indicates that the wild-type version of R-Ras2 favors pro-tumorigenic processes activated by other oncogenes. Thus, we have shown that the elimination of endogenous R-Ras2 leads the abrogation of Her2-driven mammary tumorigenesis as well as of Notch1-driven T cell acute lymphoblastic leukemia [ 18 , 23 ]. Conversely, the overexpression of R-Ras2 per se promotes the development of a B-cell chronic lymphocytic leukemia-like condition in mice [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

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Characterization of mutant versions of the R-RAS2/TC21 GTPase found in tumors

et al. 2022

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The R-RAS2 GTP hydrolase (GTPase) (also known as TC21) has been traditionally considered quite similar to classical RAS proteins at the regulatory and signaling levels. Recently, a long-tail hotspot mutation targeting the R-RAS2/TC21 Gln72 residue (Q72L) was identified as a potent oncogenic driver. Additional point mutations were also found in other tumors at low frequencies. Despite this, little information is available regarding the transforming role of these mutant versions and their relevance for the tumorigenic properties of already-transformed cancer cells. Here, we report that many of the RRAS2 mutations found in human cancers are highly transforming when expressed in immortalized cell lines. Moreover, the expression of endogenous R-RAS2Q72L is important for maintaining optimal levels of PI3K and ERK activities as well as for the adhesion, invasiveness, proliferation, and mitochondrial respiration of ovarian and breast cancer cell lines. Endogenous R-RAS2Q72L also regulates gene expression programs linked to both cell adhesion and inflammatory/immune-related responses. Endogenous R-RAS2Q72L is also quite relevant for the in vivo tumorigenic activity of these cells. This dependency is observed even though these cancer cell lines bear concurrent gain-of-function mutations in genes encoding RAS signaling elements. Finally, we show that endogenous R-RAS2, unlike the case of classical RAS proteins, specifically localizes in focal adhesions. Collectively, these results indicate that gain-of-function mutations of R-RAS2/TC21 play roles in tumor initiation and maintenance that are not fully redundant with those regulated by classical RAS oncoproteins.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Characterization of mutant versions of the R-RAS2/TC21 GTPase found in tumors

et al. 2022

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The molecular genetics of RASopathies: An update on novel disease genes and new disorders

Tartaglia

Aoki

Gelb

2022

American J of Med Genetics Pt C

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Enhanced signaling through RAS and the mitogen-associated protein kinase (MAPK) cascade underlies the RASopathies, a family of clinically related disorders affecting development and growth. In RASopathies, increased RAS-MAPK signaling can result from the upregulated activity of various RAS GTPases, enhanced function of proteins positively controlling RAS function or favoring the efficient transmission of RAS signaling to downstream transducers, functional upregulation of RAS effectors belonging to the MAPK cascade, or inefficient signaling switch-off operated by feedback mechanisms acting at different levels. The massive effort in RASopathy gene discovery performed in the last 20 years has identified more than 20 genes implicated in these disorders. It has also facilitated the characterization of several molecular acti-vating mechanisms that had remained unappreciated due to their minor impact in oncogenesis. Here, we provide an overview on the discoveries collected during the last 5 years that have delivered unexpected insights (e.g., Noonan syndrome as a recessive disease) and allowed to profile new RASopathies, novel disease genes and new molecular circuits contributing to the control of RAS-MAPK signaling.

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DeepAlloDriver: a deep learning-based strategy to predict cancer driver mutations

Song

et al. 2023

Nucleic Acids Research

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Driver mutations can contribute to the initial processes of cancer, and their identification is crucial for understanding tumorigenesis as well as for molecular drug discovery and development. Allostery regulates protein function away from the functional regions at an allosteric site. In addition to the known effects of mutations around functional sites, mutations at allosteric sites have been associated with protein structure, dynamics, and energy communication. As a result, identifying driver mutations at allosteric sites will be beneficial for deciphering the mechanisms of cancer and developing allosteric drugs. In this study, we provided a platform called DeepAlloDriver to predict driver mutations using a deep learning method that exhibited >93% accuracy and precision. Using this server, we found that a missense mutation in RRAS2 (Gln72 to Leu) might serve as an allosteric driver of tumorigenesis, revealing the mechanism of the mutation in knock-in mice and cancer patients. Overall, DeepAlloDriver would facilitate the elucidation of the mechanisms underlying cancer progression and help prioritize cancer therapeutic targets. The web server is freely available at: https://mdl.shsmu.edu.cn/DeepAlloDriver.

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A hotspot mutation targeting the R-RAS2 GTPase acts as a potent oncogenic driver in a wide spectrum of tumors

Cited by 10 publications

References 59 publications

Characterization of mutant versions of the R-RAS2/TC21 GTPase found in tumors

Characterization of mutant versions of the R-RAS2/TC21 GTPase found in tumors

The molecular genetics of RASopathies: An update on novel disease genes and new disorders

DeepAlloDriver: a deep learning-based strategy to predict cancer driver mutations

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