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2 pages, 173 KiB

Open AccessEditorial

Unveiling the Mysteries of RAS Signaling: A Journey of Discovery and Breakthroughs

by Esther Castellano

Genes 2023, 14(11), 1987; https://doi.org/10.3390/genes14111987 - 25 Oct 2023

Viewed by 786

Abstract

In the realm of molecular biology, few terms evoke as much curiosity, fascination, and determination as RAS [...] Full article

(This article belongs to the Special Issue RAS Signaling in Health and Disease)

Review

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26 pages, 3771 KiB

Open AccessReview

Ras Multimers on the Membrane: Many Ways for a Heart-to-Heart Conversation

by E. Sila Ozdemir, Anna M. Koester and Xiaolin Nan

Genes 2022, 13(2), 219; https://doi.org/10.3390/genes13020219 - 25 Jan 2022

Cited by 6 | Viewed by 4274

Abstract

Formation of Ras multimers, including dimers and nanoclusters, has emerged as an exciting, new front of research in the ‘old’ field of Ras biomedicine. With significant advances made in the past few years, we are beginning to understand the structure of Ras multimers [...] Read more.

Formation of Ras multimers, including dimers and nanoclusters, has emerged as an exciting, new front of research in the ‘old’ field of Ras biomedicine. With significant advances made in the past few years, we are beginning to understand the structure of Ras multimers and, albeit preliminary, mechanisms that regulate their formation in vitro and in cells. Here we aim to synthesize the knowledge accrued thus far on Ras multimers, particularly the presence of multiple globular (G-) domain interfaces, and discuss how membrane nanodomain composition and structure would influence Ras multimer formation. We end with some general thoughts on the potential implications of Ras multimers in basic and translational biology. Full article

(This article belongs to the Special Issue RAS Signaling in Health and Disease)

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12 pages, 1335 KiB

Open AccessReview

RAS Dimers: The Novice Couple at the RAS-ERK Pathway Ball

by Ana Herrero and Piero Crespo

Genes 2021, 12(10), 1556; https://doi.org/10.3390/genes12101556 - 30 Sep 2021

Cited by 10 | Viewed by 3347

Abstract

Signals conveyed through the RAS-ERK pathway constitute a pivotal regulatory element in cancer-related cellular processes. Recently, RAS dimerization has been proposed as a key step in the relay of RAS signals, critically contributing to RAF activation. RAS clustering at plasma membrane microdomains and [...] Read more.

Signals conveyed through the RAS-ERK pathway constitute a pivotal regulatory element in cancer-related cellular processes. Recently, RAS dimerization has been proposed as a key step in the relay of RAS signals, critically contributing to RAF activation. RAS clustering at plasma membrane microdomains and endomembranes facilitates RAS dimerization in response to stimulation, promoting RAF dimerization and subsequent activation. Remarkably, inhibiting RAS dimerization forestalls tumorigenesis in cellular and animal models. Thus, the pharmacological disruption of RAS dimers has emerged as an additional target for cancer researchers in the quest for a means to curtail aberrant RAS activity. Full article

(This article belongs to the Special Issue RAS Signaling in Health and Disease)

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40 pages, 9999 KiB

Open AccessReview

The Importance of Being PI3K in the RAS Signaling Network

by Cristina Cuesta, Cristina Arévalo-Alameda and Esther Castellano

Genes 2021, 12(7), 1094; https://doi.org/10.3390/genes12071094 - 19 Jul 2021

Cited by 31 | Viewed by 9819

Abstract

Ras proteins are essential mediators of a multitude of cellular processes, and its deregulation is frequently associated with cancer appearance, progression, and metastasis. Ras-driven cancers are usually aggressive and difficult to treat. Although the recent Food and Drug Administration (FDA) approval of the [...] Read more.

Ras proteins are essential mediators of a multitude of cellular processes, and its deregulation is frequently associated with cancer appearance, progression, and metastasis. Ras-driven cancers are usually aggressive and difficult to treat. Although the recent Food and Drug Administration (FDA) approval of the first Ras G12C inhibitor is an important milestone, only a small percentage of patients will benefit from it. A better understanding of the context in which Ras operates in different tumor types and the outcomes mediated by each effector pathway may help to identify additional strategies and targets to treat Ras-driven tumors. Evidence emerging in recent years suggests that both oncogenic Ras signaling in tumor cells and non-oncogenic Ras signaling in stromal cells play an essential role in cancer. PI3K is one of the main Ras effectors, regulating important cellular processes such as cell viability or resistance to therapy or angiogenesis upon oncogenic Ras activation. In this review, we will summarize recent advances in the understanding of Ras-dependent activation of PI3K both in physiological conditions and cancer, with a focus on how this signaling pathway contributes to the formation of a tumor stroma that promotes tumor cell proliferation, migration, and spread. Full article

(This article belongs to the Special Issue RAS Signaling in Health and Disease)

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20 pages, 617 KiB

Open AccessEditor’s ChoiceReview

Drugging the Undruggable: Advances on RAS Targeting in Cancer

by Miriam Molina-Arcas, Amit Samani and Julian Downward

Genes 2021, 12(6), 899; https://doi.org/10.3390/genes12060899 - 10 Jun 2021

Cited by 42 | Viewed by 7252

Abstract

Around 20% of all malignancies harbour activating mutations in RAS isoforms. Despite this, there is a deficiency of RAS-targeting agents licensed for therapeutic use. The picomolar affinity of RAS for GTP, and the lack of suitable pockets for high-affinity small-molecule binding, precluded effective [...] Read more.

Around 20% of all malignancies harbour activating mutations in RAS isoforms. Despite this, there is a deficiency of RAS-targeting agents licensed for therapeutic use. The picomolar affinity of RAS for GTP, and the lack of suitable pockets for high-affinity small-molecule binding, precluded effective therapies despite decades of research. Recently, characterisation of the biochemical properties of KRAS-G12C along with discovery of its ‘switch-II pocket’ have allowed development of effective mutant-specific inhibitors. Currently seven KRAS-G12C inhibitors are in clinical trials and sotorasib has become the first one to be granted FDA approval. Here, we discuss historical efforts to target RAS directly and approaches to target RAS effector signalling, including combinations that overcome limitations of single-agent targeting. We also review pre-clinical and clinical evidence for the efficacy of KRAS-G12C inhibitor monotherapy followed by an illustration of combination therapies designed to overcome primary resistance and extend durability of response. Finally, we briefly discuss novel approaches to targeting non-G12C mutant isoforms. Full article

(This article belongs to the Special Issue RAS Signaling in Health and Disease)

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30 pages, 2036 KiB

Open AccessEditor’s ChoiceReview

The Crossroads between RAS and RHO Signaling Pathways in Cellular Transformation, Motility and Contraction

by Olga Soriano, Marta Alcón-Pérez, Miguel Vicente-Manzanares and Esther Castellano

Genes 2021, 12(6), 819; https://doi.org/10.3390/genes12060819 - 27 May 2021

Cited by 37 | Viewed by 9592

Abstract

Ras and Rho proteins are GTP-regulated molecular switches that control multiple signaling pathways in eukaryotic cells. Ras was among the first identified oncogenes, and it appears mutated in many forms of human cancer. It mainly promotes proliferation and survival through the MAPK pathway [...] Read more.

Ras and Rho proteins are GTP-regulated molecular switches that control multiple signaling pathways in eukaryotic cells. Ras was among the first identified oncogenes, and it appears mutated in many forms of human cancer. It mainly promotes proliferation and survival through the MAPK pathway and the PI3K/AKT pathways, respectively. However, the myriad proteins close to the plasma membrane that activate or inhibit Ras make it a major regulator of many apparently unrelated pathways. On the other hand, Rho is weakly oncogenic by itself, but it critically regulates microfilament dynamics; that is, actin polymerization, disassembly and contraction. Polymerization is driven mainly by the Arp2/3 complex and formins, whereas contraction depends on myosin mini-filament assembly and activity. These two pathways intersect at numerous points: from Ras-dependent triggering of Rho activators, some of which act through PI3K, to mechanical feedback driven by actomyosin action. Here, we describe the main points of connection between the Ras and Rho pathways as they coordinately drive oncogenic transformation. We emphasize the biochemical crosstalk that drives actomyosin contraction driven by Ras in a Rho-dependent manner. We also describe possible routes of mechanical feedback through which myosin II activation may control Ras/Rho activation. Full article

(This article belongs to the Special Issue RAS Signaling in Health and Disease)

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17 pages, 1425 KiB

Open AccessReview

Dissecting the Involvement of Ras GTPases in Kidney Fibrosis

by José M. Muñoz-Félix and Carlos Martínez-Salgado

Genes 2021, 12(6), 800; https://doi.org/10.3390/genes12060800 - 24 May 2021

Cited by 9 | Viewed by 2585

Abstract

Many different regulatory mechanisms of renal fibrosis are known to date, and those related to transforming growth factor-β1 (TGF-β1)-induced signaling have been studied in greater depth. However, in recent years, other signaling pathways have been identified, which contribute to the regulation of these [...] Read more.

Many different regulatory mechanisms of renal fibrosis are known to date, and those related to transforming growth factor-β1 (TGF-β1)-induced signaling have been studied in greater depth. However, in recent years, other signaling pathways have been identified, which contribute to the regulation of these pathological processes. Several studies by our team and others have revealed the involvement of small Ras GTPases in the regulation of the cellular processes that occur in renal fibrosis, such as the activation and proliferation of myofibroblasts or the accumulation of extracellular matrix (ECM) proteins. Intracellular signaling mediated by TGF-β1 and Ras GTPases are closely related, and this interaction also occurs during the development of renal fibrosis. In this review, we update the available in vitro and in vivo knowledge on the role of Ras and its main effectors, such as Erk and Akt, in the cellular mechanisms that occur during the regulation of kidney fibrosis (ECM synthesis, accumulation and activation of myofibroblasts, apoptosis and survival of tubular epithelial cells), as well as the therapeutic strategies for targeting the Ras pathway to intervene on the development of renal fibrosis. Full article

(This article belongs to the Special Issue RAS Signaling in Health and Disease)

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23 pages, 1060 KiB

Open AccessEditor’s ChoiceReview

40 Years of RAS—A Historic Overview

by Alberto Fernández-Medarde, Javier De Las Rivas and Eugenio Santos

Genes 2021, 12(5), 681; https://doi.org/10.3390/genes12050681 - 1 May 2021

Cited by 24 | Viewed by 7178

Abstract

It has been over forty years since the isolation of the first human oncogene (HRAS), a crucial milestone in cancer research made possible through the combined efforts of a few selected research groups at the beginning of the 1980s. Those initial discoveries led [...] Read more.

It has been over forty years since the isolation of the first human oncogene (HRAS), a crucial milestone in cancer research made possible through the combined efforts of a few selected research groups at the beginning of the 1980s. Those initial discoveries led to a quantitative leap in our understanding of cancer biology and set up the onset of the field of molecular oncology. The following four decades of RAS research have produced a huge pool of new knowledge about the RAS family of small GTPases, including how they regulate signaling pathways controlling many cellular physiological processes, or how oncogenic mutations trigger pathological conditions, including developmental syndromes or many cancer types. However, despite the extensive body of available basic knowledge, specific effective treatments for RAS-driven cancers are still lacking. Hopefully, recent advances involving the discovery of novel pockets on the RAS surface as well as highly specific small-molecule inhibitors able to block its interaction with effectors and/or activators may lead to the development of new, effective treatments for cancer. This review intends to provide a quick, summarized historical overview of the main milestones in RAS research spanning from the initial discovery of the viral RAS oncogenes in rodent tumors to the latest attempts at targeting RAS oncogenes in various human cancers. Full article

(This article belongs to the Special Issue RAS Signaling in Health and Disease)

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18 pages, 2090 KiB

Open AccessReview

The Role of Wild-Type RAS in Oncogenic RAS Transformation

by Erin Sheffels and Robert L. Kortum

Genes 2021, 12(5), 662; https://doi.org/10.3390/genes12050662 - 28 Apr 2021

Cited by 22 | Viewed by 4692

Abstract

The RAS family of oncogenes (HRAS, NRAS, and KRAS) are among the most frequently mutated protein families in cancers. RAS-mutated tumors were originally thought to proliferate independently of upstream signaling inputs, but we now know that non-mutated wild-type [...] Read more.

The RAS family of oncogenes (HRAS, NRAS, and KRAS) are among the most frequently mutated protein families in cancers. RAS-mutated tumors were originally thought to proliferate independently of upstream signaling inputs, but we now know that non-mutated wild-type (WT) RAS proteins play an important role in modulating downstream effector signaling and driving therapeutic resistance in RAS-mutated cancers. This modulation is complex as different WT RAS family members have opposing functions. The protein product of the WT RAS allele of the same isoform as mutated RAS is often tumor-suppressive and lost during tumor progression. In contrast, RTK-dependent activation of the WT RAS proteins from the two non-mutated WT RAS family members is tumor-promoting. Further, rebound activation of RTK–WT RAS signaling underlies therapeutic resistance to targeted therapeutics in RAS-mutated cancers. The contributions of WT RAS to proliferation and transformation in RAS-mutated cancer cells places renewed interest in upstream signaling molecules, including the phosphatase/adaptor SHP2 and the RasGEFs SOS1 and SOS2, as potential therapeutic targets in RAS-mutated cancers. Full article

(This article belongs to the Special Issue RAS Signaling in Health and Disease)

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16 pages, 3343 KiB

Open AccessReview

Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling

by Aoife A. Nolan, Nourhan K. Aboud, Walter Kolch and David Matallanas

Genes 2021, 12(4), 553; https://doi.org/10.3390/genes12040553 - 10 Apr 2021

Cited by 17 | Viewed by 6993

Abstract

Oncogenic RAS (Rat sarcoma) mutations drive more than half of human cancers, and RAS inhibition is the holy grail of oncology. Thirty years of relentless efforts and harsh disappointments have taught us about the intricacies of oncogenic RAS signalling that allow us to [...] Read more.

Oncogenic RAS (Rat sarcoma) mutations drive more than half of human cancers, and RAS inhibition is the holy grail of oncology. Thirty years of relentless efforts and harsh disappointments have taught us about the intricacies of oncogenic RAS signalling that allow us to now get a pharmacological grip on this elusive protein. The inhibition of effector pathways, such as the RAF-MEK-ERK pathway, has largely proven disappointing. Thus far, most of these efforts were aimed at blocking the activation of ERK. Here, we discuss RAF-dependent pathways that are regulated through RAF functions independent of catalytic activity and their potential role as targets to block oncogenic RAS signalling. We focus on the now well documented roles of RAF kinase-independent functions in apoptosis, cell cycle progression and cell migration. Full article

(This article belongs to the Special Issue RAS Signaling in Health and Disease)

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