Special Issue "GTPase Pathways in Health and Diseases"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling and Regulated Cell Death".

Deadline for manuscript submissions: closed (31 January 2020).

Special Issue Editors

Dr. Yong Teng
E-Mail Website
Guest Editor
Department of Oral Biology and Dx Sciences, Department of Biochemistry and Molecular Biology, Georgia Cancer Center, Augusta University,Augusta, GA 30912, USA
Interests: small GTPases; drugs and inhibitors; signaling pathways; cancer genetics and biology; therapeutic strategies
Prof. Nathalie Lamarche-Vane
E-Mail Website
Co-Guest Editor
Cancer Research Program, Research Institute of the McGill University Hospital Centre; Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada
Interests: Rho GTPase signaling; cell migration; cytoskeletal dynamics; axon guidance; cancer metastasis

Special Issue Information

Dear Colleagues,

Small GTPases are a family of low-molecular-weight GTP-hydrolyzing enzymes that cycle between an inactive state when bound to GDP and an active state when associated with GTP. Small GTPases regulate key cellular processes (e.g., cell differentiation, proliferation, and motility) as well as subcellular events (e.g., vesicle trafficking), making them key participants in a great array of pathophysiological processes. Indeed, the dysfunction and deregulation of certain small GTPases have been related to the promotion and progression of cancer. It is believed that an in-depth study on the functional mechanism of small GTPases can provide a potential therapeutic strategy for cancer treatment.

In this Special Issue, we invite you to contribute original research articles, reviews, or shorter “perspective” articles on all aspects related to the theme of “The Small GTPase Pathways in Cancer Treatment”. We hope to highlight current trends and challenges with functional insights of these pathways from cellular and molecular perspectives, as well as the potential applications and therapeutic benefits of cancer treatment.

Dr. Yong Teng
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • small GTPases
  • drug targets
  • cancer biology
  • anticancer
  • treatment strategy

Published Papers (5 papers)

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Research

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Open AccessArticle
Design and Synthesis of Arf1-Targeting γ-Dipeptides as Potential Agents against Head and Neck Squamous Cell Carcinoma
Cells 2020, 9(2), 286; https://doi.org/10.3390/cells9020286 - 24 Jan 2020
Abstract
Background: Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer-related deaths and calls for new druggable targets. We have previously highlighted the critical role of ADP-ribosylation factor-1 (Arf1) activation in HNSCC. In the present study, we address [...] Read more.
Background: Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer-related deaths and calls for new druggable targets. We have previously highlighted the critical role of ADP-ribosylation factor-1 (Arf1) activation in HNSCC. In the present study, we address the question whether targeting Arf1 could be proposed as a valuable strategy against HNSCC. Methods: We rationally designed and synthesized constrained ATC-based (4-amino-(methyl)-1,3-thiazole-5-carboxylic acid) γ-dipeptides to block Arf1 activation. We evaluated the effects of these γ-dipeptides in HNSCC cells: The cell viability was determined in 2D and 3D cell cultures after 72 h treatment and Arf1 protein levels and activity were assessed by GGA3 pull-down and Western blotting assays. Results: Targeting Arf1 offers a valuable strategy to counter HNSCC. Our new Arf1-targeting compounds revealed a strong in vitro cytotoxicity against HNSCC cells, through inhibiting Arf1 activation and its downstream pathways. Conclusions: Arf1-targeting γ-dipeptides developed in this study may represent a promising targeted therapeutic to improve managing the HNSCC disease. Full article
(This article belongs to the Special Issue GTPase Pathways in Health and Diseases)
Open AccessArticle
Phosphatidylinositol Monophosphates Regulate Optimal Vav1 Signaling Output
Cells 2019, 8(12), 1649; https://doi.org/10.3390/cells8121649 - 16 Dec 2019
Abstract
Phosphatidylinositol–5 phosphate (PI5P) and other mono-phosphoinositides (mono-PIs) play second messenger roles in both physiological and pathological conditions. Despite this, their intracellular targets and mechanisms of action remain poorly characterized. Here, we show that Vav1, a protein that exhibits both Rac1 GDP/GTP exchange and [...] Read more.
Phosphatidylinositol–5 phosphate (PI5P) and other mono-phosphoinositides (mono-PIs) play second messenger roles in both physiological and pathological conditions. Despite this, their intracellular targets and mechanisms of action remain poorly characterized. Here, we show that Vav1, a protein that exhibits both Rac1 GDP/GTP exchange and adaptor activities, is positively modulated by PI5P and, possibly, other mono-PIs. Unlike other phospholipid–protein complexes, the affinity and specificity of the Vav1–lipid interaction entail a new structural solution that involves the synergistic action of the Vav1 C1 domain and an adjacent polybasic tail. This new regulatory layer, which is not conserved in the Vav family paralogs, favors the engagement of optimal Vav1 signaling outputs in lymphocytes. Full article
(This article belongs to the Special Issue GTPase Pathways in Health and Diseases)
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Open AccessArticle
ROCK Inhibition Drives Resolution of Acute Inflammation by Enhancing Neutrophil Apoptosis
Cells 2019, 8(9), 964; https://doi.org/10.3390/cells8090964 - 23 Aug 2019
Abstract
Uncontrolled inflammation leads to tissue damage and it is central for the development of chronic inflammatory diseases and autoimmunity. An acute inflammatory response is finely regulated by the action of anti-inflammatory and pro-resolutive mediators, culminating in the resolution of inflammation and restoration of [...] Read more.
Uncontrolled inflammation leads to tissue damage and it is central for the development of chronic inflammatory diseases and autoimmunity. An acute inflammatory response is finely regulated by the action of anti-inflammatory and pro-resolutive mediators, culminating in the resolution of inflammation and restoration of homeostasis. There are few studies investigating intracellular signaling pathways associated with the resolution of inflammation. Here, we investigate the role of Rho-associated kinase (ROCK), a serine/threonine kinase, in a model of self-resolving neutrophilic inflammatory. We show that ROCK activity, evaluated by P-MYPT-1 kinetics, was higher during the peak of lipopolysaccharide-induced neutrophil influx in the pleural cavity of mice. ROCK inhibition by treatment with Y-27632 decreased the accumulation of neutrophils in the pleural cavity and was associated with an increase in apoptotic events and efferocytosis, as evaluated by an in vivo assay. In a model of gout, treatment with Y-27632 reduced neutrophil accumulation, IL-1β levels and hypernociception in the joint. These were associated with reduced MYPT and IκBα phosphorylation levels and increased apoptosis. Finally, inhibition of ROCK activity also induced apoptosis in human neutrophils and destabilized cytoskeleton, extending the observed effects to human cells. Taken together, these data show that inhibition of the ROCK pathway might represent a potential therapeutic target for neutrophilic inflammatory diseases. Full article
(This article belongs to the Special Issue GTPase Pathways in Health and Diseases)
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Review

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Open AccessReview
Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy
Cells 2020, 9(1), 198; https://doi.org/10.3390/cells9010198 - 13 Jan 2020
Abstract
The RAS/RAF/MEK/ERK (MAPK) signaling cascade is essential for cell inter- and intra-cellular communication, which regulates fundamental cell functions such as growth, survival, and differentiation. The MAPK pathway also integrates signals from complex intracellular networks in performing cellular functions. Despite the initial discovery of [...] Read more.
The RAS/RAF/MEK/ERK (MAPK) signaling cascade is essential for cell inter- and intra-cellular communication, which regulates fundamental cell functions such as growth, survival, and differentiation. The MAPK pathway also integrates signals from complex intracellular networks in performing cellular functions. Despite the initial discovery of the core elements of the MAPK pathways nearly four decades ago, additional findings continue to make a thorough understanding of the molecular mechanisms involved in the regulation of this pathway challenging. Considerable effort has been focused on the regulation of RAF, especially after the discovery of drug resistance and paradoxical activation upon inhibitor binding to the kinase. RAF activity is regulated by phosphorylation and conformation-dependent regulation, including auto-inhibition and dimerization. In this review, we summarize the recent major findings in the study of the RAS/RAF/MEK/ERK signaling cascade, particularly with respect to the impact on clinical cancer therapy. Full article
(This article belongs to the Special Issue GTPase Pathways in Health and Diseases)
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Open AccessFeature PaperReview
Drugging the Small GTPase Pathways in Cancer Treatment: Promises and Challenges
Cells 2019, 8(3), 255; https://doi.org/10.3390/cells8030255 - 16 Mar 2019
Cited by 5
Abstract
Small GTPases are a family of low molecular weight GTP-hydrolyzing enzymes that cycle between an inactive state when bound to GDP and an active state when associated to GTP. Small GTPases regulate key cellular processes (e.g., cell differentiation, proliferation, and motility) as well [...] Read more.
Small GTPases are a family of low molecular weight GTP-hydrolyzing enzymes that cycle between an inactive state when bound to GDP and an active state when associated to GTP. Small GTPases regulate key cellular processes (e.g., cell differentiation, proliferation, and motility) as well as subcellular events (e.g., vesicle trafficking), making them key participants in a great array of pathophysiological processes. Indeed, the dysfunction and deregulation of certain small GTPases, such as the members of the Ras and Arf subfamilies, have been related with the promotion and progression of cancer. Therefore, the development of inhibitors that target dysfunctional small GTPases could represent a potential therapeutic strategy for cancer treatment. This review covers the basic biochemical mechanisms and the diverse functions of small GTPases in cancer. We also discuss the strategies and challenges of inhibiting the activity of these enzymes and delve into new approaches that offer opportunities to target them in cancer therapy. Full article
(This article belongs to the Special Issue GTPase Pathways in Health and Diseases)
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