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3 pages, 208 KiB

Open AccessEditorial

GTPase Pathways in Health and Diseases

by Yong Teng

Cells 2022, 11(24), 4055; https://doi.org/10.3390/cells11244055 - 15 Dec 2022

Cited by 1 | Viewed by 915

Abstract

GTPases, the molecular switches toggling between an inactive GDP-bound state and an active GTP-bound state, play a pivotal role in controlling complex cellular processes (e [...] Full article

(This article belongs to the Special Issue GTPase Pathways in Health and Diseases)

Research

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13 pages, 3075 KiB

Open AccessArticle

Impaired Function of PLEKHG2, a Rho-Guanine Nucleotide-Exchange Factor, Disrupts Corticogenesis in Neurodevelopmental Phenotypes

by Masashi Nishikawa, Hidenori Ito, Hidenori Tabata, Hiroshi Ueda and Koh-ichi Nagata

Cells 2022, 11(4), 696; https://doi.org/10.3390/cells11040696 - 16 Feb 2022

Cited by 3 | Viewed by 2282

Abstract

Homozygosity of the p.Arg204Trp variation in the Pleckstrin homology and RhoGEF domain containing G2 (PLEKHG2) gene, which encodes a Rho family-specific guanine nucleotide-exchange factor, is responsible for microcephaly with intellectual disability. However, the role of PLEKHG2 during neurodevelopment remains unknown. In [...] Read more.

Homozygosity of the p.Arg204Trp variation in the Pleckstrin homology and RhoGEF domain containing G2 (PLEKHG2) gene, which encodes a Rho family-specific guanine nucleotide-exchange factor, is responsible for microcephaly with intellectual disability. However, the role of PLEKHG2 during neurodevelopment remains unknown. In this study, we analyzed mouse Plekhg2 function during cortical development, both in vitro and in vivo. The p.Arg200Trp variant in mouse (Plekhg2-RW), which corresponds to the p.Arg204Trp variant in humans, showed decreased guanine nucleotide-exchange activity for Rac1, Rac3, and Cdc42. Acute knockdown of Plekhg2 using in utero electroporation-mediated gene transfer did not affect the migration of excitatory neurons during corticogenesis. On the other hand, silencing Plekhg2 expression delayed dendritic arbor formation at postnatal day 7 (P7), perhaps because of impaired Rac/Cdc42 and p21-activated kinase 1 signaling pathways. This phenotype was rescued by expressing an RNAi-resistant version of wildtype Plekhg2, but not of Plekhg2-RW. Axon pathfinding was also impaired in vitro and in vivo in Plekhg2-deficient cortical neurons. At P14, knockdown of Plekhg2 was observed to cause defects in dendritic spine morphology formation. Collectively, these results strongly suggest that PLEKHG2 has essential roles in the maturation of axon, dendrites, and spines. Moreover, impairment of PLEKHG2 function is most likely to cause defects in neuronal functions that lead to neurodevelopmental disorders. Full article

(This article belongs to the Special Issue GTPase Pathways in Health and Diseases)

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17 pages, 2397 KiB

Open AccessArticle

Molecular Regulation of the RhoGAP GRAF3 and Its Capacity to Limit Blood Pressure In Vivo

by Rachel A. Dee, Xue Bai, Christopher P. Mack and Joan M. Taylor

Cells 2020, 9(4), 1042; https://doi.org/10.3390/cells9041042 - 22 Apr 2020

Cited by 7 | Viewed by 3028

Abstract

Anti-hypertensive therapies are usually prescribed empirically and are often ineffective. Given the prevalence and deleterious outcomes of hypertension (HTN), improved strategies are needed. We reported that the Rho-GAP GRAF3 is selectively expressed in smooth muscle cells (SMC) and controls blood pressure (BP) by [...] Read more.

Anti-hypertensive therapies are usually prescribed empirically and are often ineffective. Given the prevalence and deleterious outcomes of hypertension (HTN), improved strategies are needed. We reported that the Rho-GAP GRAF3 is selectively expressed in smooth muscle cells (SMC) and controls blood pressure (BP) by limiting the RhoA-dependent contractility of resistance arterioles. Importantly, genetic variants at the GRAF3 locus controls BP in patients. The goal of this study was to validate GRAF3 as a druggable candidate for future anti-HTN therapies. Importantly, using a novel mouse model, we found that modest induction of GRAF3 in SMC significantly decreased basal and vasoconstrictor-induced BP. Moreover, we found that GRAF3 protein toggles between inactive and active states by processes controlled by the mechano-sensing kinase, focal adhesion kinase (FAK). Using resonance energy transfer methods, we showed that agonist-induced FAK-dependent phosphorylation at ^Y376GRAF3 reverses an auto-inhibitory interaction between the GAP and BAR-PH domains. Y376 is located in a linker between the PH and GAP domains and is invariant in GRAF3 homologues and a phosphomimetic ^E376GRAF3 variant exhibited elevated GAP activity. Collectively, these data provide strong support for the future identification of allosteric activators of GRAF3 for targeted anti-hypertensive therapies. Full article

(This article belongs to the Special Issue GTPase Pathways in Health and Diseases)

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21 pages, 4310 KiB

Open AccessArticle

Lysine Acetylation Reshapes the Downstream Signaling Landscape of Vav1 in Lymphocytes

by Sonia Rodríguez-Fdez, Lucía Fernández-Nevado, L. Francisco Lorenzo-Martín and Xosé R. Bustelo

Cells 2020, 9(3), 609; https://doi.org/10.3390/cells9030609 - 4 Mar 2020

Cited by 6 | Viewed by 2843

Abstract

Vav1 works both as a catalytic Rho GTPase activator and an adaptor molecule. These functions, which are critical for T cell development and antigenic responses, are tyrosine phosphorylation-dependent. However, it is not known whether other posttranslational modifications can contribute to the regulation of [...] Read more.

Vav1 works both as a catalytic Rho GTPase activator and an adaptor molecule. These functions, which are critical for T cell development and antigenic responses, are tyrosine phosphorylation-dependent. However, it is not known whether other posttranslational modifications can contribute to the regulation of the biological activity of this protein. Here, we show that Vav1 becomes acetylated on lysine residues in a stimulation- and SH2 domain-dependent manner. Using a collection of both acetylation- and deacetylation-mimicking mutants, we show that the acetylation of four lysine residues (Lys²²², Lys²⁵², Lys⁵⁸⁷, and Lys⁷¹⁶) leads to the downmodulation of the adaptor function of Vav1 that triggers the stimulation of the nuclear factor of activated T cells (NFAT). These sites belong to two functional subclasses according to mechanistic criteria. We have also unveiled additional acetylation sites potentially involved in either the stimulation (Lys⁷⁸²) or the downmodulation (Lys³³⁵, Lys³⁷⁴) of specific Vav1-dependent downstream responses. Collectively, these results indicate that Nε-lysine acetylation can play variegated roles in the regulation of Vav1 signaling. Unlike the case of the tyrosine phosphorylation step, this new regulatory layer is not conserved in other Vav family paralogs. Full article

(This article belongs to the Special Issue GTPase Pathways in Health and Diseases)

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16 pages, 2101 KiB

Open AccessArticle

Design and Synthesis of Arf1-Targeting γ-Dipeptides as Potential Agents against Head and Neck Squamous Cell Carcinoma

by Yen Vo-Hoang, Sergio Paiva, Leilei He, Sébastien Estaran and Yong Teng

Cells 2020, 9(2), 286; https://doi.org/10.3390/cells9020286 - 24 Jan 2020

Cited by 5 | Viewed by 2493

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)

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24 pages, 4496 KiB

Open AccessArticle

Phosphatidylinositol Monophosphates Regulate Optimal Vav1 Signaling Output

by Sonia Rodríguez-Fdez, Carmen Citterio, L. Francisco Lorenzo-Martín, Jesús Baltanás-Copado, Clara Llorente-González, Senena Corbalán-García, Miguel Vicente-Manzanares and Xosé R. Bustelo

Cells 2019, 8(12), 1649; https://doi.org/10.3390/cells8121649 - 16 Dec 2019

Cited by 7 | Viewed by 4375

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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21 pages, 3293 KiB

Open AccessArticle

ROCK Inhibition Drives Resolution of Acute Inflammation by Enhancing Neutrophil Apoptosis

by Izabela Galvão, Rayssa M. Athayde, Denise A. Perez, Alesandra C. Reis, Luisa Rezende, Vivian Louise S. de Oliveira, Barbara M. Rezende, William A. Gonçalves, Lirlândia P. Sousa, Mauro M. Teixeira and Vanessa Pinho

Cells 2019, 8(9), 964; https://doi.org/10.3390/cells8090964 - 23 Aug 2019

Cited by 23 | Viewed by 4150

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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33 pages, 4305 KiB

Open AccessReview

Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy

by Ufuk Degirmenci, Mei Wang and Jiancheng Hu

Cells 2020, 9(1), 198; https://doi.org/10.3390/cells9010198 - 13 Jan 2020

Cited by 309 | Viewed by 22745

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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24 pages, 1212 KiB

Open AccessFeature PaperReview

Drugging the Small GTPase Pathways in Cancer Treatment: Promises and Challenges

by Néstor Prieto-Dominguez, Christopher Parnell and Yong Teng

Cells 2019, 8(3), 255; https://doi.org/10.3390/cells8030255 - 16 Mar 2019

Cited by 52 | Viewed by 6676

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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