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Small GTPases 2019
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Small GTPases 2019

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 28933

Special Issue Editor

Prof. Dr. Takaya Satoh

E-Mail Website
Guest Editor
Laboratory of Cell Biology, Department of Biological Science, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka, Japan
Interests: cell biology; animal cells; intracellular signal transduction; small GTPases; type II diabetes; insulin signaling; glucose transporter; skeletal muscle; adipocytes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The family of signal transducing small GTPases serves as a molecular switch of intracellular signal transduction in eukaryotic cells. It has been implicated in a diverse array of cell functions, such as gene expression, cytoskeletal rearrangements, the intracellular transport of vesicles, and macromolecular transport across the nuclear envelope. In humans, defects in small GTPase-mediated signaling are intimately involved in various diseases, including cancer. In contrast to heterotrimeric G proteins, another family of signal transducing GTPases, small GTPases act as a monomer (single polypeptide) attached to cell and intracellular membranes through post-translational lipid modifications. Virtually all small GTPases exist in either GDP-bound or GTP-bound conformation, interacting with specific regulatory and target proteins in a manner dependent on the bound GDP or GTP. In many cases, upstream signals, such as receptor-mediated signals, stimulate the formation of the GTP-bound conformation, which in turn activates downstream targets.

This Special Issue “Small GTPases” aims to provide new insights into physiological functions and regulatory mechanisms of any kinds of signal transducing small GTPases in the cell. Authors are invited to submit original research and review articles related to these subjects.

Prof. Dr. Takaya Satoh
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 submissions that pass pre-check are 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • Animal cells
  • Cell growth
  • Cell motility
  • Guanine nucleotide exchange
  • Human disease
  • Protein–protein interaction
  • Signal transduction
  • Vesicular transportkeyword.

Related Special Issues

Published Papers (7 papers)

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Editorial

Jump to: Research, Review

4 pages, 202 KiB  
Editorial
Diverse Physiological Functions and Regulatory Mechanisms for Signal-Transducing Small GTPases
by Takaya Satoh
Int. J. Mol. Sci. 2020, 21(19), 7291; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197291 - 02 Oct 2020
Cited by 2 | Viewed by 1252
Abstract
Diverse GTPases act as signal transducing enzymes in a variety of organisms and cell types [...] Full article
(This article belongs to the Special Issue Small GTPases 2019)

Research

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15 pages, 8911 KiB  
Article
Inhibition of Protein Prenylation of GTPases Alters Endothelial Barrier Function
by Muhammad Aslam, Christian Troidl, Christian Tanislav, Susanne Rohrbach, Dursun Gündüz and Christian W. Hamm
Int. J. Mol. Sci. 2020, 21(1), 2; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010002 - 18 Dec 2019
Cited by 8 | Viewed by 3778
Abstract
The members of Rho family of GTPases, RhoA and Rac1 regulate endothelial cytoskeleton dynamics and hence barrier integrity. The spatial activities of these GTPases are regulated by post-translational prenylation. In the present study, we investigated the effect of prenylation inhibition on the endothelial [...] Read more.
The members of Rho family of GTPases, RhoA and Rac1 regulate endothelial cytoskeleton dynamics and hence barrier integrity. The spatial activities of these GTPases are regulated by post-translational prenylation. In the present study, we investigated the effect of prenylation inhibition on the endothelial cytoskeleton and barrier properties. The study was carried out in human umbilical vein endothelial cells (HUVEC) and protein prenylation is manipulated with various pharmacological inhibitors. Inhibition of either complete prenylation using statins or specifically geranylgeranylation but not farnesylation has a biphasic effect on HUVEC cytoskeleton and permeability. Short-term treatment inhibits the spatial activity of RhoA/Rho kinase (Rock) to actin cytoskeleton resulting in adherens junctions (AJ) stabilization and ameliorates thrombin-induced barrier disruption whereas long-term inhibition results in collapse of endothelial cytoskeleton leading to increased basal permeability. These effects are reversed by supplementing the cells with geranylgeranyl but not farnesyl pyrophosphate. Moreover, long-term inhibition of protein prenylation results in basal hyper activation of RhoA/Rock signaling that is antagonized by a specific Rock inhibitor or an activation of cAMP signaling. In conclusion, inhibition of geranylgeranylation in endothelial cells (ECs) exerts biphasic effect on endothelial barrier properties. Short-term inhibition stabilizes AJs and hence barrier function whereas long-term treatment results in disruption of barrier properties. Full article
(This article belongs to the Special Issue Small GTPases 2019)
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21 pages, 5876 KiB  
Article
Analysis of Functional Domains in Rho5, the Yeast Homolog of Human Rac1 GTPase, in Oxidative Stress Response
by Carolin Sterk, Lauren Gräber, Hans-Peter Schmitz and Jürgen J. Heinisch
Int. J. Mol. Sci. 2019, 20(22), 5550; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225550 - 07 Nov 2019
Cited by 8 | Viewed by 2837
Abstract
The small GTPase Rho5 of Saccharomyces cerevisiae is required for proper regulation of different signaling pathways, which includes the response to cell wall, osmotic, nutrient, and oxidative stress. We here show that proper in vivo function and intracellular distribution of Rho5 depends on [...] Read more.
The small GTPase Rho5 of Saccharomyces cerevisiae is required for proper regulation of different signaling pathways, which includes the response to cell wall, osmotic, nutrient, and oxidative stress. We here show that proper in vivo function and intracellular distribution of Rho5 depends on its hypervariable region at the carboxyterminal end, which includes the CAAX box for lipid modification, a preceding polybasic region (PBR) carrying a serine residue, and a 98 amino acid–specific insertion only present in Rho5 of S. cerevisiae but not in its human homolog Rac1. Results from trapping GFP-Rho5 variants to the mitochondrial surface suggest that the GTPase needs to be activated at the plasma membrane prior to its translocation to mitochondria in order to fulfil its role in oxidative stress response. These findings are supported by heterologous expression of a codon-optimized human RAC1 gene, which can only complement a yeast rho5 deletion in a chimeric fusion with RHO5 sequences that restore the correct spatiotemporal distribution of the encoded protein. Full article
(This article belongs to the Special Issue Small GTPases 2019)
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15 pages, 3016 KiB  
Article
A Crucial Role for the Small GTPase Rac1 Downstream of the Protein Kinase Akt2 in Insulin Signaling that Regulates Glucose Uptake in Mouse Adipocytes
by Nobuyuki Takenaka, Mika Nakao, Sayaka Matsui and Takaya Satoh
Int. J. Mol. Sci. 2019, 20(21), 5443; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215443 - 31 Oct 2019
Cited by 16 | Viewed by 2830
Abstract
Insulin-stimulated glucose uptake is mediated by translocation of the glucose transporter GLUT4 to the plasma membrane in adipocytes and skeletal muscle cells. In both types of cells, phosphoinositide 3-kinase and the protein kinase Akt2 have been implicated as critical regulators. In skeletal muscle, [...] Read more.
Insulin-stimulated glucose uptake is mediated by translocation of the glucose transporter GLUT4 to the plasma membrane in adipocytes and skeletal muscle cells. In both types of cells, phosphoinositide 3-kinase and the protein kinase Akt2 have been implicated as critical regulators. In skeletal muscle, the small GTPase Rac1 plays an important role downstream of Akt2 in the regulation of insulin-stimulated glucose uptake. However, the role for Rac1 in adipocytes remains controversial. Here, we show that Rac1 is required for insulin-dependent GLUT4 translocation also in adipocytes. A Rac1-specific inhibitor almost completely suppressed GLUT4 translocation induced by insulin or a constitutively activated mutant of phosphoinositide 3-kinase or Akt2. Constitutively activated Rac1 also enhanced GLUT4 translocation. Insulin-induced, but not constitutively activated Rac1-induced, GLUT4 translocation was abrogated by inhibition of phosphoinositide 3-kinase or Akt2. On the other hand, constitutively activated Akt2 caused Rac1 activation, and insulin-induced Rac1 activation was suppressed by an Akt2-specific inhibitor. Moreover, GLUT4 translocation induced by a constitutively activated mutant of Akt2 or Rac1 was diminished by knockdown of another small GTPase RalA. RalA was activated by a constitutively activated mutant of Akt2 or Rac1, and insulin-induced RalA activation was suppressed by an Akt2- or Rac1-specific inhibitor. Collectively, these results suggest that Rac1 plays an important role in the regulation of insulin-dependent GLUT4 translocation downstream of Akt2, leading to RalA activation in adipocytes. Full article
(This article belongs to the Special Issue Small GTPases 2019)
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Review

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16 pages, 1716 KiB  
Review
The Hypervariable Region of K-Ras4B Governs Molecular Recognition and Function
by Hazem Abdelkarim, Avik Banerjee, Patrick Grudzien, Nicholas Leschinsky, Mahmoud Abushaer and Vadim Gaponenko
Int. J. Mol. Sci. 2019, 20(22), 5718; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225718 - 14 Nov 2019
Cited by 10 | Viewed by 3397
Abstract
The flexible C-terminal hypervariable region distinguishes K-Ras4B, an important proto-oncogenic GTPase, from other Ras GTPases. This unique lysine-rich portion of the protein harbors sites for post-translational modification, including cysteine prenylation, carboxymethylation, phosphorylation, and likely many others. The functions of the hypervariable region are [...] Read more.
The flexible C-terminal hypervariable region distinguishes K-Ras4B, an important proto-oncogenic GTPase, from other Ras GTPases. This unique lysine-rich portion of the protein harbors sites for post-translational modification, including cysteine prenylation, carboxymethylation, phosphorylation, and likely many others. The functions of the hypervariable region are diverse, ranging from anchoring K-Ras4B at the plasma membrane to sampling potentially auto-inhibitory binding sites in its GTPase domain and participating in isoform-specific protein–protein interactions and signaling. Despite much research, there are still many questions about the hypervariable region of K-Ras4B. For example, mechanistic details of its interaction with plasma membrane lipids and with the GTPase domain require further clarification. The roles of the hypervariable region in K-Ras4B-specific protein–protein interactions and signaling are incompletely defined. It is also unclear why post-translational modifications frequently found in protein polylysine domains, such as acetylation, glycation, and carbamoylation, have not been observed in K-Ras4B. Expanding knowledge of the hypervariable region will likely drive the development of novel highly-efficient and selective inhibitors of K-Ras4B that are urgently needed by cancer patients. Full article
(This article belongs to the Special Issue Small GTPases 2019)
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23 pages, 1961 KiB  
Review
The Small GTPase Arf6: An Overview of Its Mechanisms of Action and of Its Role in Host–Pathogen Interactions and Innate Immunity
by Tim Van Acker, Jan Tavernier and Frank Peelman
Int. J. Mol. Sci. 2019, 20(9), 2209; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092209 - 05 May 2019
Cited by 54 | Viewed by 7417
Abstract
The small GTase Arf6 has several important functions in intracellular vesicular trafficking and regulates the recycling of different types of cargo internalized via clathrin-dependent or -independent endocytosis. It activates the lipid modifying enzymes PIP 5-kinase and phospholipase D, promotes actin polymerization, and affects [...] Read more.
The small GTase Arf6 has several important functions in intracellular vesicular trafficking and regulates the recycling of different types of cargo internalized via clathrin-dependent or -independent endocytosis. It activates the lipid modifying enzymes PIP 5-kinase and phospholipase D, promotes actin polymerization, and affects several functionally distinct processes in the cell. Arf6 is used for the phagocytosis of pathogens and can be directly or indirectly targeted by various pathogens to block phagocytosis or induce the uptake of intracellular pathogens. Arf6 is also used in the signaling of Toll-like receptors and in the activation of NADPH oxidases. In this review, we first give an overview of the different roles and mechanisms of action of Arf6 and then focus on its role in innate immunity and host–pathogen interactions. Full article
(This article belongs to the Special Issue Small GTPases 2019)
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31 pages, 903 KiB  
Review
Regulators of Rho GTPases in the Nervous System: Molecular Implication in Axon Guidance and Neurological Disorders
by Sadig Niftullayev and Nathalie Lamarche-Vane
Int. J. Mol. Sci. 2019, 20(6), 1497; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20061497 - 25 Mar 2019
Cited by 27 | Viewed by 7003
Abstract
One of the fundamental steps during development of the nervous system is the formation of proper connections between neurons and their target cells—a process called neural wiring, failure of which causes neurological disorders ranging from autism to Down’s syndrome. Axons navigate through the [...] Read more.
One of the fundamental steps during development of the nervous system is the formation of proper connections between neurons and their target cells—a process called neural wiring, failure of which causes neurological disorders ranging from autism to Down’s syndrome. Axons navigate through the complex environment of a developing embryo toward their targets, which can be far away from their cell bodies. Successful implementation of neuronal wiring, which is crucial for fulfillment of all behavioral functions, is achieved through an intimate interplay between axon guidance and neural activity. In this review, our focus will be on axon pathfinding and the implication of some of its downstream molecular components in neurological disorders. More precisely, we will talk about axon guidance and the molecules implicated in this process. After, we will briefly review the Rho family of small GTPases, their regulators, and their involvement in downstream signaling pathways of the axon guidance cues/receptor complexes. We will then proceed to the final and main part of this review, where we will thoroughly comment on the implication of the regulators for Rho GTPases—GEFs (Guanine nucleotide Exchange Factors) and GAPs (GTPase-activating Proteins)—in neurological diseases and disorders. Full article
(This article belongs to the Special Issue Small GTPases 2019)
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