Regulation and Function of Small GTPases 2.0

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

Deadline for manuscript submissions: closed (10 July 2021) | Viewed by 30973

Special Issue Editor

Special Issue Information

Dear Colleagues,

The Ras superfamily of small GTPases function as molecular switches in regulating diverse cellular events in both physiological and pathophysiological settings. Working in tandem with regulators of their guanine nucleotide-binding status (i.e., the guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs)), the small GTPases act as crucial relays that link upstream events (such as ligand-receptor-based signaling) to downstream activities affecting cellular architecture, cytoskeletal dynamics, membrane trafficking, transcriptional changes and many other processes underlying cellular homeostasis. Advances in our understanding of the mechanisms of regulation and action of the small GTPases have provided unprecedented insights into the workings of the cell. Furthermore, findings associated with mutations and dysregulated expression of the small GTPases have broadened our understanding of disease pathways and generated many useful disease biomarkers and therapeutic handles.

Cells previously put together a Special Issue on the “Regulation and Function of Small GTPases”, which has, in its collection, a good number of articles. We now invite your contributions, in the form of either original research articles or reviews, on all aspects of small GTPase biology and medicine in “Regulation and Function of Small GTPases 2.0”. Articles with mechanistic and functional insights are especially welcome.

Dr. Bor Luen Tang
Guest Editor

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Keywords

  • Small GTPases
  • Ras
  • Rho family GTPases
  • Ran
  • Rab
  • Arf
  • cell signaling
  • cytoskeleton
  • cancer
  • membrane transport

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Published Papers (7 papers)

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Editorial

Jump to: Research, Review

2 pages, 173 KiB  
Editorial
At the Research Frontiers of Small GTPases
by Bor Luen Tang
Cells 2022, 11(23), 3708; https://doi.org/10.3390/cells11233708 - 22 Nov 2022
Viewed by 797
Abstract
Small GTPases act as molecular switches in regulating a myriad of cellular signaling, cytoskeletal dynamics, vesicular trafficking, and membrane/organelle transport processes. Here, I provide an editorial overview of papers collected in this Special Issue on the “Regulation and Function of Small GTPases 2.0”. [...] Read more.
Small GTPases act as molecular switches in regulating a myriad of cellular signaling, cytoskeletal dynamics, vesicular trafficking, and membrane/organelle transport processes. Here, I provide an editorial overview of papers collected in this Special Issue on the “Regulation and Function of Small GTPases 2.0”. Full article
(This article belongs to the Special Issue Regulation and Function of Small GTPases 2.0)

Research

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21 pages, 2383 KiB  
Article
P-Rex1 Controls Sphingosine 1-Phosphate Receptor Signalling, Morphology, and Cell-Cycle Progression in Neuronal Cells
by Elizabeth Hampson, Elpida Tsonou, Martin J. Baker, David C. Hornigold, Roderick E. Hubbard, Andrew Massey and Heidi C. E. Welch
Cells 2021, 10(9), 2474; https://doi.org/10.3390/cells10092474 - 18 Sep 2021
Cited by 2 | Viewed by 2240
Abstract
P-Rex1 is a guanine-nucleotide exchange factor (GEF) that activates Rac-type small G proteins in response to the stimulation of a range of receptors, particularly G protein-coupled receptors (GPCRs), to control cytoskeletal dynamics and other Rac-dependent cell responses. P-Rex1 is mainly expressed in leukocytes [...] Read more.
P-Rex1 is a guanine-nucleotide exchange factor (GEF) that activates Rac-type small G proteins in response to the stimulation of a range of receptors, particularly G protein-coupled receptors (GPCRs), to control cytoskeletal dynamics and other Rac-dependent cell responses. P-Rex1 is mainly expressed in leukocytes and neurons. Whereas its roles in leukocytes have been studied extensively, relatively little is known about its functions in neurons. Here, we used CRISPR/Cas9-mediated P-Rex1 deficiency in neuronal PC12 cells that stably overexpress the GPCR S1PR1, a receptor for sphingosine 1-phosphate (S1P), to investigate the role of P-Rex1 in neuronal GPCR signalling and cell responses. We show that P-Rex1 is required for the S1P-stimulated activation of Rac1 and Akt, basal Rac3 activity, and constitutive cAMP production in PC12-S1PR1 cells. The constitutive cAMP production was not due to increased expression levels of major neuronal adenylyl cyclases, suggesting that P-Rex1 may regulate adenylyl cyclase activity. P-Rex1 was required for maintenance of neurite protrusions and spreading in S1P-stimulated PC12-S1PR1 cells, as well as for cell-cycle progression and proliferation. In summary, we identified novel functional roles of P-Rex1 in neuronal Rac, Akt and cAMP signalling, as well as in neuronal cell-cycle progression and proliferation. Full article
(This article belongs to the Special Issue Regulation and Function of Small GTPases 2.0)
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Review

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24 pages, 5969 KiB  
Review
The RHO Family GTPases: Mechanisms of Regulation and Signaling
by Niloufar Mosaddeghzadeh and Mohammad Reza Ahmadian
Cells 2021, 10(7), 1831; https://doi.org/10.3390/cells10071831 - 20 Jul 2021
Cited by 115 | Viewed by 10958
Abstract
Much progress has been made toward deciphering RHO GTPase functions, and many studies have convincingly demonstrated that altered signal transduction through RHO GTPases is a recurring theme in the progression of human malignancies. It seems that 20 canonical RHO GTPases are likely regulated [...] Read more.
Much progress has been made toward deciphering RHO GTPase functions, and many studies have convincingly demonstrated that altered signal transduction through RHO GTPases is a recurring theme in the progression of human malignancies. It seems that 20 canonical RHO GTPases are likely regulated by three GDIs, 85 GEFs, and 66 GAPs, and eventually interact with >70 downstream effectors. A recurring theme is the challenge in understanding the molecular determinants of the specificity of these four classes of interacting proteins that, irrespective of their functions, bind to common sites on the surface of RHO GTPases. Identified and structurally verified hotspots as functional determinants specific to RHO GTPase regulation by GDIs, GEFs, and GAPs as well as signaling through effectors are presented, and challenges and future perspectives are discussed. Full article
(This article belongs to the Special Issue Regulation and Function of Small GTPases 2.0)
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29 pages, 3316 KiB  
Review
The Small GTPases in Fungal Signaling Conservation and Function
by Mitzuko Dautt-Castro, Montserrat Rosendo-Vargas and Sergio Casas-Flores
Cells 2021, 10(5), 1039; https://doi.org/10.3390/cells10051039 - 28 Apr 2021
Cited by 24 | Viewed by 3975
Abstract
Monomeric GTPases, which belong to the Ras superfamily, are small proteins involved in many biological processes. They are fine-tuned regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Several families have been identified in organisms from different kingdoms. Overall, the most [...] Read more.
Monomeric GTPases, which belong to the Ras superfamily, are small proteins involved in many biological processes. They are fine-tuned regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Several families have been identified in organisms from different kingdoms. Overall, the most studied families are Ras, Rho, Rab, Ran, Arf, and Miro. Recently, a new family named Big Ras GTPases was reported. As a general rule, the proteins of all families have five characteristic motifs (G1–G5), and some specific features for each family have been described. Here, we present an exhaustive analysis of these small GTPase families in fungi, using 56 different genomes belonging to different phyla. For this purpose, we used distinct approaches such as phylogenetics and sequences analysis. The main functions described for monomeric GTPases in fungi include morphogenesis, secondary metabolism, vesicle trafficking, and virulence, which are discussed here. Their participation during fungus–plant interactions is reviewed as well. Full article
(This article belongs to the Special Issue Regulation and Function of Small GTPases 2.0)
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27 pages, 2120 KiB  
Review
Rho Family GTPases and Rho GEFs in Glucose Homeostasis
by Polly A. Machin, Elpida Tsonou, David C. Hornigold and Heidi C. E. Welch
Cells 2021, 10(4), 915; https://doi.org/10.3390/cells10040915 - 16 Apr 2021
Cited by 17 | Viewed by 4156
Abstract
Dysregulation of glucose homeostasis leading to metabolic syndrome and type 2 diabetes is the cause of an increasing world health crisis. New intriguing roles have emerged for Rho family GTPases and their Rho guanine nucleotide exchange factor (GEF) activators in the regulation of [...] Read more.
Dysregulation of glucose homeostasis leading to metabolic syndrome and type 2 diabetes is the cause of an increasing world health crisis. New intriguing roles have emerged for Rho family GTPases and their Rho guanine nucleotide exchange factor (GEF) activators in the regulation of glucose homeostasis. This review summates the current knowledge, focusing in particular on the roles of Rho GEFs in the processes of glucose-stimulated insulin secretion by pancreatic β cells and insulin-stimulated glucose uptake into skeletal muscle and adipose tissues. We discuss the ten Rho GEFs that are known so far to regulate glucose homeostasis, nine of which are in mammals, and one is in yeast. Among the mammalian Rho GEFs, P-Rex1, Vav2, Vav3, Tiam1, Kalirin and Plekhg4 were shown to mediate the insulin-stimulated translocation of the glucose transporter GLUT4 to the plasma membrane and/or insulin-stimulated glucose uptake in skeletal muscle or adipose tissue. The Rho GEFs P-Rex1, Vav2, Tiam1 and β-PIX were found to control the glucose-stimulated release of insulin by pancreatic β cells. In vivo studies demonstrated the involvement of the Rho GEFs P-Rex2, Vav2, Vav3 and PDZ-RhoGEF in glucose tolerance and/or insulin sensitivity, with deletion of these GEFs either contributing to the development of metabolic syndrome or protecting from it. This research is in its infancy. Considering that over 80 Rho GEFs exist, it is likely that future research will identify more roles for Rho GEFs in glucose homeostasis. Full article
(This article belongs to the Special Issue Regulation and Function of Small GTPases 2.0)
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10 pages, 2000 KiB  
Review
Understand KRAS and the Quest for Anti-Cancer Drugs
by Chang Woo Han, Mi Suk Jeong and Se Bok Jang
Cells 2021, 10(4), 842; https://doi.org/10.3390/cells10040842 - 08 Apr 2021
Cited by 11 | Viewed by 3684
Abstract
The KRAS oncogene is mutated in approximately ~30% of human cancers, and the targeting of KRAS has long been highlighted in many studies. Nevertheless, attempts to target KRAS directly have been ineffective. This review provides an overview of the structure of KRAS and [...] Read more.
The KRAS oncogene is mutated in approximately ~30% of human cancers, and the targeting of KRAS has long been highlighted in many studies. Nevertheless, attempts to target KRAS directly have been ineffective. This review provides an overview of the structure of KRAS and its characteristic signaling pathways. Additionally, we examine the problems associated with currently available KRAS inhibitors and discuss promising avenues for drug development. Full article
(This article belongs to the Special Issue Regulation and Function of Small GTPases 2.0)
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10 pages, 4885 KiB  
Review
The Game of Tubulins
by Maria Alvarado Kristensson
Cells 2021, 10(4), 745; https://doi.org/10.3390/cells10040745 - 28 Mar 2021
Cited by 14 | Viewed by 4039
Abstract
Members of the tubulin superfamily are GTPases; the activities of GTPases are necessary for life. The members of the tubulin superfamily are the constituents of the microtubules and the γ-tubulin meshwork. Mutations in members of the tubulin superfamily are involved in developmental brain [...] Read more.
Members of the tubulin superfamily are GTPases; the activities of GTPases are necessary for life. The members of the tubulin superfamily are the constituents of the microtubules and the γ-tubulin meshwork. Mutations in members of the tubulin superfamily are involved in developmental brain disorders, and tubulin activities are the target for various chemotherapies. The intricate functions (game) of tubulins depend on the activities of the GTP-binding domain of α-, β-, and γ-tubulin. This review compares the GTP-binding domains of γ-tubulin, α-tubulin, and β-tubulin and, based on their similarities, recapitulates the known functions and the impact of the γ-tubulin GTP-binding domain in the regulation of the γ-tubulin meshwork and cellular homeostasis. Full article
(This article belongs to the Special Issue Regulation and Function of Small GTPases 2.0)
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