Special Issue "Regulation and Function of Small GTPases"

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (20 December 2015) | Viewed by 35288

Special Issue Editor

Dr. Bor Luen Tang
E-Mail Website
Guest Editor
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Interests: membrane trafficking; neuronal death and regeneration; Sirt1 and aging
Special Issues, Collections and Topics in MDPI journals

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.

In this Special Issue, we invite your contributions, either in the form of original research articles or reviews, on all aspects of small GTPases biology and medicine. Articles with mechanistic and functional insights are especially welcome

Dr. Bor Luen Tang
Guest Editor

Manuscript Submission Information

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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 semimonthly 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 2200 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
  • 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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Review

Review
Multiple Roles of the Small GTPase Rab7
Cells 2016, 5(3), 34; https://doi.org/10.3390/cells5030034 - 18 Aug 2016
Cited by 184 | Viewed by 8055
Abstract
Rab7 is a small GTPase that belongs to the Rab family and controls transport to late endocytic compartments such as late endosomes and lysosomes. The mechanism of action of Rab7 in the late endocytic pathway has been extensively studied. Rab7 is fundamental for [...] Read more.
Rab7 is a small GTPase that belongs to the Rab family and controls transport to late endocytic compartments such as late endosomes and lysosomes. The mechanism of action of Rab7 in the late endocytic pathway has been extensively studied. Rab7 is fundamental for lysosomal biogenesis, positioning and functions, and for trafficking and degradation of several signaling receptors, thus also having implications on signal transduction. Several Rab7 interacting proteins have being identified leading to the discovery of a number of different important functions, beside its established role in endocytosis. Furthermore, Rab7 has specific functions in neurons. This review highlights and discusses the role and the importance of Rab7 on different cellular pathways and processes. Full article
(This article belongs to the Special Issue Regulation and Function of Small GTPases)
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Review
Atypical Rho GTPases of the RhoBTB Subfamily: Roles in Vesicle Trafficking and Tumorigenesis
Cells 2016, 5(2), 28; https://doi.org/10.3390/cells5020028 - 14 Jun 2016
Cited by 32 | Viewed by 3436
Abstract
RhoBTB proteins constitute a subfamily of atypical Rho GTPases represented in mammals by RhoBTB1, RhoBTB2, and RhoBTB3. Their characteristic feature is a carboxyl terminal extension that harbors two BTB domains capable of assembling cullin 3-dependent ubiquitin ligase complexes. The expression of all three [...] Read more.
RhoBTB proteins constitute a subfamily of atypical Rho GTPases represented in mammals by RhoBTB1, RhoBTB2, and RhoBTB3. Their characteristic feature is a carboxyl terminal extension that harbors two BTB domains capable of assembling cullin 3-dependent ubiquitin ligase complexes. The expression of all three RHOBTB genes has been found reduced or abolished in a variety of tumors. They are considered tumor suppressor genes and recent studies have strengthened their implication in tumorigenesis through regulation of the cell cycle and apoptosis. RhoBTB3 is also involved in retrograde transport from endosomes to the Golgi apparatus. One aspect that makes RhoBTB proteins atypical among the Rho GTPases is their proposed mechanism of activation. No specific guanine nucleotide exchange factors or GTPase activating proteins are known. Instead, RhoBTB might be activated through interaction with other proteins that relieve their auto-inhibited conformation and inactivated through auto-ubiquitination and destruction in the proteasome. In this review we discuss our current knowledge on the molecular mechanisms of action of RhoBTB proteins and the implications for tumorigenesis and other pathologic conditions. Full article
(This article belongs to the Special Issue Regulation and Function of Small GTPases)
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Review
Structural Mechanisms and Drug Discovery Prospects of Rho GTPases
Cells 2016, 5(2), 26; https://doi.org/10.3390/cells5020026 - 13 Jun 2016
Cited by 24 | Viewed by 3474
Abstract
Rho GTPases regulate cellular morphology and dynamics, and some are key drivers of cancer progression. This superfamily offers attractive potential targets for therapeutic intervention, with RhoA, Rac1 and Cdc42 being prime examples. The challenges in developing agents that act on these signaling enzymes [...] Read more.
Rho GTPases regulate cellular morphology and dynamics, and some are key drivers of cancer progression. This superfamily offers attractive potential targets for therapeutic intervention, with RhoA, Rac1 and Cdc42 being prime examples. The challenges in developing agents that act on these signaling enzymes include the lack of obvious druggable pockets and their membrane-bound activities. However, progress in targeting the similar Ras protein is illuminating new strategies for specifically inhibiting oncogenic GTPases. The structures of multiple signaling and regulatory states of Rho proteins have been determined, and the post-translational modifications including acylation and phosphorylation points have been mapped and their functional effects examined. The development of inhibitors to probe the significance of overexpression and mutational hyperactivation of these GTPases underscores their importance in cancer progression. The ability to integrate in silico, in vitro, and in vivo investigations of drug-like molecules indicates the growing tractability of GTPase systems for lead optimization. Although no Rho-targeted drug molecules have yet been clinically approved, this family is clearly showing increasing promise for the development of precision medicine and combination cancer therapies. Full article
(This article belongs to the Special Issue Regulation and Function of Small GTPases)
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Review
The Regulation of Cellular Responses to Mechanical Cues by Rho GTPases
Cells 2016, 5(2), 17; https://doi.org/10.3390/cells5020017 - 06 Apr 2016
Cited by 67 | Viewed by 4182
Abstract
The Rho GTPases regulate many cellular signaling cascades that modulate cell motility, migration, morphology and cell division. A large body of work has now delineated the biochemical cues and pathways, which stimulate the GTPases and their downstream effectors. However, cells also respond exquisitely [...] Read more.
The Rho GTPases regulate many cellular signaling cascades that modulate cell motility, migration, morphology and cell division. A large body of work has now delineated the biochemical cues and pathways, which stimulate the GTPases and their downstream effectors. However, cells also respond exquisitely to biophysical and mechanical cues such as stiffness and topography of the extracellular matrix that profoundly influence cell migration, proliferation and differentiation. As these cellular responses are mediated by the actin cytoskeleton, an involvement of Rho GTPases in the transduction of such cues is not unexpected. In this review, we discuss an emerging role of Rho GTPase proteins in the regulation of the responses elicited by biophysical and mechanical stimuli. Full article
(This article belongs to the Special Issue Regulation and Function of Small GTPases)
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Review
Rab GTPases and the Autophagy Pathway: Bacterial Targets for a Suitable Biogenesis and Trafficking of Their Own Vacuoles
Cells 2016, 5(1), 11; https://doi.org/10.3390/cells5010011 - 08 Mar 2016
Cited by 22 | Viewed by 5453
Abstract
Autophagy is an intracellular process that comprises degradation of damaged organelles, protein aggregates and intracellular pathogens, having an important role in controlling the fate of invading microorganisms. Intracellular pathogens are internalized by professional and non-professional phagocytes, localizing in compartments called phagosomes. To degrade [...] Read more.
Autophagy is an intracellular process that comprises degradation of damaged organelles, protein aggregates and intracellular pathogens, having an important role in controlling the fate of invading microorganisms. Intracellular pathogens are internalized by professional and non-professional phagocytes, localizing in compartments called phagosomes. To degrade the internalized microorganism, the microbial phagosome matures by fusion events with early and late endosomal compartments and lysosomes, a process that is regulated by Rab GTPases. Interestingly, in order to survive and replicate in the phagosome, some pathogens employ different strategies to manipulate vesicular traffic, inhibiting phagolysosomal biogenesis (e.g., Staphylococcus aureus and Mycobacterium tuberculosis) or surviving in acidic compartments and forming replicative vacuoles (e.g., Coxiella burnetti and Legionella pneumophila). The bacteria described in this review often use secretion systems to control the host’s response and thus disseminate. To date, eight types of secretion systems (Type I to Type VIII) are known. Some of these systems are used by bacteria to translocate pathogenic proteins into the host cell and regulate replicative vacuole formation, apoptosis, cytokine responses, and autophagy. Herein, we have focused on how bacteria manipulate small Rab GTPases to control many of these processes. The growing knowledge in this field may facilitate the development of new treatments or contribute to the prevention of these types of bacterial infections. Full article
(This article belongs to the Special Issue Regulation and Function of Small GTPases)
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Review
Functions of Rab Proteins at Presynaptic Sites
Cells 2016, 5(1), 7; https://doi.org/10.3390/cells5010007 - 06 Feb 2016
Cited by 35 | Viewed by 5129
Abstract
Presynaptic neurotransmitter release is dominated by the synaptic vesicle (SV) cycle and entails the biogenesis, fusion, recycling, reformation or turnover of synaptic vesicles—a process involving bulk movement of membrane and proteins. As key mediators of membrane trafficking, small GTPases from the Rab family [...] Read more.
Presynaptic neurotransmitter release is dominated by the synaptic vesicle (SV) cycle and entails the biogenesis, fusion, recycling, reformation or turnover of synaptic vesicles—a process involving bulk movement of membrane and proteins. As key mediators of membrane trafficking, small GTPases from the Rab family of proteins play critical roles in this process by acting as molecular switches that dynamically interact with and regulate the functions of different sets of macromolecular complexes involved in each stage of the cycle. Importantly, mutations affecting Rabs, and their regulators or effectors have now been identified that are implicated in severe neurological and neurodevelopmental disorders. Here, we summarize the roles and functions of presynaptic Rabs and discuss their involvement in the regulation of presynaptic function. Full article
(This article belongs to the Special Issue Regulation and Function of Small GTPases)
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Review
MIRO GTPases in Mitochondrial Transport, Homeostasis and Pathology
Cells 2016, 5(1), 1; https://doi.org/10.3390/cells5010001 - 31 Dec 2015
Cited by 34 | Viewed by 5080
Abstract
The evolutionarily-conserved mitochondrial Rho (MIRO) small GTPase is a Ras superfamily member with three unique features. It has two GTPase domains instead of the one found in other small GTPases, and it also has two EF hand calcium binding domains, which allow Ca [...] Read more.
The evolutionarily-conserved mitochondrial Rho (MIRO) small GTPase is a Ras superfamily member with three unique features. It has two GTPase domains instead of the one found in other small GTPases, and it also has two EF hand calcium binding domains, which allow Ca2+-dependent modulation of its activity and functions. Importantly, it is specifically associated with the mitochondria and via a hydrophobic transmembrane domain, rather than a lipid-based anchor more commonly found in other small GTPases. At the mitochondria, MIRO regulates mitochondrial homeostasis and turnover. In metazoans, MIRO regulates mitochondrial transport and organization at cellular extensions, such as axons, and, in some cases, intercellular transport of the organelle through tunneling nanotubes. Recent findings have revealed a myriad of molecules that are associated with MIRO, particularly the kinesin adaptor Milton/TRAK, mitofusin, PINK1 and Parkin, as well as the endoplasmic reticulum-mitochondria encounter structure (ERMES) complex. The mechanistic aspects of the roles of MIRO and its interactors in mitochondrial homeostasis and transport are gradually being revealed. On the other hand, MIRO is also increasingly associated with neurodegenerative diseases that have roots in mitochondrial dysfunction. In this review, I discuss what is currently known about the cellular physiology and pathophysiology of MIRO functions. Full article
(This article belongs to the Special Issue Regulation and Function of Small GTPases)
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