Special Issue "Rho GTPases in Health and Disease"

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 (15 March 2019)

Special Issue Editor

Guest Editor
Prof. Cord Brakebusch

Biotech Research & Innovation Centre, The University of Copenhagen; Copenhagen, Denmark
Website | E-Mail
Interests: Rho GTPases; keratinocytes; mouse disease models

Special Issue Information

Dear Colleagues,

Rho GTPases are crucial organizers of the actin cytoskeleton with essential functions in cell migration and cell–cell contacts. In addition, Rho GTPases are involved in the regulation of stemness, proliferation and differentiation, and other cellular processes. Not surprisingly, this exciting family of molecules plays important roles in development and in disease. Genetically modified mice provided, in the last few years, important and often surprising insights into the in vivo function of Rho GTPases, and cellular studies in vitro suggested novel molecular mechanisms underlying the observed effects.

Still, many questions remain to be investigated in order to understand Rho GTPase function in development and disease. For example, what is the role of Rho GTPase crosstalk in vivo? What is the importance of posttranslational modifications of Rho GTPases? How crucial is the parallel activation of different effector pathways by an activated Rho GTPase? How is Rho GTPase function in 3D systems related to 2D models, the currently preferred system for the molecular analysis of Rho GTPase signalling?

For this Special Issue of Cells on “Rho GTPases in Health and Disease” we invite scientists now to contribute review articles and primary research papers on the subject. Ideally, the review articles should, not only describe the current state-of-the-art, but also give personal opinions about future challenges and research goals in that area.

We hope that such a Special Issue will make the scientific community aware of possible links of their work to Rho GTPases, which will trigger fruitful discussions, and that it will motivate young researchers to enter the Rho GTPase field and tackle the open questions of Rho GTPase functions in health and disease.

Dr. Cord Brakebusch
Guest Editor

Manuscript Submission Information

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Keywords

  • Rho GTPases
  • Actin cytoskeleton
  • In vivo disease models
  • Rho GTPase regulation
  • 3D in vitro models
  • Development

Published Papers (14 papers)

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Research

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Open AccessArticle
RHOG Activates RAC1 through CDC42 Leading to Tube Formation in Vascular Endothelial Cells
Received: 9 January 2019 / Revised: 12 February 2019 / Accepted: 13 February 2019 / Published: 18 February 2019
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Abstract
Angiogenesis is a hallmark of cancer cell malignancy. The role of the RHO family GTPase RHOG in angiogenesis in vascular endothelial cells has recently been elucidated. However, the regulation of RHOG during this process, as well as its cross-talk with other RHO GTPases, [...] Read more.
Angiogenesis is a hallmark of cancer cell malignancy. The role of the RHO family GTPase RHOG in angiogenesis in vascular endothelial cells has recently been elucidated. However, the regulation of RHOG during this process, as well as its cross-talk with other RHO GTPases, have yet to be fully examined. In this study, we found that siRNA-mediated depletion of RHOG strongly inhibits tube formation in vascular endothelial cells (ECV cells), an effect reversed by transfecting dominant active constructs of CDC42 or RAC1 in the RHOG-depleted cells. We also found CDC42 to be upstream from RAC1 in these cells. Inhibiting either Phosphatidyl inositol (3) kinase (PI3K) with Wortmannin or the mitogen-activated protein kinase extracellular-regulated kinase (MAPK ERK) with U0126 leads to the inhibition of tube formation. While knocking down either RHO, GTPase did not affect p-AKT levels, and p-ERK decreased in response to the knocking down of RHOG, CDC42 or RAC1. Recovering active RHO GTPases in U0126-treated cells also did not reverse the inhibition of tube formation, placing ERK downstream from PI3K-RHOG-CDC42-RAC1 in vascular endothelial cells. Finally, RHOA and the Rho activated protein kinases ROCK1 and ROCK2 positively regulated tube formation independently of ERK, while RHOC seemed to inhibit the process. Collectively, our data confirmed the essential role of RHOG in angiogenesis, shedding light on a potential new therapeutic target for cancer malignancy and metastasis. Full article
(This article belongs to the Special Issue Rho GTPases in Health and Disease)
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Open AccessArticle
Overexpression of CDC42SE1 in A431 Cells Reduced Cell Proliferation by Inhibiting the Akt Pathway
Received: 19 December 2018 / Revised: 25 January 2019 / Accepted: 30 January 2019 / Published: 2 February 2019
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Abstract
Cell division cycle 42 (CDC42), a small Rho GTPase, plays a critical role in many cellular processes, including cell proliferation and survival. CDC42 interacts with the CRIB (Cdc42- and Rac-interactive binding) domain of CDC42SE1, a small effector protein of 9 kDa. We found [...] Read more.
Cell division cycle 42 (CDC42), a small Rho GTPase, plays a critical role in many cellular processes, including cell proliferation and survival. CDC42 interacts with the CRIB (Cdc42- and Rac-interactive binding) domain of CDC42SE1, a small effector protein of 9 kDa. We found that the expression of CDC42SE1 was reduced in human skin cancer samples relative to matched perilesional control. Exogenous expression of CDC42SE1 but not CDC42SE1H38A (mutation within CRIB domain) in A431 cells (A431SE1, A431SE1-H38A) reduced cell proliferation. Antibody microarray analysis of A431Ctrl and A431SE1 lysate suggested that reduced A431SE1 cells proliferation was due to inhibition of Akt pathway, which was confirmed by the reduced P-Akt and P-mTOR levels in A431SE1 cells compared to A431Ctrl cells. This suggests that CDC42SE1 modulates the CDC42-mediated Akt pathway by competing with other effector proteins to bind CDC42. A431SE1 cells formed smaller colonies in soft agar compared to A431Ctrl and A431SE1-H38A cells. These findings correlate with nude mice xenograft assays, where A431SE1 cells formed tumors with significantly-reduced volume compared to the tumors formed by A431Ctrl cells. Our results suggest that CDC42SE1 is downregulated in skin cancer to promote tumorigenesis, and thus CDC42SE1 might be an important marker of skin cancer progression. Full article
(This article belongs to the Special Issue Rho GTPases in Health and Disease)
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Review

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Open AccessReview
Rho GTPases in the Physiology and Pathophysiology of Peripheral Sensory Neurons
Cells 2019, 8(6), 591; https://doi.org/10.3390/cells8060591 (registering DOI)
Received: 22 May 2019 / Revised: 10 June 2019 / Accepted: 11 June 2019 / Published: 15 June 2019
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Abstract
Numerous experimental studies demonstrate that the Ras homolog family of guanosine triphosphate hydrolases (Rho GTPases) Ras homolog family member A (RhoA), Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division cycle 42 (Cdc42) are important regulators in somatosensory neurons, where they elicit [...] Read more.
Numerous experimental studies demonstrate that the Ras homolog family of guanosine triphosphate hydrolases (Rho GTPases) Ras homolog family member A (RhoA), Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division cycle 42 (Cdc42) are important regulators in somatosensory neurons, where they elicit changes in the cellular cytoskeleton and are involved in diverse biological processes during development, differentiation, survival and regeneration. This review summarizes the status of research regarding the expression and the role of the Rho GTPases in peripheral sensory neurons and how these small proteins are involved in development and outgrowth of sensory neurons, as well as in neuronal regeneration after injury, inflammation and pain perception. In sensory neurons, Rho GTPases are activated by various extracellular signals through membrane receptors and elicit their action through a wide range of downstream effectors, such as Rho-associated protein kinase (ROCK), phosphoinositide 3-kinase (PI3K) or mixed-lineage kinase (MLK). While RhoA is implicated in the assembly of stress fibres and focal adhesions and inhibits neuronal outgrowth through growth cone collapse, Rac1 and Cdc42 promote neuronal development, differentiation and neuroregeneration. The functions of Rho GTPases are critically important in the peripheral somatosensory system; however, their signalling interconnections and partially antagonistic actions are not yet fully understood. Full article
(This article belongs to the Special Issue Rho GTPases in Health and Disease)
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Open AccessReview
Spatiotemporal Regulation of Rho GTPases in Neuronal Migration
Received: 28 April 2019 / Revised: 1 June 2019 / Accepted: 4 June 2019 / Published: 10 June 2019
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Abstract
Neuronal migration is essential for the orchestration of brain development and involves several contiguous steps: interkinetic nuclear movement (INM), multipolar–bipolar transition, locomotion, and translocation. Growing evidence suggests that Rho GTPases, including RhoA, Rac, Cdc42, and the atypical Rnd members, play critical roles in [...] Read more.
Neuronal migration is essential for the orchestration of brain development and involves several contiguous steps: interkinetic nuclear movement (INM), multipolar–bipolar transition, locomotion, and translocation. Growing evidence suggests that Rho GTPases, including RhoA, Rac, Cdc42, and the atypical Rnd members, play critical roles in neuronal migration by regulating both actin and microtubule cytoskeletal components. This review focuses on the spatiotemporal-specific regulation of Rho GTPases as well as their regulators and effectors in distinct steps during the neuronal migration process. Their roles in bridging extracellular signals and cytoskeletal dynamics to provide optimal structural support to the migrating neurons will also be discussed. Full article
(This article belongs to the Special Issue Rho GTPases in Health and Disease)
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Open AccessReview
RhoGTPase in Vascular Disease
Received: 18 March 2019 / Revised: 24 May 2019 / Accepted: 27 May 2019 / Published: 6 June 2019
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Abstract
Ras-homologous (Rho)A/Rho-kinase pathway plays an essential role in many cellular functions, including contraction, motility, proliferation, and apoptosis, inflammation, and its excessive activity induces oxidative stress and promotes the development of cardiovascular diseases. Given its role in many physiological and pathological functions, targeting can [...] Read more.
Ras-homologous (Rho)A/Rho-kinase pathway plays an essential role in many cellular functions, including contraction, motility, proliferation, and apoptosis, inflammation, and its excessive activity induces oxidative stress and promotes the development of cardiovascular diseases. Given its role in many physiological and pathological functions, targeting can result in adverse effects and limit its use for therapy. In this review, we have summarized the role of RhoGTPases with an emphasis on RhoA in vascular disease and its impact on endothelial, smooth muscle, and heart and lung fibroblasts. It is clear from the various studies that understanding the regulation of RhoGTPases and their regulators in physiology and pathological conditions is required for effective targeting of Rho. Full article
(This article belongs to the Special Issue Rho GTPases in Health and Disease)
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Open AccessReview
Building Blood Vessels—One Rho GTPase at a Time
Received: 7 May 2019 / Revised: 1 June 2019 / Accepted: 3 June 2019 / Published: 6 June 2019
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Abstract
Blood vessels are required for the survival of any organism larger than the oxygen diffusion limit. Blood vessel formation is a tightly regulated event and vessel growth or changes in permeability are linked to a number of diseases. Elucidating the cell biology of [...] Read more.
Blood vessels are required for the survival of any organism larger than the oxygen diffusion limit. Blood vessel formation is a tightly regulated event and vessel growth or changes in permeability are linked to a number of diseases. Elucidating the cell biology of endothelial cells (ECs), which are the building blocks of blood vessels, is thus critical to our understanding of vascular biology and to the development of vascular-targeted disease treatments. Small GTPases of the Rho GTPase family are known to regulate several processes critical for EC growth and maintenance. In fact, many of the 21 Rho GTPases in mammals are known to regulate EC junctional remodeling, cell shape changes, and other processes. Rho GTPases are thus an attractive target for disease treatments, as they often have unique functions in specific vascular cell types. In fact, some Rho GTPases are even expressed with relative specificity in diseased vessels. Interestingly, many Rho GTPases are understudied in ECs, despite their known expression in either developing or mature vessels, suggesting an even greater wealth of knowledge yet to be gleaned from these complex signaling pathways. This review aims to provide an overview of Rho GTPase signaling contributions to EC vasculogenesis, angiogenesis, and mature vessel barrier function. A particular emphasis is placed on so-called “alternative” Rho GTPases, as they are largely understudied despite their likely important contributions to EC biology. Full article
(This article belongs to the Special Issue Rho GTPases in Health and Disease)
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Open AccessFeature PaperReview
The Vav GEF Family: An Evolutionary and Functional Perspective
Received: 22 April 2019 / Revised: 10 May 2019 / Accepted: 15 May 2019 / Published: 16 May 2019
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Abstract
Vav proteins play roles as guanosine nucleotide exchange factors for Rho GTPases and signaling adaptors downstream of protein tyrosine kinases. The recent sequencing of the genomes of many species has revealed that this protein family originated in choanozoans, a group of unicellular organisms [...] Read more.
Vav proteins play roles as guanosine nucleotide exchange factors for Rho GTPases and signaling adaptors downstream of protein tyrosine kinases. The recent sequencing of the genomes of many species has revealed that this protein family originated in choanozoans, a group of unicellular organisms from which animal metazoans are believed to have originated from. Since then, the Vav family underwent expansions and reductions in its members during the evolutionary transitions that originated the agnates, chondrichthyes, some teleost fish, and some neoaves. Exotic members of the family harboring atypical structural domains can be also found in some invertebrate species. In this review, we will provide a phylogenetic perspective of the evolution of the Vav family. We will also pay attention to the structure, signaling properties, regulatory layers, and functions of Vav proteins in both invertebrate and vertebrate species. Full article
(This article belongs to the Special Issue Rho GTPases in Health and Disease)
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Open AccessReview
Rho GTPases—Emerging Regulators of Glucose Homeostasis and Metabolic Health
Received: 12 April 2019 / Revised: 2 May 2019 / Accepted: 6 May 2019 / Published: 9 May 2019
Cited by 1 | PDF Full-text (3169 KB) | HTML Full-text | XML Full-text
Abstract
Rho guanosine triphosphatases (GTPases) are key regulators in a number of cellular functions, including actin cytoskeleton remodeling and vesicle traffic. Traditionally, Rho GTPases are studied because of their function in cell migration and cancer, while their roles in metabolism are less documented. However, [...] Read more.
Rho guanosine triphosphatases (GTPases) are key regulators in a number of cellular functions, including actin cytoskeleton remodeling and vesicle traffic. Traditionally, Rho GTPases are studied because of their function in cell migration and cancer, while their roles in metabolism are less documented. However, emerging evidence implicates Rho GTPases as regulators of processes of crucial importance for maintaining metabolic homeostasis. Thus, the time is now ripe for reviewing Rho GTPases in the context of metabolic health. Rho GTPase-mediated key processes include the release of insulin from pancreatic β cells, glucose uptake into skeletal muscle and adipose tissue, and muscle mass regulation. Through the current review, we cast light on the important roles of Rho GTPases in skeletal muscle, adipose tissue, and the pancreas and discuss the proposed mechanisms by which Rho GTPases act to regulate glucose metabolism in health and disease. We also describe challenges and goals for future research. Full article
(This article belongs to the Special Issue Rho GTPases in Health and Disease)
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Open AccessReview
Coordination between Rac1 and Rab Proteins: Functional Implications in Health and Disease
Received: 9 April 2019 / Revised: 25 April 2019 / Accepted: 26 April 2019 / Published: 29 April 2019
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Abstract
The small GTPases of the Rho family regulate many aspects of actin dynamics, but are functionally connected to many other cellular processes. Rac1, a member of this family, besides its known function in the regulation of actin cytoskeleton, plays a key role in [...] Read more.
The small GTPases of the Rho family regulate many aspects of actin dynamics, but are functionally connected to many other cellular processes. Rac1, a member of this family, besides its known function in the regulation of actin cytoskeleton, plays a key role in the production of reactive oxygen species, in gene transcription, in DNA repair, and also has been proven to have specific roles in neurons. This review focuses on the cooperation between Rac1 and Rab proteins, analyzing how the coordination between these GTPases impact on cells and how alterations of their functions lead to disease. Full article
(This article belongs to the Special Issue Rho GTPases in Health and Disease)
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Open AccessReview
RAC1 Takes the Lead in Solid Tumors
Received: 4 March 2019 / Revised: 18 April 2019 / Accepted: 24 April 2019 / Published: 26 April 2019
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Abstract
Three GTPases, RAC, RHO, and Cdc42, play essential roles in coordinating many cellular functions during embryonic development, both in healthy cells and in disease conditions like cancers. We have presented patterns of distribution of the frequency of RAC1-alteration(s) in cancers as obtained from [...] Read more.
Three GTPases, RAC, RHO, and Cdc42, play essential roles in coordinating many cellular functions during embryonic development, both in healthy cells and in disease conditions like cancers. We have presented patterns of distribution of the frequency of RAC1-alteration(s) in cancers as obtained from cBioPortal. With this background data, we have interrogated the various functions of RAC1 in tumors, including proliferation, metastasis-associated phenotypes, and drug-resistance with a special emphasis on solid tumors in adults. We have reviewed the activation and regulation of RAC1 functions on the basis of its sub-cellular localization in tumor cells. Our review focuses on the role of RAC1 in cancers and summarizes the regulatory mechanisms, inhibitory efficacy, and the anticancer potential of RAC1-PAK targeting agents. Full article
(This article belongs to the Special Issue Rho GTPases in Health and Disease)
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Open AccessReview
p190RhoGAPs, the ARHGAP35- and ARHGAP5-Encoded Proteins, in Health and Disease
Received: 19 March 2019 / Revised: 5 April 2019 / Accepted: 9 April 2019 / Published: 12 April 2019
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Abstract
Small guanosine triphosphatases (GTPases) gathered in the Rat sarcoma (Ras) superfamily represent a large family of proteins involved in several key cellular mechanisms. Within the Ras superfamily, the Ras homolog (Rho) family is specialized in the regulation of actin cytoskeleton-based mechanisms. These proteins [...] Read more.
Small guanosine triphosphatases (GTPases) gathered in the Rat sarcoma (Ras) superfamily represent a large family of proteins involved in several key cellular mechanisms. Within the Ras superfamily, the Ras homolog (Rho) family is specialized in the regulation of actin cytoskeleton-based mechanisms. These proteins switch between an active and an inactive state, resulting in subsequent inhibiting or activating downstream signals, leading finally to regulation of actin-based processes. The On/Off status of Rho GTPases implicates two subsets of regulators: GEFs (guanine nucleotide exchange factors), which favor the active GTP (guanosine triphosphate) status of the GTPase and GAPs (GTPase activating proteins), which inhibit the GTPase by enhancing the GTP hydrolysis. In humans, the 20 identified Rho GTPases are regulated by over 70 GAP proteins suggesting a complex, but well-defined, spatio-temporal implication of these GAPs. Among the quite large number of RhoGAPs, we focus on p190RhoGAP, which is known as the main negative regulator of RhoA, but not exclusively. Two isoforms, p190A and p190B, are encoded by ARHGAP35 and ARHGAP5 genes, respectively. We describe here the function of each of these isoforms in physiological processes and sum up findings on their role in pathological conditions such as neurological disorders and cancers. Full article
(This article belongs to the Special Issue Rho GTPases in Health and Disease)
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Open AccessReview
Focus on Cdc42 in Breast Cancer: New Insights, Target Therapy Development and Non-Coding RNAs
Received: 30 December 2018 / Revised: 30 January 2019 / Accepted: 8 February 2019 / Published: 11 February 2019
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Abstract
Breast cancer is the most common malignant tumors in females. Although the conventional treatment has demonstrated a certain effect, some limitations still exist. The Rho guanosine triphosphatase (GTPase) Cdc42 (Cell division control protein 42 homolog) is often upregulated by some cell surface receptors [...] Read more.
Breast cancer is the most common malignant tumors in females. Although the conventional treatment has demonstrated a certain effect, some limitations still exist. The Rho guanosine triphosphatase (GTPase) Cdc42 (Cell division control protein 42 homolog) is often upregulated by some cell surface receptors and oncogenes in breast cancer. Cdc42 switches from inactive guanosine diphosphate (GDP)-bound to active GTP-bound though guanine-nucleotide-exchange factors (GEFs), results in activation of signaling cascades that regulate various cellular processes such as cytoskeletal changes, proliferation and polarity establishment. Targeting Cdc42 also provides a strategy for precise breast cancer therapy. In addition, Cdc42 is a potential target for several types of non-coding RNAs including microRNAs and lncRNAs. These non-coding RNAs is extensively involved in Cdc42-induced tumor processes, while many of them are aberrantly expressed. Here, we focus on the role of Cdc42 in cell morphogenesis, proliferation, motility, angiogenesis and survival, introduce the Cdc42-targeted non-coding RNAs, as well as present current development of effective Cdc42-targeted inhibitors in breast cancer. Full article
(This article belongs to the Special Issue Rho GTPases in Health and Disease)
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Open AccessReview
Rho-Family Small GTPases: From Highly Polarized Sensory Neurons to Cancer Cells
Received: 28 December 2018 / Revised: 19 January 2019 / Accepted: 23 January 2019 / Published: 28 January 2019
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Abstract
The small GTPases of the Rho-family (Rho-family GTPases) have various physiological functions, including cytoskeletal regulation, cell polarity establishment, cell proliferation and motility, transcription, reactive oxygen species (ROS) production, and tumorigenesis. A relatively large number of downstream targets of Rho-family GTPases have been reported [...] Read more.
The small GTPases of the Rho-family (Rho-family GTPases) have various physiological functions, including cytoskeletal regulation, cell polarity establishment, cell proliferation and motility, transcription, reactive oxygen species (ROS) production, and tumorigenesis. A relatively large number of downstream targets of Rho-family GTPases have been reported for in vitro studies. However, only a small number of signal pathways have been established at the in vivo level. Cumulative evidence for the functions of Rho-family GTPases has been reported for in vivo studies using genetically engineered mouse models. It was based on different cell- and tissue-specific conditional genes targeting mice. In this review, we introduce recent advances in in vivo studies, including human patient trials on Rho-family GTPases, focusing on highly polarized sensory organs, such as the cochlea, which is the primary hearing organ, host defenses involving reactive oxygen species (ROS) production, and tumorigenesis (especially associated with RAC, novel RAC1-GSPT1 signaling, RHOA, and RHOBTB2). Full article
(This article belongs to the Special Issue Rho GTPases in Health and Disease)
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Open AccessReview
RAC1B: A Rho GTPase with Versatile Functions in Malignant Transformation and Tumor Progression
Received: 5 December 2018 / Revised: 28 December 2018 / Accepted: 2 January 2019 / Published: 4 January 2019
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Abstract
RAC1B is an alternatively spliced isoform of the monomeric GTPase RAC1. It differs from RAC1 by a 19 amino acid in frame insertion, termed exon 3b, resulting in an accelerated GDP/GTP-exchange and an impaired GTP-hydrolysis. Although RAC1B has been ascribed several protumorigenic functions [...] Read more.
RAC1B is an alternatively spliced isoform of the monomeric GTPase RAC1. It differs from RAC1 by a 19 amino acid in frame insertion, termed exon 3b, resulting in an accelerated GDP/GTP-exchange and an impaired GTP-hydrolysis. Although RAC1B has been ascribed several protumorigenic functions such as cell cycle progression and apoptosis resistance, its role in malignant transformation, and other functions driving tumor progression like epithelial-mesenchymal transition, migration/invasion and metastasis are less clear. Insertion of exon 3b endows RAC1B with specific biochemical properties that, when compared to RAC1, encompass both loss-of-functions and gain-of-functions with respect to the type of upstream activators, downstream targets, and binding partners. In its extreme, this may result in RAC1B and RAC1 acting in an antagonistic fashion in regulating a specific cellular response with RAC1B behaving as an endogenous inhibitor of RAC1. In this review, we strive to provide the reader with a comprehensive overview, rather than critical discussions, on various aspects of RAC1B biology in eukaryotic cells. Full article
(This article belongs to the Special Issue Rho GTPases in Health and Disease)
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