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4 pages, 208 KiB

Open AccessEditorial

Rho GTPases in Model Systems

by Vedrana Filić and Igor Weber

Cells 2023, 12(5), 779; https://doi.org/10.3390/cells12050779 - 1 Mar 2023

Viewed by 1325

Abstract

Since the discovery of their role in the regulation of actin cytoskeleton 30 years ago, Rho GTPases have taken center stage in cell motility research [...] Full article

(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)

Research

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15 pages, 6145 KiB

Open AccessArticle

Acute RhoA/Rho Kinase Inhibition Is Sufficient to Restore Phagocytic Capacity to Retinal Pigment Epithelium Lacking the Engulfment Receptor MerTK

by Yingyu Mao and Silvia C. Finnemann

Cells 2021, 10(8), 1927; https://doi.org/10.3390/cells10081927 - 29 Jul 2021

Cited by 5 | Viewed by 3963

Abstract

The diurnal phagocytosis of spent photoreceptor outer segment fragments (POS) by retinal pigment epithelial (RPE) cells is essential for visual function. POS internalization by RPE cells requires the assembly of F-actin phagocytic cups beneath surface-tethered POS and Mer tyrosine kinase (MerTK) signaling. The [...] Read more.

The diurnal phagocytosis of spent photoreceptor outer segment fragments (POS) by retinal pigment epithelial (RPE) cells is essential for visual function. POS internalization by RPE cells requires the assembly of F-actin phagocytic cups beneath surface-tethered POS and Mer tyrosine kinase (MerTK) signaling. The activation of the Rho family GTPase Rac1 is necessary for phagocytic cup formation, and Rac1 is activated normally in MerTK-deficient RPE. We show here that mutant RPE lacking MerTK and wild-type RPE deprived of MerTK ligand both fail to form phagocytic cups regardless of Rac1 activation. However, in wild-type RPE in vivo, a decrease in RhoA activity coincides with the daily phagocytosis burst, while RhoA activity in MerTK-deficient RPE is constant. Elevating RhoA activity blocks phagocytic cup formation and phagocytosis by wild-type RPE. Conversely, inhibiting RhoA effector Rho kinases (ROCKs) rescues both F-actin assembly and POS internalization of primary RPE if MerTK or its ligand are lacking. Most strikingly, acute ROCK inhibition is sufficient to induce the formation and acidification of endogenous POS phagosomes by MerTK-deficient RPE ex vivo. Altogether, RhoA pathway inactivation is a necessary and sufficient downstream effect of MerTK phagocytic signaling such that the acute manipulation of cytosolic ROCK activity suffices to restore phagocytic capacity to MerTK-deficient RPE. Full article

(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)

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19 pages, 3935 KiB

Open AccessArticle

RNA Interference Screening Identifies Novel Roles for RhoBTB1 and RhoBTB3 in Membrane Trafficking Events in Mammalian Cells

by Maeve Long, Tilen Kranjc, Margaritha M. Mysior and Jeremy C. Simpson

Cells 2020, 9(5), 1089; https://doi.org/10.3390/cells9051089 - 28 Apr 2020

Cited by 6 | Viewed by 3656

Abstract

In the endomembrane system of mammalian cells, membrane traffic processes require a high degree of regulation in order to ensure their specificity. The range of molecules that participate in trafficking events is truly vast, and much attention to date has been given to [...] Read more.

In the endomembrane system of mammalian cells, membrane traffic processes require a high degree of regulation in order to ensure their specificity. The range of molecules that participate in trafficking events is truly vast, and much attention to date has been given to the Rab family of small GTPases. However, in recent years, a role in membrane traffic for members of the Rho GTPase family, in particular Cdc42, has emerged. This prompted us to develop and apply an image-based high-content screen, initially focussing on the Golgi complex, using RNA interference to systematically perturb each of the 21 Rho family members and assess their importance to the overall organisation of this organelle. Analysis of our data revealed previously unreported roles for two atypical Rho family members, RhoBTB1 and RhoBTB3, in membrane traffic events. We find that depletion of RhoBTB3 affects the morphology of the Golgi complex and causes changes in the trafficking speeds of carriers operating at the interface of the Golgi and endoplasmic reticulum. In addition, RhoBTB3 was found to be present on these carriers. Depletion of RhoBTB1 was also found to cause a disturbance to the Golgi architecture, however, this phenotype seems to be linked to endocytosis and retrograde traffic pathways. RhoBTB1 was found to be associated with early endosomal intermediates, and changes in the levels of RhoBTB1 not only caused profound changes to the organisation and distribution of endosomes and lysosomes, but also resulted in defects in the delivery of two different classes of cargo molecules to downstream compartments. Together, our data reveal new roles for these atypical Rho family members in the endomembrane system. Full article

(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)

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Review

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21 pages, 4093 KiB

Open AccessReview

Rac GTPase Signaling in Immune-Mediated Mechanisms of Atherosclerosis

by Cadence F. Lee, Rachel E. Carley, Celia A. Butler and Alan R. Morrison

Cells 2021, 10(11), 2808; https://doi.org/10.3390/cells10112808 - 20 Oct 2021

Cited by 11 | Viewed by 4167

Abstract

Coronary artery disease caused by atherosclerosis is a major cause of morbidity and mortality around the world. Data from preclinical and clinical studies support the belief that atherosclerosis is an inflammatory disease that is mediated by innate and adaptive immune signaling mechanisms. This [...] Read more.

Coronary artery disease caused by atherosclerosis is a major cause of morbidity and mortality around the world. Data from preclinical and clinical studies support the belief that atherosclerosis is an inflammatory disease that is mediated by innate and adaptive immune signaling mechanisms. This review sought to highlight the role of Rac-mediated inflammatory signaling in the mechanisms driving atherosclerotic calcification. In addition, current clinical treatment strategies that are related to targeting hypercholesterolemia as a critical risk factor for atherosclerotic vascular disease are addressed in relation to the effects on Rac immune signaling and the implications for the future of targeting immune responses in the treatment of calcific atherosclerosis. Full article

(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)

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25 pages, 1927 KiB

Open AccessReview

Post-Translational Modification and Subcellular Compartmentalization: Emerging Concepts on the Regulation and Physiopathological Relevance of RhoGTPases

by Inmaculada Navarro-Lérida, Miguel Sánchez-Álvarez and Miguel Ángel del Pozo

Cells 2021, 10(8), 1990; https://doi.org/10.3390/cells10081990 - 5 Aug 2021

Cited by 18 | Viewed by 3864

Abstract

Cells and tissues are continuously exposed to both chemical and physical stimuli and dynamically adapt and respond to this variety of external cues to ensure cellular homeostasis, regulated development and tissue-specific differentiation. Alterations of these pathways promote disease progression—a prominent example being cancer. [...] Read more.

Cells and tissues are continuously exposed to both chemical and physical stimuli and dynamically adapt and respond to this variety of external cues to ensure cellular homeostasis, regulated development and tissue-specific differentiation. Alterations of these pathways promote disease progression—a prominent example being cancer. Rho GTPases are key regulators of the remodeling of cytoskeleton and cell membranes and their coordination and integration with different biological processes, including cell polarization and motility, as well as other signaling networks such as growth signaling and proliferation. Apart from the control of GTP–GDP cycling, Rho GTPase activity is spatially and temporally regulated by post-translation modifications (PTMs) and their assembly onto specific protein complexes, which determine their controlled activity at distinct cellular compartments. Although Rho GTPases were traditionally conceived as targeted from the cytosol to the plasma membrane to exert their activity, recent research demonstrates that active pools of different Rho GTPases also localize to endomembranes and the nucleus. In this review, we discuss how PTM-driven modulation of Rho GTPases provides a versatile mechanism for their compartmentalization and functional regulation. Understanding how the subcellular sorting of active small GTPase pools occurs and what its functional significance is could reveal novel therapeutic opportunities. Full article

(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)

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25 pages, 1932 KiB

Open AccessReview

Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

by Maria Luísa da Silveira Hahmeyer and José Eduardo da Silva-Santos

Cells 2021, 10(8), 1844; https://doi.org/10.3390/cells10081844 - 21 Jul 2021

Cited by 13 | Viewed by 6369

Abstract

Sepsis and septic shock are associated with acute and sustained impairment in the function of the cardiovascular system, kidneys, lungs, liver, and brain, among others. Despite the significant advances in prevention and treatment, sepsis and septic shock sepsis remain global health problems with [...] Read more.

Sepsis and septic shock are associated with acute and sustained impairment in the function of the cardiovascular system, kidneys, lungs, liver, and brain, among others. Despite the significant advances in prevention and treatment, sepsis and septic shock sepsis remain global health problems with elevated mortality rates. Rho proteins can interact with a considerable number of targets, directly affecting cellular contractility, actin filament assembly and growing, cell motility and migration, cytoskeleton rearrangement, and actin polymerization, physiological functions that are intensively impaired during inflammatory conditions, such as the one that occurs in sepsis. In the last few decades, Rho proteins and their downstream pathways have been investigated in sepsis-associated experimental models. The most frequently used experimental design included the exposure to bacterial lipopolysaccharide (LPS), in both in vitro and in vivo approaches, but experiments using the cecal ligation and puncture (CLP) model of sepsis have also been performed. The findings described in this review indicate that Rho proteins, mainly RhoA and Rac1, are associated with the development of crucial sepsis-associated dysfunction in different systems and cells, including the endothelium, vessels, and heart. Notably, the data found in the literature suggest that either the inhibition or activation of Rho proteins and associated pathways might be desirable in sepsis and septic shock, accordingly with the cellular system evaluated. This review included the main findings, relevance, and limitations of the current knowledge connecting Rho proteins and sepsis-associated experimental models. Full article

(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)

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15 pages, 1754 KiB

Open AccessReview

RhoA Signaling in Immune Cell Response and Cardiac Disease

by Lucia Sophie Kilian, Derk Frank and Ashraf Yusuf Rangrez

Cells 2021, 10(7), 1681; https://doi.org/10.3390/cells10071681 - 3 Jul 2021

Cited by 7 | Viewed by 4091

Abstract

Chronic inflammation, the activation of immune cells and their cross-talk with cardiomyocytes in the pathogenesis and progression of heart diseases has long been overlooked. However, with the latest research developments, it is increasingly accepted that a vicious cycle exists where cardiomyocytes release cardiocrine [...] Read more.

Chronic inflammation, the activation of immune cells and their cross-talk with cardiomyocytes in the pathogenesis and progression of heart diseases has long been overlooked. However, with the latest research developments, it is increasingly accepted that a vicious cycle exists where cardiomyocytes release cardiocrine signaling molecules that spiral down to immune cell activation and chronic state of low-level inflammation. For example, cardiocrine molecules released from injured or stressed cardiomyocytes can stimulate macrophages, dendritic cells, neutrophils and even T-cells, which then subsequently increase cardiac inflammation by co-stimulation and positive feedback loops. One of the key proteins involved in stress-mediated cardiomyocyte signal transduction is a small GTPase RhoA. Importantly, the regulation of RhoA activation is critical for effective immune cell response and is being considered as one of the potential therapeutic targets in many immune-cell-mediated inflammatory diseases. In this review we provide an update on the role of RhoA at the juncture of immune cell activation, inflammation and cardiac disease. Full article

(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)

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39 pages, 2242 KiB

Open AccessFeature PaperReview

Regulation of the Actin Cytoskeleton via Rho GTPase Signalling in Dictyostelium and Mammalian Cells: A Parallel Slalom

by Vedrana Filić, Lucija Mijanović, Darija Putar, Antea Talajić, Helena Ćetković and Igor Weber

Cells 2021, 10(7), 1592; https://doi.org/10.3390/cells10071592 - 24 Jun 2021

Cited by 12 | Viewed by 4931

Abstract

Both Dictyostelium amoebae and mammalian cells are endowed with an elaborate actin cytoskeleton that enables them to perform a multitude of tasks essential for survival. Although these organisms diverged more than a billion years ago, their cells share the capability of chemotactic migration, [...] Read more.

Both Dictyostelium amoebae and mammalian cells are endowed with an elaborate actin cytoskeleton that enables them to perform a multitude of tasks essential for survival. Although these organisms diverged more than a billion years ago, their cells share the capability of chemotactic migration, large-scale endocytosis, binary division effected by actomyosin contraction, and various types of adhesions to other cells and to the extracellular environment. The composition and dynamics of the transient actin-based structures that are engaged in these processes are also astonishingly similar in these evolutionary distant organisms. The question arises whether this remarkable resemblance in the cellular motility hardware is accompanied by a similar correspondence in matching software, the signalling networks that govern the assembly of the actin cytoskeleton. Small GTPases from the Rho family play pivotal roles in the control of the actin cytoskeleton dynamics. Indicatively, Dictyostelium matches mammals in the number of these proteins. We give an overview of the Rho signalling pathways that regulate the actin dynamics in Dictyostelium and compare them with similar signalling networks in mammals. We also provide a phylogeny of Rho GTPases in Amoebozoa, which shows a variability of the Rho inventories across different clades found also in Metazoa. Full article

(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)

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24 pages, 2868 KiB

Open AccessReview

Emerging Roles of Small GTPases in Islet β-Cell Function

by Rajakrishnan Veluthakal and Debbie C. Thurmond

Cells 2021, 10(6), 1503; https://doi.org/10.3390/cells10061503 - 15 Jun 2021

Cited by 21 | Viewed by 5812

Abstract

Several small guanosine triphosphatases (GTPases) from the Ras protein superfamily regulate glucose-stimulated insulin secretion in the pancreatic islet β-cell. The Rho family GTPases Cdc42 and Rac1 are primarily involved in relaying key signals in several cellular functions, including vesicle trafficking, plasma membrane homeostasis, [...] Read more.

Several small guanosine triphosphatases (GTPases) from the Ras protein superfamily regulate glucose-stimulated insulin secretion in the pancreatic islet β-cell. The Rho family GTPases Cdc42 and Rac1 are primarily involved in relaying key signals in several cellular functions, including vesicle trafficking, plasma membrane homeostasis, and cytoskeletal dynamics. They orchestrate specific changes at each spatiotemporal region within the β-cell by coordinating with signal transducers, guanine nucleotide exchange factors (GEFs), GTPase-activating factors (GAPs), and their effectors. The Arf family of small GTPases is involved in vesicular trafficking (exocytosis and endocytosis) and actin cytoskeletal dynamics. Rab-GTPases regulate pre-exocytotic and late endocytic membrane trafficking events in β-cells. Several additional functions for small GTPases include regulating transcription factor activity and mitochondrial dynamics. Importantly, defects in several of these GTPases have been found associated with type 2 diabetes (T2D) etiology. The purpose of this review is to systematically denote the identities and molecular mechanistic steps in the glucose-stimulated insulin secretion pathway that leads to the normal release of insulin. We will also note newly identified defects in these GTPases and their corresponding regulatory factors (e.g., GDP dissociation inhibitors (GDIs), GEFs, and GAPs) in the pancreatic β-cells, which contribute to the dysregulation of metabolism and the development of T2D. Full article

(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)

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33 pages, 4132 KiB

Open AccessReview

The Multiple Functions of Rho GTPases in Fission Yeasts

by Jero Vicente-Soler, Teresa Soto, Alejandro Franco, José Cansado and Marisa Madrid

Cells 2021, 10(6), 1422; https://doi.org/10.3390/cells10061422 - 7 Jun 2021

Cited by 6 | Viewed by 4110

Abstract

The Rho family of GTPases represents highly conserved molecular switches involved in a plethora of physiological processes. Fission yeast Schizosaccharomyces pombe has become a fundamental model organism to study the functions of Rho GTPases over the past few decades. In recent years, another [...] Read more.

The Rho family of GTPases represents highly conserved molecular switches involved in a plethora of physiological processes. Fission yeast Schizosaccharomyces pombe has become a fundamental model organism to study the functions of Rho GTPases over the past few decades. In recent years, another fission yeast species, Schizosaccharomyces japonicus, has come into focus offering insight into evolutionary changes within the genus. Both fission yeasts contain only six Rho-type GTPases that are spatiotemporally controlled by multiple guanine–nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and whose intricate regulation in response to external cues is starting to be uncovered. In the present review, we will outline and discuss the current knowledge and recent advances on how the fission yeasts Rho family GTPases regulate essential physiological processes such as morphogenesis and polarity, cellular integrity, cytokinesis and cellular differentiation. Full article

(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)

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22 pages, 1332 KiB

Open AccessReview

MMP-9 Signaling Pathways That Engage Rho GTPases in Brain Plasticity

by Izabela Figiel, Patrycja K. Kruk, Monika Zaręba-Kozioł, Paulina Rybak, Monika Bijata, Jakub Wlodarczyk and Joanna Dzwonek

Cells 2021, 10(1), 166; https://doi.org/10.3390/cells10010166 - 15 Jan 2021

Cited by 17 | Viewed by 5249

Abstract

The extracellular matrix (ECM) has been identified as a critical factor affecting synaptic function. It forms a functional scaffold that provides both the structural support and the reservoir of signaling molecules necessary for communication between cellular constituents of the central nervous system (CNS). [...] Read more.

The extracellular matrix (ECM) has been identified as a critical factor affecting synaptic function. It forms a functional scaffold that provides both the structural support and the reservoir of signaling molecules necessary for communication between cellular constituents of the central nervous system (CNS). Among numerous ECM components and modifiers that play a role in the physiological and pathological synaptic plasticity, matrix metalloproteinase 9 (MMP-9) has recently emerged as a key molecule. MMP-9 may contribute to the dynamic remodeling of structural and functional plasticity by cleaving ECM components and cell adhesion molecules. Notably, MMP-9 signaling was shown to be indispensable for long-term memory formation that requires synaptic remodeling. The core regulators of the dynamic reorganization of the actin cytoskeleton and cell adhesion are the Rho family of GTPases. These proteins have been implicated in the control of a wide range of cellular processes occurring in brain physiology and pathology. Here, we discuss the contribution of Rho GTPases to MMP-9-dependent signaling pathways in the brain. We also describe how the regulation of Rho GTPases by post-translational modifications (PTMs) can influence these processes. Full article

(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)

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24 pages, 2051 KiB

Open AccessReview

Rho GTPases as Key Molecular Players within Intestinal Mucosa and GI Diseases

by Rashmita Pradhan, Phuong A. Ngo, Luz d. C. Martínez-Sánchez, Markus F. Neurath and Rocío López-Posadas

Cells 2021, 10(1), 66; https://doi.org/10.3390/cells10010066 - 4 Jan 2021

Cited by 15 | Viewed by 7377

Abstract

Rho proteins operate as key regulators of the cytoskeleton, cell morphology and trafficking. Acting as molecular switches, the function of Rho GTPases is determined by guanosine triphosphate (GTP)/guanosine diphosphate (GDP) exchange and their lipidation via prenylation, allowing their binding to cellular membranes and [...] Read more.

Rho proteins operate as key regulators of the cytoskeleton, cell morphology and trafficking. Acting as molecular switches, the function of Rho GTPases is determined by guanosine triphosphate (GTP)/guanosine diphosphate (GDP) exchange and their lipidation via prenylation, allowing their binding to cellular membranes and the interaction with downstream effector proteins in close proximity to the membrane. A plethora of in vitro studies demonstrate the indispensable function of Rho proteins for cytoskeleton dynamics within different cell types. However, only in the last decades we have got access to genetically modified mouse models to decipher the intricate regulation between members of the Rho family within specific cell types in the complex in vivo situation. Translationally, alterations of the expression and/or function of Rho GTPases have been associated with several pathological conditions, such as inflammation and cancer. In the context of the GI tract, the continuous crosstalk between the host and the intestinal microbiota requires a tight regulation of the complex interaction between cellular components within the intestinal tissue. Recent studies demonstrate that Rho GTPases play important roles for the maintenance of tissue homeostasis in the gut. We will summarize the current knowledge on Rho protein function within individual cell types in the intestinal mucosa in vivo, with special focus on intestinal epithelial cells and T cells. Full article

(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)

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20 pages, 973 KiB

Open AccessReview

Rho GTPases Signaling in Zebrafish Development and Disease

by Marie-José Boueid, Aya Mikdache, Emilie Lesport, Cindy Degerny and Marcel Tawk

Cells 2020, 9(12), 2634; https://doi.org/10.3390/cells9122634 - 8 Dec 2020

Cited by 10 | Viewed by 3672

Abstract

Cells encounter countless external cues and the specificity of their responses is translated through a myriad of tightly regulated intracellular signals. For this, Rho GTPases play a central role and transduce signals that contribute to fundamental cell dynamic and survival events. Here, we [...] Read more.

Cells encounter countless external cues and the specificity of their responses is translated through a myriad of tightly regulated intracellular signals. For this, Rho GTPases play a central role and transduce signals that contribute to fundamental cell dynamic and survival events. Here, we review our knowledge on how zebrafish helped us understand the role of some of these proteins in a multitude of in vivo cellular behaviors. Zebrafish studies offer a unique opportunity to explore the role and more specifically the spatial and temporal dynamic of Rho GTPases activities within a complex environment at a level of details unachievable in any other vertebrate organism. Full article

(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)

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27 pages, 10484 KiB

Open AccessEditor’s ChoiceReview

Rho Family of Ras-Like GTPases in Early-Branching Animals

by Silvestar Beljan, Maja Herak Bosnar and Helena Ćetković

Cells 2020, 9(10), 2279; https://doi.org/10.3390/cells9102279 - 13 Oct 2020

Cited by 16 | Viewed by 4341

Abstract

Non-bilaterian animals consist of four phyla; Porifera, Cnidaria, Ctenophora, and Placozoa. These early-diverging animals are crucial for understanding the evolution of the entire animal lineage. The Rho family of proteins make up a major branch of the Ras superfamily of small GTPases, which [...] Read more.

Non-bilaterian animals consist of four phyla; Porifera, Cnidaria, Ctenophora, and Placozoa. These early-diverging animals are crucial for understanding the evolution of the entire animal lineage. The Rho family of proteins make up a major branch of the Ras superfamily of small GTPases, which function as key molecular switches that play important roles in converting and amplifying external signals into cellular responses. This review represents a compilation of the current knowledge on Rho-family GTPases in non-bilaterian animals, the available experimental data about their biochemical characteristics and functions, as well as original bioinformatics analysis, in order to gain a general insight into the evolutionary history of Rho-family GTPases in simple animals. Full article

(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)

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22 pages, 1396 KiB

Open AccessEditor’s ChoiceReview

Rho GTPases: Big Players in Breast Cancer Initiation, Metastasis and Therapeutic Responses

by Brock Humphries, Zhishan Wang and Chengfeng Yang

Cells 2020, 9(10), 2167; https://doi.org/10.3390/cells9102167 - 25 Sep 2020

Cited by 44 | Viewed by 5778

Abstract

Rho GTPases, a family of the Ras GTPase superfamily, are key regulators of the actin cytoskeleton. They were originally thought to primarily affect cell migration and invasion; however, recent advances in our understanding of the biology and function of Rho GTPases have demonstrated [...] Read more.

Rho GTPases, a family of the Ras GTPase superfamily, are key regulators of the actin cytoskeleton. They were originally thought to primarily affect cell migration and invasion; however, recent advances in our understanding of the biology and function of Rho GTPases have demonstrated their diverse roles within the cell, including membrane trafficking, gene transcription, migration, invasion, adhesion, survival and growth. As these processes are critically involved in cancer initiation, metastasis and therapeutic responses, it is not surprising that studies have demonstrated important roles of Rho GTPases in cancer. Although the majority of data indicates an oncogenic role of Rho GTPases, tumor suppressor functions of Rho GTPases have also been revealed, suggesting a context and cell-type specific function for Rho GTPases in cancer. This review aims to summarize recent progresses in our understanding of the regulation and functions of Rho GTPases, specifically in the context of breast cancer. The potential of Rho GTPases as therapeutic targets and prognostic tools for breast cancer patients are also discussed. Full article

(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)

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20 pages, 1298 KiB

Open AccessReview

Regulation and Functions of ROP GTPases in Plant–Microbe Interactions

by Stefan Engelhardt, Adriana Trutzenberg and Ralph Hückelhoven

Cells 2020, 9(9), 2016; https://doi.org/10.3390/cells9092016 - 2 Sep 2020

Cited by 19 | Viewed by 5606

Abstract

Rho proteins of plants (ROPs) form a specific clade of Rho GTPases, which are involved in either plant immunity or susceptibility to diseases. They are intensively studied in grass host plants, in which ROPs are signaling hubs downstream of both cell surface immune [...] Read more.

Rho proteins of plants (ROPs) form a specific clade of Rho GTPases, which are involved in either plant immunity or susceptibility to diseases. They are intensively studied in grass host plants, in which ROPs are signaling hubs downstream of both cell surface immune receptor kinases and intracellular nucleotide-binding leucine-rich repeat receptors, which activate major branches of plant immune signaling. Additionally, invasive fungal pathogens may co-opt the function of ROPs for manipulation of the cytoskeleton, cell invasion and host cell developmental reprogramming, which promote pathogenic colonization. Strikingly, mammalian bacterial pathogens also initiate both effector-triggered susceptibility for cell invasion and effector-triggered immunity via Rho GTPases. In this review, we summarize central concepts of Rho signaling in disease and immunity of plants and briefly compare them to important findings in the mammalian research field. We focus on Rho activation, downstream signaling and cellular reorganization under control of Rho proteins involved in disease progression and pathogen resistance. Full article

(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)

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19 pages, 1412 KiB

Open AccessReview

Rho GTPases in the Amygdala—A Switch for Fears?

by Tasnuva Sarowar and Andreas M. Grabrucker

Cells 2020, 9(9), 1972; https://doi.org/10.3390/cells9091972 - 26 Aug 2020

Cited by 6 | Viewed by 4399

Abstract

Fear is a fundamental evolutionary process for survival. However, excess or irrational fear hampers normal activity and leads to phobia. The amygdala is the primary brain region associated with fear learning and conditioning. There, Rho GTPases are molecular switches that act as signaling [...] Read more.

Fear is a fundamental evolutionary process for survival. However, excess or irrational fear hampers normal activity and leads to phobia. The amygdala is the primary brain region associated with fear learning and conditioning. There, Rho GTPases are molecular switches that act as signaling molecules for further downstream processes that modulate, among others, dendritic spine morphogenesis and thereby play a role in fear conditioning. The three main Rho GTPases—RhoA, Rac1, and Cdc42, together with their modulators, are known to be involved in many psychiatric disorders that affect the amygdala′s fear conditioning mechanism. Rich2, a RhoGAP mainly for Rac1 and Cdc42, has been studied extensively in such regard. Here, we will discuss these effectors, along with Rich2, as a molecular switch for fears, especially in the amygdala. Understanding the role of Rho GTPases in fear controlling could be beneficial for the development of therapeutic strategies targeting conditions with abnormal fear/anxiety-like behaviors. Full article

(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)

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17 pages, 1196 KiB

Open AccessReview

High Throughput strategies Aimed at Closing the GAP in Our Knowledge of Rho GTPase Signaling

by Manel Dahmene, Laura Quirion and Mélanie Laurin

Cells 2020, 9(6), 1430; https://doi.org/10.3390/cells9061430 - 9 Jun 2020

Cited by 7 | Viewed by 4877

Abstract

Since their discovery, Rho GTPases have emerged as key regulators of cytoskeletal dynamics. In humans, there are 20 Rho GTPases and more than 150 regulators that belong to the RhoGEF, RhoGAP, and RhoGDI families. Throughout development, Rho GTPases choregraph a plethora of cellular [...] Read more.

Since their discovery, Rho GTPases have emerged as key regulators of cytoskeletal dynamics. In humans, there are 20 Rho GTPases and more than 150 regulators that belong to the RhoGEF, RhoGAP, and RhoGDI families. Throughout development, Rho GTPases choregraph a plethora of cellular processes essential for cellular migration, cell–cell junctions, and cell polarity assembly. Rho GTPases are also significant mediators of cancer cell invasion. Nevertheless, to date only a few molecules from these intricate signaling networks have been studied in depth, which has prevented appreciation for the full scope of Rho GTPases’ biological functions. Given the large complexity involved, system level studies are required to fully grasp the extent of their biological roles and regulation. Recently, several groups have tackled this challenge by using proteomic approaches to map the full repertoire of Rho GTPases and Rho regulators protein interactions. These studies have provided in-depth understanding of Rho regulators specificity and have contributed to expand Rho GTPases’ effector portfolio. Additionally, new roles for understudied family members were unraveled using high throughput screening strategies using cell culture models and mouse embryos. In this review, we highlight theses latest large-scale efforts, and we discuss the emerging opportunities that may lead to the next wave of discoveries. Full article

(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)

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