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RhoA, Rac1 and CDC42 are small G proteins that play a crucial role in regulating various cellular processes, such as the formation of actin cytoskeleton, cell shape and cell migration. Our recent results suggest that MLL is responsible for maintaining the balance of these small Rho GTPases. MLL depletion affects the stability of Rho GTPases, leading to a decrease in their protein levels and loss of activity. These changes manifest in the form of abnormal cell shape and disrupted actin cytoskeleton, resulting in reduced cell spreading and migration. Interestingly, their chaperone protein RhoGDI1 but not the Rho GTPases, is under the direct transcriptional regulation of MLL. Here, we comment on the possible implications of these observations on the signalling by Rho GTPases protein network. [ABSTRACT FROM AUTHOR]

Rho family GTPases are molecular switches best known for their pivotal role in dynamic regulation of the actin cytoskeleton, but also of cellular morphology, motility, adhesion and proliferation. The prototypic members of this family (RhoA, Rac1 and Cdc42) also contribute to the normal kidney function and play important roles in the structure and function of various kidney cells including tubular epithelial cells, mesangial cells and podocytes. The kidney's vital filtration function depends on the structural integrity of the glomerulus, the proximal portion of the nephron. Within the glomerulus, the architecturally actin-based cytoskeleton podocyte forms the final cellular barrier to filtration. The glomerulus appears as a highly dynamic signalling hub that is capable of integrating intracellular cues from its individual structural components. Dynamic regulation of the podocyte cytoskeleton is required for efficient barrier function of the kidney. As master regulators of actin cytoskeletal dynamics, Rho GTPases are therefore of critical importance for sustained kidney barrier function. Dysregulated activities of the Rho GTPases and of their effectors are implicated in the pathogenesis of both hereditary and idiopathic forms of kidney diseases. Diabetic nephropathy is a progressive kidney disease that is caused by injury to kidney glomeruli. High glucose activates RhoA/Rho-kinase in mesangial cells, leading to excessive extracellular matrix production (glomerulosclerosis). This RhoA/Rho-kinase pathway also seems involved in the post-transplant hypertension frequently observed during treatment with calcineurin inhibitors, whereas Rac1 activation was observed in post-transplant ischaemic acute kidney injury. [ABSTRACT FROM AUTHOR]

Cytokinesis is required to cleave the daughter cells at the end of mitosis and relies on the spatiotemporal control of RhoA GTPase. Cytokinesis failure can lead to changes in cell fate or aneuploidy, which can be detrimental during development and/or can lead to cancer. However, our knowledge of the pathways that regulate RhoA during cytokinesis is limited, and the role of other Rho family GTPases is not clear. This is largely because the study of Rho GTPases presents unique challenges using traditional cell biological and biochemical methods, and they have pleiotropic functions making genetic studies difficult to interpret. The recent generation of optogenetic tools and biosensors that control and detect active Rho has overcome some of these challenges and is helping to elucidate the role of RhoA in cytokinesis. However, improvements are needed to reveal the role of other Rho GTPases in cytokinesis, and to identify the molecular mechanisms that control Rho activity. This review examines some of the outstanding questions in cytokinesis, and explores tools for the imaging and control of Rho GTPases. [ABSTRACT FROM AUTHOR]

A growing body of evidence implicates requisite roles for GTP and its binding proteins (Rho GTPases) in the cascade of events leading to physiological insulin secretion from the islet beta cell. Interestingly, chronic exposure of these cells to hyperglycaemic conditions appears to result in sustained activation of specific Rho GTPases (e.g. Rac1) leading to significant alterations in cellular functions including defects in mitochondrial function and nuclear collapse culminating in beta cell demise. One of the objectives of this review is to highlight our current understanding of the regulatory roles of GTP and Rho GTPases in normal islet function (e.g. proliferation and insulin secretion) as well potential defects in these signalling molecules and metabolic pathways that could contribute islet beta cell dysfunction and loss of functional beta cell mass leading to the onset of diabetes. Potential knowledge gaps in this field and possible avenues for future research are also highlighted. Abbreviations: ARNO: ADP-ribosylation factor nucleotide binding site opener; CML: carboxyl methylation; Epac: exchange protein directly activated by cAMP; ER stress: endoplasmic reticulum stress; FTase: farnesyltransferase; GAP: GTPase activating protein; GDI: GDP dissociation inhibitor; GEF: guanine nucleotide exchange factor; GGTase: geranylgeranyltransferase; GGpp: geranylgeranylpyrophosphate; GGPPS: geranylgeranyl pyrophosphate synthase; GSIS: glucose-stimulated insulin secretion; HGPRTase: hypoxanthine-guanine phosphoribosyltransferase; IMPDH: inosine monophosphate dehydrogenase; α-KIC: α-ketoisocaproic acid; MPA: mycophenolic acid; MVA: mevalonic acid; NDPK: nucleoside diphosphate kinase; NMPK: nucleoside monophosphate kinase; Nox2: phagocyte-like NADPH oxidase; PAK-I: p21-activated kinase-I; β-PIX: β-Pak-interacting exchange factor; PRMT: protein arginine methyltransferase; Rac1: ras-related C3 botulinum toxin substrate 1; Tiam1: T-cell lymphoma invasion and metastasis-inducing protein 1; Trx-1: thioredoxin-1; Vav2: vav guanine nucleotide exchange factor 2 [ABSTRACT FROM AUTHOR]

Rho GTPases are known to play an essential role in fundamental processes such as defining cell shape, polarity and migration. As such, the majority of Rho GTPases localize and function at, or close to, the plasma membrane. However, it is becoming increasingly clear that a number of Rho family proteins are also associated with the Golgi complex, where they not only regulate events at this organelle but also more widely across the cell. Given the central location of this organelle, and the numerous membrane trafficking pathways that connect it to both the endocytic and secretory systems of cells, it is clear that the Golgi is fundamental for maintaining cellular homoeostasis. In this review, we describe these GTPases in the context of how they regulate Golgi architecture, membrane trafficking into and away from this organelle, and cell polarity and migration. We summarize the key findings that show the growing importance of the pool of Rho GTPases associated with Golgi function, namely Cdc42, RhoA, RhoD, RhoBTB1 and RhoBTB3, and we discuss how they act in concert with other key families of molecules associated with the Golgi, including Rab GTPases and matrix proteins. [ABSTRACT FROM AUTHOR]

The Rho GTPases were discovered more than 30 years ago, and they were for a long time considered to follow simple cycling between GDP-bound and GTP-bound conformations, as for the Ras subfamily of small GTPases. The Rho GTPases consist of 20 members, but at least 10 of these do not follow this classical GTPase cycle. Thus, based on their kinetic properties, these Rho GTPases can instead be classified as atypical. Some of these atypical Rho GTPases do not hydrolyze GTP, and some have significantly increased intrinsic GDP/GTP exchange activity. This review focuses on this latter category of atypical Rho GTPases, the so-called 'fast-cycling' Rho GTPases. The different members of these fast-cycling atypical Rho GTPases are described in more detail here, along with their potential regulatory mechanisms. Finally, some insights are provided into the involvement of the atypical Rho GTPases in human pathologies. [ABSTRACT FROM AUTHOR]

Oncogenic protein kinase C epsilon (PKCε) promotes the formation of membrane ruffles and motility in non-small cell lung cancer (NSCLC) cells. We found that PKCε is down-regulated when NSCLC cells undergo epithelial-to-mesenchymal transition (EMT) in response to TGF-β, thus becoming dispensable for migration and invasion in the mesenchymal state. PKCε silencing or inhibition leads to stress fibre formation, suggesting that this kinase negatively regulates RhoA activity. Ruffle formation induced by PKCε activation in the epithelial state is dependent on PI3K, but does not involve the PI3K-dependent Rac-GEFs Ect2, Trio, Vav2 or Tiam1, suggesting alternative Rac-GEFs as mediators of this response. In the proposed model, PKCε acts as a rheostat for Rho GTPases that differs in the epithelial and mesenchymal states. [ABSTRACT FROM AUTHOR]

The Arf and Rho subfamilies of small GTPases are nucleotide-dependent molecular switches that act as master regulators of vesicular trafficking and the actin cytoskeleton organization. Small GTPases control cell processes with high fidelity by acting through distinct repertoires of binding partners called effectors. While we understand a great deal about how these GTPases act individually, relatively little is known about how they cooperate, especially in the control of effectors. This review highlights how Arf GTPases collaborate with Rac1 to regulate actin cytoskeleton dynamics at the membrane via recruiting and activating the Wave Regulatory Complex (WRC), a Rho effector that underpins lamellipodia formation and macropinocytosis. This provides insight into Arf regulation of the actin cytoskeleton, while putting the spotlight on small GTPase cooperation with emerging evidence of its importance in fundamental cell biology and interactions with pathogenic bacteria. [ABSTRACT FROM AUTHOR]

Neutrophils are short-lived, abundant peripheral blood leukocytes that provide a first line of defense against bacterial and fungal infections while also being a key part of the inflammatory response. Chemokines induce neutrophil recruitment to inflammatory sites, where neutrophils perform several diverse functions that are aimed at fighting infections. Neutrophil effector functions are tightly regulated processes that are governed by an array of intracellular signaling pathways and initiated by receptor-ligand binding events. Dysregulated neutrophil activation can result in excessive inflammation and host damage, as is evident in several autoimmune diseases. Rho family small GTPases and agonist-activated phosphoinositide 3-kinases (PI3Ks) represent 2 classes of key regulators of the highly specialized neutrophil. Here we review cross-talk between these important signaling intermediates in the context of neutrophil functions. We include PI3K-dependent activation of Rho family small GTPases and of their guanine nucleotide exchange factors and GTPase activating proteins, as well as Rho GTPase-dependent regulation of PI3K. [ABSTRACT FROM AUTHOR]

DOCK6 is a RAC1/CDC42 guanine nucleotide exchange factor, however, little is known about its function and sub-cellular localization. DOCK6 regulates the balance between RAC1 and RHOA activity during cell adhesion and is important for CDC42-dependent mitotic chromosome alignment. Surprisingly, a cell intrinsic adaptation mechanism compensates for errors in these DOCK6 functions that arise as a consequence of prolonged DOCK6 depletion or complete removal in DOCK6 knockout cells. Down-regulation of the ubiquitin-like modifier ISG15 accounts for this adaptation. Strikingly, although most other DOCK family proteins are deployed on the plasma membrane, here we show that DOCK6 localizes to the endoplasmic reticulum (ER) in dependence of its DHR-1 domain. ER localization of DOCK6 opens up new insights into its functions. [ABSTRACT FROM AUTHOR]

Neural tube closure is an important morphogenetic event that involves dramatic reshaping of both neural and non-neural tissues. Rho GTPases are key cytoskeletal regulators involved in cell motility and in several developmental processes, and are thus expected to play pivotal roles in neurulation. Here, we discuss 2 recent studies that shed light on the roles of distinct Rho GTPases in different tissues during neurulation. RhoA plays an essential role in regulating actomyosin dynamics in the neural epithelium of the elevating neural folds, while Rac1 is required for the formation of cell protrusions in the non-neural surface ectoderm during neural fold fusion. [ABSTRACT FROM AUTHOR]

Migratory polarity and epithelial polarity share many common regulatory mechanisms. Rho GTPases play a key role in modulating cell polarity, which in migrating cells has been conventionally studied along the solitary front-rear axis. In recent work, we discovered that Prickle1 (Pk1), a core com-ponent of planar cell polarity (PCP) signaling, mediates a novel lateral signaling pathway that coordinates multi-axial protrusive activities from the lateral cortex of migrating cancer cells. We identified that Arhgap21 and 23 are essential effectors of Pk1, and that lateral signaling regulates RhoA, actomyosin and focal adhesion dynamics. Interestingly, we showed that lateral signaling coordinates shape dynamics that are critical during cell migration and function orthogonally to front-rear directional polarity. [ABSTRACT FROM AUTHOR]

The 20 members of the Rho GTPase family are key regulators of a wide-variety of biological activities. In response to activation, they signal via downstream effector proteins to induce dynamic alterations in the organization of the actomyosin cytoskeleton. In this review, post-translational modifications, mechanisms of dysregulation identified in human pathological conditions, and the ways that Rho GTPases might be targeted for chemotherapy will be discussed. [ABSTRACT FROM AUTHOR]

In vitroandin vivostudies and evidence from human tumors have long implicated Rho GTPase signaling in the formation and dissemination of a range of cancers. Recently next generation sequencing has identified direct mutations of Rho GTPases in human cancers. Moreover, the effects of ablating genes encoding Rho GTPases and their regulators in mouse models, or through pharmacological inhibition, strongly suggests that targeting Rho GTPase signaling could constitute an effective treatment. In this review we will explore the various ways in which Rho signaling can be deregulated in human cancers. [ABSTRACT FROM PUBLISHER]

Since their discovery in the late eighties, the role of Rho GTPases in the regulation of cell migration has been extensively studied and has mainly focused on the hallmark family members Rho, Rac, and Cdc42. Recent technological advances in cell biology, such as Rho-family GTPase activity biosensors, studies in 3D, and unbiased RNAi-based screens, have revealed an increasingly complex role for Rho GTPases during cell migration, with many inter-connected functions and a strong dependency on the physical and chemical properties of the surrounding environment. This review aims to give an overview of recent studies on the role of Rho-family GTPase members in the modulation of cell migration in different environments, and discuss future directions. [ABSTRACT FROM PUBLISHER]

Megakaryocytes (MKs) are the bone marrow (BM) cells that generate blood platelets by a process that requires: i) polyploidization responsible for the increased MK size and ii) cytoplasmic organization leading to extension of long pseudopods, called proplatelets, through the endothelial barrier to allow platelet release into blood. Low level of localized RHOA activation prevents actomyosin accumulation at the cleavage furrow and participates in MK polyploidization. In the platelet production, RHOA and CDC42 play opposite, but complementary roles. RHOA inhibits both proplatelet formation and MK exit from BM, whereas CDC42 drives the development of the demarcation membranes and MK migration in BM. Moreover, the RhoA or Cdc42 MK specific knock-out in mice and the genetic alterations in their down-stream effectors in human induce a thrombocytopenia demonstrating their key roles in platelet production. A better knowledge of Rho-GTPase signalling is thus necessary to develop therapies for diseases associated with platelet production defects. Abbreviations: AKT: Protein Kinase BARHGEF2: Rho/Rac Guanine Nucleotide Exchange Factor 2ARP2/3: Actin related protein 2/3BM: Bone marrowCDC42: Cell division control protein 42 homologCFU-MK: Colony-forming-unit megakaryocyteCIP4: Cdc42-interacting protein 4mDIA: DiaphanousDIAPH1; Protein diaphanous homolog 1ECT2: Epithelial Cell Transforming Sequence 2FLNA: Filamin AGAP: GTPase-activating proteins or GTPase-accelerating proteinsGDI: GDP Dissociation InhibitorGEF: Guanine nucleotide exchange factorHDAC: Histone deacetylaseLIMK: LIM KinaseMAL: Megakaryoblastic leukaemiaMARCKS: Myristoylated alanine-rich C-kinase substrateMKL: Megakaryoblastic leukaemiaMLC: Myosin light chainMRTF: Myocardin Related Transcription FactorOTT: One-Twenty Two ProteinPACSIN2: Protein Kinase C And Casein Kinase Substrate In Neurons 2PAK: P21-Activated KinasePDK: Pyruvate Dehydrogenase kinasePI3K: Phosphoinositide 3-kinasePKC: Protein kinase CPTPRJ: Protein tyrosine phosphatase receptor type JRAC: Ras-related C3 botulinum toxin substrate 1RBM15: RNA Binding Motif Protein 15RHO: Ras homologousROCK: Rho-associated protein kinaseSCAR: Suppressor of cAMP receptorSRF: Serum response factorSRC: SarcTAZ: Transcriptional coactivator with PDZ motifTUBB1: Tubulin β1VEGF: Vascular endothelial growth factorWAS: Wiskott Aldrich syndromeWASP: Wiskott Aldrich syndrome proteinWAVE: WASP-family verprolin-homologous proteinWIP: WASP-interacting proteinYAP: Yes-associated protein.

Rho GTPases are involved in the acquisition of all the hallmarks of cancer, which comprise 6 biological capabilities acquired during the development of human tumors. The hallmarks include proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis programs, as defined by Hanahan and Weinberg.1 Controlling these hallmarks are genome instability and inflammation. Emerging hallmarks are reprogramming of energy metabolism and evading immune destruction. To give a different view to the readers, we will not be focusing on invasion, metastasis, or cytoskeletal remodeling, but we will review here how Rho GTPases contribute to other hallmarks of cancer with a special emphasis on malignant transformation. [ABSTRACT FROM AUTHOR]

Rho-GTPases belong to the Ras superfamily and are crucial signal transducing proteins downstream of many receptors. In general, the Rho-GTPases function as molecular switches, cycling between inactive (GDP-bound) and active (GTP-bound) states. The activated GTP bound Rho-GTPases interact with a broad spectrum of effectors to regulate a plethora of biological pathways including cytoskeletal dynamics, motility, cytokinesis, cell growth, apoptosis, transcriptional activity and nuclear signaling. Recently, gene targeting in mice allowed the selective inactivation of different Rho-GTPases and has advanced our understanding of the physiological role of these proteins, particularly in the immune system. Particularly, these proteins are key signaling molecules in T lymphocytes, which are generated in the thymus and are major players in the immune system. The scope of this review is to discuss recent data obtained in Rho-GTPases deficient mice by focusing on the role-played by Rho-GTPases in T-lymphocyte development, migration, activation and differentiation. [ABSTRACT FROM PUBLISHER]

The Rho family of GTPases (members of the Ras superfamily) are best known for their roles in regulating cytoskeletal dynamics. It is also well established that misregulation of Rho proteins contributes to tumorigenesis and metastasis. Unlike Ras proteins, which are frequently mutated in cancer (around 30%), Rho proteins themselves are generally not found to be mutated in cancer. rather, misregulation of Rho activity in cancer was thought to occur by overexpression of these proteins or by misregulation of molecules that control Rho activity, such as activation or overexpression of GeFs and inactivation or loss of GaPs or GDIs. recent studies, enabled by next-generation tumor exome sequencing, report activating point mutations in Rho GTPases as driver mutations in melanoma, as well as breast, and head and neck cancers. The 771(P29L) mutation identified in these tumor studies was previously identified by our lab as an activating Rac mutation in C. elegans neuronal development, highlighting the conserved nature of this mutation. Furthermore, this finding supports the relevance of studying Rho GTPases in model organisms such as C. elegans to study the mechanisms that underlie carcinogenesis. This review will describe the recent findings that report activating Rho mutations in various cancer types, moving Rho GTPases from molecules misregulated in cancer to mutagenic targets that drive tumorigenesis. [ABSTRACT FROM AUTHOR]

The family of Rho GTPases are intracellular signal transducers that link cell surface signals to multiple intracellular responses. They are best known for their role in regulating actin dynamics required for cell migration, but in addition control cell-cell adhesion, polarization, vesicle trafficking, and the cell cycle. The roles of Rho GTPases in single mesenchymal cell migration are well established and rely on Cdc42- and Rac-dependent cell protrusion of a leading edge, coupled to Rho-dependent contractility required to move the cell body forward. In cells migrating collectively, cell-cell junctions are maintained, and migrating leader cells are mechanically coupled to, and coordinate, migration with follower cells. Recent evidence suggests that Rho GTPases provide multifunctional input to collective cell polarization, cell-cell interaction, and migration. Here, we discuss the role of Rho GTPases in initiating and maintaining front-rear, apical-basal cell polarization, mechanotransduction, and cell-cell junction stability between leader and follower cells, and how these roles are integrated in collective migration. Thereby, spatiotemporal fine-tuning of Rho GTPases within the same cell and among cells in the cell group are crucial in controlling potentially conflicting, divergent cell adhesion and cytoskeletal functions to achieve supracellular coordination and mechanocoupling. [ABSTRACT FROM PUBLISHER]

Formin proteins were recognized as effectors of Rho GTPases some 15 years ago. They contribute to different cellular actin cytoskeleton structures by their ability to polymerize straight actin filaments at the barbed end. While not all formins necessarily interact with Rho GTPases, a subgroup of mammalian formins, termed Diaphanous-related formins or DRFs, were shown to be activated by small GTPases of the Rho superfamily. DRFs are autoinhibited in the resting state by an N- to C-terminal interaction that renders the central actin polymerization domain inactive. Upon the interaction with a GTP-bound Rho, Rac, or Cdc42 GTPase, the C-terminal autoregulation domain is displaced from its N-terminal recognition site and the formin becomes active to polymerize actin filaments. In this review we discuss the current knowledge on the structure, activation, and function of formin-GTPase interactions for the mammalian formin families Dia, Daam, FMNL, and FHOD. We describe both direct and indirect interactions of formins with GTPases, which lead to formin activation and cytoskeletal rearrangements. The multifaceted function of formins as effector proteins of Rho GTPases thus reflects the diversity of the actin cytoskeleton in cells. [ABSTRACT FROM PUBLISHER]

In the last decade, several mouse models for RhoA, Rac1, and Cdc42 have emerged and have contributed a great deal to understanding the precise functions of Rho GTPases at early stages of development. This review summarizes our current knowledge of various mouse models of tissue-specific ablation of Cdc42, Rac1, and RhoA with emphasis on early embryogenesis, epithelial and skin morphogenesis, tubulogenesis, development of the central nervous system, and limb development. [ABSTRACT FROM PUBLISHER]

Signaling via the Rho GTPases provides crucial regulation of numerous cell polarization events, including apicobasal (AB) polarity, polarized cell migration, polarized cell division and neuronal polarity. Here we review the relationships between the Rho family GTPases and epithelial AB polarization events, focusing on the 3 best-characterized members: Rho, Rac and Cdc42. We discuss a multitude of processes that are important for AB polarization, including lumen formation, apical membrane specification, cell-cell junction assembly and maintenance, as well as tissue polarity. Our discussions aim to highlight the immensely complex regulatory mechanisms that encompass Rho GTPase signaling during AB polarization. More specifically, in this review we discuss several emerging common themes, that include: 1) the need for Rho GTPase activities to be carefully balanced in both a spatial and temporal manner through a multitude of mechanisms; 2) the existence of signaling feedback loops and crosstalk to create robust cellular responses; and 3) the frequent multifunctionality that exists among AB polarity regulators. Regarding this latter theme, we provide further discussion of the potential plasticity of the cell polarity machinery and as a result the possible implications for human disease. [ABSTRACT FROM PUBLISHER]

An introduction to the journal is presented in which the editors discuss various reports within the issue on topics depicting Rho family GTPases from biochemistry to physiopathology.

Pathogens have evolved highly specialized mechanisms to infect hosts. Several microorganisms modulate the eukaryotic cell surface to facilitate their engulfment. Once internalized, they hijack the molecular machinery of the infected cell for their own benefit. At different stages of phagocytosis, particularly during invasion, certain pathogens manipulate pathways governed by small GTPases. In this review, we focus on the role of Rho proteins on curable, sexually transmitted infections caused by Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis and Treponema pallidum. Despite the high, worldwide frequencies of these sexually-transmitted diseases, very little is known about the strategies developed by these microorganisms to usurp key eukaryotic proteins that control intracellular signaling and actin dynamics. Improved knowledge of these molecular mechanisms will contribute to the elucidation of how these clinically important pathogens manipulate intracellular processes and parasitize their hosts. [ABSTRACT FROM AUTHOR]

Phagocytosis is defined as a cellular uptake pathway for particles of greater than 0.5 μm in diameter. Particle clearance by phagocytosis is of critical importance for tissue health and homeostasis. The ultimate goal of anti-pathogen phagocytosis is to destroy engulfed bacteria or fungi and to stimulate cell-cell signaling that mount an efficient immune defense. In contrast, clearance phagocytosis of apoptotic cells and cell debris is anti-inflammatory. High capacity clearance phagocytosis pathways are available to professional phagocytes of the immune system and the retina. Additionally, a low capacity, so-called bystander phagocytic pathway is available to most other cell types. Different phagocytic pathways are stimulated by particle ligation of distinct surface receptors but all forms of phagocytosis require F-actin recruitment beneath tethered particles and F-actin re-arrangement promoting engulfment, which are controlled by Rho family GTPases. The specificity of Rho GTPase activity during the different forms of phagocytosis by mammalian cells is the subject of this review. [ABSTRACT FROM PUBLISHER]

Proper regulation of arterial blood pressure is essential to allow permanent adjustment of nutrient and oxygen supply to organs and tissues according to their need. This is achieved through highly coordinated regulation processes controlling vascular resistance through modulation of arterial smooth muscle contraction, cardiac output, and kidney function. Members of the Rho family of small GTPases, in particular RhoA and Rac1, have been identified as key signaling molecules playing important roles in several different steps of these regulatory processes. Here, we review the current state of knowledge regarding the involvement of Rho GTPase signaling in the control of blood pressure and the pathogenesis of hypertension. We describe how knockout models in mouse, genetic, and pharmacological studies in human have been useful to address this question. [ABSTRACT FROM PUBLISHER]

Cell cycle regulators, such as cyclins, are often upregulated in many proliferative disorders and Cyclin A2 is generally considered as a marker of aggressive cancers. Our recent work, which revealed decreased expression of Cyclin A2 upon metastasis of colorectal cancer, suggests a more complicated situation. Consistent with this, we identified a role for Cyclin A2, via RhoA, in regulation of the actin cytoskeleton and the control of cell invasion. Cyclin A2 also regulates spindle orientation which, when misoriented, could disrupt cell polarity and favor cancer cell detachment from the tumor as part of a transforming process, such as epithelial to mesenchymal transition (EMT). During EMT, cells undergo morphological and molecular changes toward a mesenchymal phenotype. Upregulation, or increased activity of some Rho GTPases, such as Cdc42, Rac1 or RhoC, increases the invasive potential of these cells. This correlates with the inverse relationship between RhoA and RhoC activities we observed in an epithelial cell type. Altogether, these observations raise the possibility that Cyclin A2 is instrumental in preventing EMT and therefore cancers of epithelial tissues. [ABSTRACT FROM AUTHOR]

Rnd proteins constitute a subfamily of Rho GTPases represented in mammals by Rnd1, Rnd2 and Rnd3. Despite their GTPase structure, their specific feature is the inability to hydrolyse GTP-bound nucleotide. This aspect makes them atypical among Rho GTPases. Rnds are regulated for their expression at the transcriptional or post-transcriptional levels and they are activated through post-translational modifications and interactions with other proteins. Rnd proteins are mainly involved in the regulation of the actin cytoskeleton and cell proliferation. Whereas Rnd3 is ubiquitously expressed, Rnd1 and 2 are tissue-specific. Increasing data has described their important role during development and diseases. Herein, we describe their involvement in physiological and pathological conditions with a focus on the neuronal and vascular systems, and summarize their implications in tumorigenesis. [ABSTRACT FROM AUTHOR]

The Ras homologous (Rho) protein family of GTPases (RhoA, RhoB and RhoC) are the members of the Ras superfamily and regulate cellular processes such as cell migration, proliferation, polarization, adhesion, gene transcription and cytoskeletal structure. Rho GTPases function as molecular switches that cycle between GTP-bound (active state) and GDP-bound (inactive state) forms. Leukaemia-associated RhoGEF (LARG) is a guanine nucleotide exchange factor (GEF) that activates RhoA subfamily GTPases by promoting the exchange of GDP for GTP. LARG is selective for RhoA subfamily GTPases and is an essential regulator of cell migration and invasion. Here, we describe the mechanisms by which LARG is regulated to facilitate the understanding of how LARG mediates functions like cell motility and to provide insight for better therapeutic targeting of these functions. [ABSTRACT FROM AUTHOR]

Cell invasion is associated with numerous patho-physiologic states including cell development and metastatic dissemination. This process couples the activation of cell motility with the capacity to degrade the extracellular matrix, thereby permitting cells to pass through basal membranes. Invasion is sustained by the actions of invadosomes, an ensemble of subcellular structures with high functional homology. Invadosomes are 3D acto-adhesive structures that can also mediate local extracellular matrix degradation through the controlled delivery of proteases. Intracellular RHO GTPases play a central role in the regulation of invadosomes where their complex interplay regulates multiple invadosome functions. This review aims to provide an overview of the synergistic activities of the small GTPases in invadosome biology. This broad-based review also reinforces the importance of the spatiotemporal regulation of small GTPases and the impact of this process on invadosome dynamics. [ABSTRACT FROM AUTHOR]

Since the discovery by Madaule and Axel in 1985 of the first Ras homologue (Rho) protein in Aplysia and its human orthologue RhoB, membership in the Rho GTPase family has grown to 20 proteins, with representatives in all eukaryotic species. These GTPases are molecular switches that cycle between active (GTP bound) and inactivate (GDP bound) states. The exchange of GDP for GTP on Rho GTPases is facilitated by guanine exchange factors (GEFs). Approximately 80 Rho GEFs have been identified to date, and only a few GEFs associate with microtubules. The guanine nucleotide exchange factor H1, GEF-H1, is a unique GEF that associates with microtubules and is regulated by the polymerization state of microtubule networks. This review summarizes the regulation and functions of GEF-H1 and discusses the roles of GEF-H1 in human diseases. [ABSTRACT FROM AUTHOR]

Rho GTPases play central roles in a wide variety of cellular processes, including cytoskeletal dynamics, cell adhesion and cell polarity. RhoU and RhoV are Rho GTPases that have some atypical properties compared with classical Rho family members, such as the presence of N- and C-terminal extension regions, unusual GDP/GTP cycling and post-translational modification by palmitoylation but not prenylation. Their activity and localization is regulated by the N-terminal and C-terminal regions, and so far no GEFs or GAPs have been identified for them. Similar to Rac and Cdc42, they interact with PAK serine/threonine kinases, and in the case of PAK4, this interaction leads to RhoU protein stabilization. In cells, RhoU and RhoV alter cell shape and cell adhesion, which probably underlies some of the phenotypes reported for these proteins in vivo, for example in heart development and epithelial morphogenesis. However, the molecular basis for these functions of RhoU and RhoV remains to be characterized. [ABSTRACT FROM AUTHOR]

Cell migration, a crucial step in numerous biological processes, is tightly regulated in space and time. Cells employ Rho GTPases, primarily Rho, Rac, and Cdc42, to regulate their motility. Like other small G proteins, Rho GTPases function as biomolecular switches in regulating cell migration by operating between GDP bound 'OFF' and GTP bound 'ON' states. Guanine nucleotide exchange factors (GEFs) catalyse the shuttling of GTPases from OFF to ON state. G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors that are involved in many signalling phenomena including cell survival and cell migration events. In this review, we summarize signalling mechanisms, involving GPCRs, leading to the activation of RhoGEFs. GPCRs exhibit diverse GEF activation modes that include the interaction of heterotrimeric G protein subunits with different domains of GEFs, phosphorylation, protein–protein interaction, protein–lipid interaction, and/or a combination of these processes. [ABSTRACT FROM AUTHOR]

Rho GTPases are well known for their roles in regulating cell migration, and also contribute to a variety of other cellular responses. They are subdivided into 2 groups: typical and atypical. The typical Rho family members, including RhoA, Rac1 and Cdc42, cycle between an active GTP-bound and inactive GDP-bound conformation, and are regulated by GEFs, GAPs and GDIs, whereas atypical Rho family members have amino acid substitutions that alter their ability to interact with GTP/GDP and hence are regulated by different mechanisms. Both typical and atypical Rho GTPases contribute to cancer progression. In a few cancers, RhoA or Rac1 are mutated, but in most cancers expression levels and/or activity of Rho GTPases is altered. Rho GTPase signaling could therefore be therapeutically targeted in cancer treatment. [ABSTRACT FROM AUTHOR]

Cell migration, a key feature of embryonic development, immunity, angiogenesis, and tumor metastasis, is based on the coordinated regulation of actin dynamics and integrin-mediated adhesion. Rho GTPases play a major role in this phenomenon by regulating the onset and maintenance of actin-based protruding structures at cell leading edges (i.e. lamellipodia and filopodia) and contractile structures (i.e., stress fibers) at their trailing edge. While spatio-temporal analysis demonstrated the tight regulation of Rho GTPases at the migration front during cell locomotion, little is known about how the main regulators of Rho GTPase activity, such as GAPs, GEFs and GDIs, play a role in this process. In this review, we focus on a major negative regulator of RhoA, p190RhoGAP-A and its close isoform p190RhoGAP-B, which are necessary for efficient cell migration. Recent studies, including our, demonstrated that p190RhoGAP-A localization and activity undergo a complex regulatory mechanism, accounting for the tight regulation of RhoA, but also other members of the Rho GTPase family, at the cell periphery. [ABSTRACT FROM AUTHOR]