51,821 results on '"RHO GTPases"'
Search Results
202. Sequential inactivation of Rho GTPases and Lim kinase by Pseudomonas aeruginosa toxins ExoS and ExoT leads to endothelial monolayer breakdown
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Huber, P., Bouillot, S., Elsen, S., and Attrée, I.
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- 2014
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203. Aberrant Rho GTPases signaling and cognitive dysfunction: In vivo evidence for a compelling molecular relationship
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De Filippis, Bianca, Romano, Emilia, and Laviola, Giovanni
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- 2014
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204. Modulation of Rho GTPases and the Actin Cytoskeleton by YopT of Yersinia
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Aepfelbacher, M., Zumbihl, R., Heesemann, J., Compans, R.W., editor, Cooper, M.D., editor, Honjo, T., editor, Koprowski, H., editor, Melchers, F., editor, Oldstone, M.B.A., editor, Olsnes, S., editor, Potter, M., editor, Vogt, P.K., editor, Wagner, H., editor, Boquet, Patrice, editor, and Lemichez, Emmanuel, editor
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- 2005
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205. Rho GTPases and the Control of the Oxidative Burst in Polymorphonuclear Leukocytes
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Diebold, B. A., Bokoch, G. M., Compans, R.W., editor, Cooper, M.D., editor, Honjo, T., editor, Koprowski, H., editor, Melchers, F., editor, Oldstone, M.B.A., editor, Olsnes, S., editor, Potter, M., editor, Vogt, P.K., editor, Wagner, H., editor, Boquet, Patrice, editor, and Lemichez, Emmanuel, editor
- Published
- 2005
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206. Regulation of Phagocytosis by Rho GTPases
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Niedergang, F., Chavrier, P., Compans, R.W., editor, Cooper, M.D., editor, Honjo, T., editor, Koprowski, H., editor, Melchers, F., editor, Oldstone, M.B.A., editor, Olsnes, S., editor, Potter, M., editor, Vogt, P.K., editor, Wagner, H., editor, Boquet, Patrice, editor, and Lemichez, Emmanuel, editor
- Published
- 2005
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207. PLK1 phosphorylates RhoGDI1 and promotes cancer cell migration and invasion.
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Lim, Jeewon, Hwang, Yo Sep, Yoon, Hyang Ran, Yoo, Jiyun, Yoon, Suk Ran, Jung, Haiyoung, Cho, Hee Jun, and Lee, Hee Gu
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CANCER cell migration ,GUANOSINE triphosphate ,CELL migration ,RHO GTPases ,CELL motility - Abstract
Background: Rho guanine nucleotide dissociation inhibitor 1 (RhoGDI1) plays an important role in diverse cellular processes by regulating Rho guanosine triphosphate (GTP)ases activity. RhoGDI1 phosphorylation regulates the spatiotemporal activation of Rho GTPases during cell migration. In this study, we identified polo-like kinase 1 (PLK1) as a novel kinase of RhoGDI1 and investigated the molecular mechanism by which the interaction between RhoGDI1 and PLK1 regulates cancer cell migration. Methods: Immunoprecipitation, GST pull-down assay, and proximity ligation assay (PLA) were performed to analyze the interaction between RhoGDI1 and PLK1. In vitro kinase assay and immunoprecipitation were performed with Phospho-(Ser/Thr) antibody. We evaluated RhoA activation using RhoGTPases activity assay. Cell migration and invasion were analyzed by transwell assays. Results: GST pull-down assays and PLA showed that PLK1 directly interacted with RhoGDI1 in vitro and in vivo. Truncation mutagenesis revealed that aa 90-111 of RhoGDI1 are critical for interacting with PLK1. We also showed that PLK1 phosphorylated RhoGDI1 at Thr7 and Thr91, which induces cell motility. Overexpression of the GFP-tagged RhoGDI1 truncated mutant (aa 90-111) inhibited the interaction of PLK1 with RhoGDI1 and attenuated RhoA activation by PLK1. Furthermore, the overexpression of the RhoGDI1 truncated mutant reduced cancer cell migration and invasion in vitro and suppressed lung metastasis in vivo. Conclusions: Collectively, we demonstrate that the phosphorylation of RhoGDI1 by PLK1 promotes cancer cell migration and invasion through RhoA activation. This study connects the interaction between PLK1 and RhoGDI1 to the promotion of cancer cell behavior associated with malignant progression, thereby providing opportunities for cancer therapeutic interventions. [ABSTRACT FROM AUTHOR]
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- 2024
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208. Cortactin is in a complex with VE-cadherin and is required for endothelial adherens junction stability through Rap1/Rac1 activation.
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Moztarzadeh, Sina, Sepic, Sara, Hamad, Ibrahim, Waschke, Jens, Radeva, Mariya Y., and García-Ponce, Alexander
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ADHERENS junctions , *RHO GTPases , *CYTOSKELETON , *CELLULAR signal transduction , *ENDOTHELIAL cells , *CLAUDINS - Abstract
Vascular permeability is mediated by Cortactin (Cttn) and regulated by several molecules including cyclic-adenosine-monophosphate, small Rho family GTPases and the actin cytoskeleton. However, it is unclear whether Cttn directly interacts with any of the junctional components or if Cttn intervenes with signaling pathways affecting the intercellular contacts and the cytoskeleton. To address these questions, we employed immortalized microvascular myocardial endothelial cells derived from wild-type and Cttn-knock-out mice. We found that lack of Cttn compromised barrier integrity due to fragmented membrane distribution of different junctional proteins. Moreover, immunoprecipitations revealed that Cttn is within the VE-cadherin-based adherens junction complex. In addition, lack of Cttn slowed-down barrier recovery after Ca2+ repletion. The role of Cttn for cAMP-mediated endothelial barrier regulation was analyzed using Forskolin/Rolipram. In contrast to Cttn-KO, WT cells reacted with increased transendothelial electrical resistance. Absence of Cttn disturbed Rap1 and Rac1 activation in Cttn-depleted cells. Surprisingly, despite the absence of Cttn, direct activation of Rac1/Cdc42/RhoA by CN04 increased barrier resistance and induced well-defined cortical actin and intracellular actin bundles. In summary, our data show that Cttn is required for basal barrier integrity by allowing proper membrane distribution of junctional proteins and for cAMP–mediated activation of the Rap1/Rac1 signaling pathway. [ABSTRACT FROM AUTHOR]
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- 2024
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209. Collapsin response mediator protein and Rho GTPases in neuronal differentiation
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Brown, Matthew David
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611.01898 - Abstract
In the developing nervous system the modelling of axons and their growth cones is dependent on the dynamic regulation of the Rho family of GTPases, which play a crucial role in the regulation of the actin cytoskeleton. The guidance cues controlling axon path finding, either repulsive or attractive, require the Rho GTPases to effect changes in morphology. The signalling pathways linking the guidance molecules, and their receptors, to the Rho family GTPases remain unclear. Collapsin Response Mediator Protein-2 (CRMP-2) is a neurospecific protein involved in axonal outgrowth and the semaphorin3A collapse pathway. CRMP-2 is also a Rho kinase substrate, suggesting an involvement with the Rho GTPases. To investigate this, CRMP-2 was co-expressed in the neuroblastoma cell line, N1E-115, with active and inactive GTPase mutants. Cells expressing dominant active Rac1 and CRMP-2 became contracted, normally a RhoA effect, while co-expression of dominant active RhoA and CRMP-2 resulted in a phenotype typically associated with Rac1 signalling. CRMP-2 could bind directly to RhoA and Rac1, and, to a much lesser extent, Cdc42 in an overlay assay. In vivo CRMP-2 associated with active RhoA, but immunoprecipitated with active and inactive Rac1 mutants. Cdk5 inhibitors, but not Rho-kinase inhibitors blocked semaphorin3A-induced collapse in dorsal root ganglion neurones and N1E-115. Mutation of the Cdk5 phosphorylation site in CRMP-2 also inhibited sema3A collapse, suggesting a specific role of Cdk5 and CRMP-2 in the semaphorin3A growth cone collapse pathway. These results show CRMP-2 can switch RhoA and Rac1, and may link the guidance cues to the Rho-GTPases, which define growth cone morphology through their regulation of the actin cytoskeleton. Downstream of sema3A, CRMP-2 plays a crucial role in growth cone collapse, in a pathway involving Cdk5, and possibly phosphorylation at serine 522.
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- 2004
210. Reciprocal integrin/integrin antagonism through kindlin-2 and Rho GTPases regulates cell cohesion and collective migration
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Nathalie R. Reinhard, Ana Jimenez Orgaz, Ugne Kazlauskaite, Simon Tol, Ivo van der Bijl, Anne-Marieke D. van Stalborch, Iman van den Bout, Arnoud Sonnenberg, Kalim Nawaz, Coert Margadant, and Medical Biochemistry
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Cytoplasm ,RHOA ,Cell Plasticity ,Integrin ,Neuroepithelial Cells ,Morphogenesis ,Embryonic Development ,Collective cell migration ,Kindlin-2 ,Cell junction ,Cell Movement ,Rho GTPases ,Human Umbilical Vein Endothelial Cells ,Humans ,Epithelial–mesenchymal transition ,Fibronectin ,Molecular Biology ,Sprouting angiogenesis ,biology ,Inhibition of integrin function ,Chemistry ,Integrin beta1 ,Integrin beta3 ,Membrane Proteins ,Cell migration ,Neoplasm Proteins ,Cell biology ,HEK293 Cells ,Phenotype ,Epithelial-to-mesenchymal transition ,biology.protein ,rhoA GTP-Binding Protein - Abstract
Collective cell behaviour during embryogenesis and tissue repair requires the coordination of intercellular junctions, cytoskeleton-dependent shape changes controlled by Rho GTPases, and integrin-dependent cell-matrix adhesion. Many different integrins are simultaneously expressed during wound healing, embryonic development, and sprouting angiogenesis, suggesting that there is extensive integrin/integrin cross-talk to regulate cell behaviour. Here, we show that fibronectin-binding β1 and β3 integrins do not act synergistically, but rather antagonize each other during collective cell processes in neuro-epithelial cells, placental trophoblasts, and endothelial cells. Reciprocal β1/β3 antagonism controls RhoA activity in a kindlin-2-dependent manner, balancing cell spreading, contractility, and intercellular adhesion. In this way, reciprocal β1/β3 antagonism controls cell cohesion and cellular plasticity to switch between extreme and opposing states, including epithelial versus mesenchymal-like phenotypes and collective versus individual cell migration. We propose that integrin/integrin antagonism is a universal mechanism to effectuate social cellular interactions, important for tissue morphogenesis, endothelial barrier function, trophoblast invasion, and sprouting angiogenesis.
- Published
- 2020
211. Regulation of Rho GTPases by post-translational modification in endothelial barrier function
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Majolée, Johanna Hendrika, Hordijk, Peter Lodewijk, Kovacevic, Igor, ACS - Atherosclerosis & ischemic syndromes, Physiology, Hordijk, P.L., and Kovacevic, I.
- Subjects
ubiquitine ,prenylatie ,endothelium ,Rho GTPase ,endothelial barrier ,cytoskeleton ,RhoB ,prenylation ,post-translationele modificaties ,endothelial cells ,cytoskelet ,Rho GTPases ,ubiquitin ,post-translational modifications ,endotheelcel ,endotheel ,endotheel barrière ,Rac1 - Abstract
The inside of our blood vessels is lined with a single layer of endothelial cells, known as the endothelium. The endothelium forms a barrier with a strict degree of permeability for nutrients, waste products and cells from the blood to the tissues. Important regulators of the endothelial barrier are proteins called the Rho GTPases, of which the most researched are RhoA, RhoB, Rac1, and Cdc42. RhoA and RhoB cause the cells to contract, creating holes in the endothelial barrier that lead to vascular leakage. Rac1 and Cdc42 do the opposite: they cause the endothelial cells to expand and promote the formation of cell-cell connections. Rho GTPases can switch between an active and inactive form, allowing endothelial cells to adapt their cytoskeleton as needed. However, there are more aspects to the regulation of Rho GTPases. In this thesis, we mainly focus on the regulation of Rho GTPases by two post-translational modifications called ubiquitination and prenylation. A post-translational modification is a change made to a protein after it has been transcribed from the DNA. Ubiquitination is the attachment of a ubiquitin molecule to a protein. Ubiquitination of a protein usually leads to recognition by the proteasome, which then breaks down the protein. In chapter 2 we summarized the current knowledge on regulation of the endothelial barrier by ubiquitination. In chapter 3 we describe the role of RhoB ubiquitination in the endothelial barrier. The RhoB gene is continuously transcribed and translated into protein, but under healthy conditions the RhoB protein is also continuously broken down. By specifically removing the ubiquitin ligases Cullin-1, Cullin-2 and Cullin-3 and some adapter proteins, we found that the Cullin-3-Rbx1-KCTD10 complex is most important for RhoB ubiquitination. Next, we activated Cullin ubiquitin ligases (chapter 4). We expected that this would lead to increased RhoB degradation and an enhanced endothelial barrier. However, we soon discovered that the activation of all Cullin E3 ligases led to an imbalance in the endothelium. There was more RhoB transcription than degradation in the endothelial cells treated with CSN5i-3, leading to a high RhoB protein level and contraction of the endothelial cells. We concluded that the chemical activation of all Cullin E3 ligases is not a good strategy for reducing endothelial cell contraction. The role of a group of ubiquitin ligase adaptors called the F-box proteins in the regulation of the endothelial barrier was still unknown. In our study described in chapter 5, we found that removing FBXW7 disrupted the endothelial barrier. This was caused by a disruption of the cholesterol synthesis pathway, leading to an increase in and differential functioning of RhoB. In chapter 6, we investigated the relationship between GDI binding, activity and ubiquitination of Rac1. These three components of Rac1 regulation had not been linked in this way before. We introduced mutations in Rac1, each known to cause different activity, ubiquitination or GDI binding of Rac1. This allowed us to show that Rac1 activity and ubiquitination are positively correlated to each other. However, we did not see loss of RhoGDI binding with increased Rac1 activity as we expected, which puts the regulation of Rac1 by RhoGDI in a new light. In summary, we established the link between post-translational regulation of Rho GTPases, specifically RhoB and Rac1, and the regulation of the endothelial barrier. For some experiments, we expressed fluorescently synthesized Rho GTPases to better track them in the cells. The molecular cell biology research we performed in this thesis will help to understand the physiological regulation of Rho GTPase signaling in endothelial cells. We hope that these insights will contribute to the development or adaptation of strategies against vascular leakage.
- Published
- 2021
212. The Role of Rho GTPases in Motility and Invasion of Glioblastoma Cells
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Houssam Al-Koussa, Oula El Atat, Leila Jaafar, Hagop Tashjian, and Mirvat El-Sibai
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
Astrocytomas are primary malignant brain tumors that originate from astrocytes. Grade IV astrocytoma or glioblastoma is a highly invasive tumor that occur within the brain parenchyma. The Rho family of small GTPases, which includes Rac1, Cdc42, and RhoA, is an important family whose members are key regulators of the invasion and migration of glioblastoma cells. In this review, we describe the role played by the Rho family of GTPases in the regulation of the invasion and migration of glioblastoma cells. Specifically, we focus on the role played by RhoA, Rac1, RhoG, and Cdc42 in cell migration through rearrangement of actin cytoskeleton, cell adhesion, and invasion. Finally, we highlight the importance of potentially targeting Rho GTPases in the treatment of glioblastoma.
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- 2020
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213. Differential Regulation of Phagosome Maturation in Macrophages and Dendritic Cells Mediated by Rho GTPases and Ezrin-Radixin-Moesin (ERM) Proteins
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Erwig, Lars-Peter, McPhilips, Kathleen A., Wynes, Murray W., Ivetic, Alexander, Ridley, Anne J., and Henson, Peter M.
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- 2006
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214. Signalling through Rho GTPases in cardiomyocytes
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Marshall, Andrew Keith, Clerk, Angela, and Sugden, Peter
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612.1 - Abstract
Endothelin-1 (ET-1) promotes changes in gene/protein expression in cardiomyocytes leading to hypertrophy. This results from activation of intracellular signalling pathways including small G proteins that activate protein kinases. Thus, ET-1 activates RhoA that stimulates ROCK and PKN, and Ras that promotes activation of extracellular signal-regulated kinases 1/2 (ERK1/2). Microarrays were used to dissect the roles of ERK1/2 vs RhoA in the cardiomyocyte transcriptomic response to ET-1 using PD184352 and C3 endotoxin from C. botulinum (C3T) for selective inhibition of the ERK1/2 cascade and RhoA, respectively. Microarray data were analysed using GeneSpring and data were validated by qPCR. ERK1/2 signalling positively regulated ~65% of the early gene expression response to ET-1 with a small (~2%) negative effect, whereas RhoA signalling positively regulated ~11% of the early gene expression response to ET-1 with a greater (~14%) negative contribution. Of RNAs non-responsive to ET-1, 66 or 448 were regulated by PD184352 or C3T, respectively, indicating that RhoA had a more significant effect on baseline RNA expression. mRNAs upregulated by ET-1 encoded several receptor ligands (e.g. Ereg, Areg) and transcription factors (e.g. Abra/STARS, Srf) that potentially propagate the response. Published studies suggest that PKN1 (activated by RhoA) is important in cardiomyocyte gene expression. Adenoviruses were generated to overexpress FLAG-tagged PKN1 in cardiomyocytes for protein kinase studies. Unexpectedly, PKN1 was not activated by ET-1, but was activated by oxidative stress, insulin, or hyperosmotic shock, stimuli that do not activate RhoA. Thus, PKN1 is not necessarily an effector of RhoA in cardiomyocytes. In conclusion, ERK1/2 dominates over RhoA in the early transcriptomic response to ET-1. RhoA plays a major role in maintaining baseline RNA expression but, as with upregulation of Abra/Srf by ET-1, RhoA may regulate changes in RNA expression over longer times. However, the effects of RhoA on cardiomyocyte gene expression are unlikely to be mediated through PKN1.
- Published
- 2011
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215. Roles of GTP and Rho GTPases in pancreatic islet beta cell function and dysfunction
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Anjaneyulu Kowluru
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rho GTP-Binding Proteins ,GTP' ,Beta-cell Function ,RAC1 ,Review ,Biology ,Biochemistry ,DNA-binding protein ,Islets of Langerhans ,03 medical and health sciences ,0302 clinical medicine ,Insulin-Secreting Cells ,Diabetes mellitus ,medicine ,Animals ,Humans ,030304 developmental biology ,0303 health sciences ,geography ,geography.geographical_feature_category ,Rho GTPases ,Cell Biology ,medicine.disease ,Islet ,Cell biology ,Pancreatic Neoplasms ,030220 oncology & carcinogenesis ,Guanosine Triphosphate ,Beta cell - Abstract
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
- Published
- 2020
216. Rho GTPases in cancer radiotherapy and metastasis
- Author
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Ruijie Zeng, Chunwen Zheng, En-Min Li, Li-Yan Xu, and Wan-Xian Chen
- Subjects
0301 basic medicine ,Cancer Research ,business.industry ,medicine.medical_treatment ,Rho GTPases ,Cancer ,RAC1 ,GTPase ,medicine.disease ,Metastasis ,Radiation therapy ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Cancer Radiotherapy ,Radioresistance ,medicine ,Cancer research ,business - Abstract
Despite treatment advances, radioresistance and metastasis markedly impair the benefits of radiotherapy to patients with malignancies. Functioning as molecular switches, Rho guanosine triphosphatases (GTPases) have well-recognized roles in regulating various downstream signaling pathways in a wide range of cancers. In recent years, accumulating evidence indicates the involvement of Rho GTPases in cancer radiotherapeutic efficacy and metastasis, as well as radiation-induced metastasis. The functions of Rho GTPases in radiotherapeutic efficacy are divergent and context-dependent; thereby, a comprehensive integration of their roles and correlated mechanisms is urgently needed. This review integrates current evidence supporting the roles of Rho GTPases in mediating radiotherapeutic efficacy and the underlying mechanisms. In addition, their correlations with metastasis and radiation-induced metastasis are discussed. Under the prudent application of Rho GTPase inhibitors based on critical evaluations of biological contexts, targeting Rho GTPases can be a promising strategy in overcoming radioresistance and simultaneously reducing the metastatic potential of tumor cells.
- Published
- 2020
217. Rho GTPases are Involved on Regulation of Cytodifferentiation of SCC-4 Oral Squamous Cell Carcinoma Cell Line: A Preliminary Study
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Virgínia Oliveira Crema, Nanci M Pineiro, and Anna Cecília Dias Maciel Carneiro
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rho GTP-Binding Proteins ,0301 basic medicine ,Cytodifferentiation ,Short Communication ,Confocal ,Bacterial Toxins ,Clostridium difficile toxin A ,Vimentin ,macromolecular substances ,Immunofluorescence ,03 medical and health sciences ,Cytokeratin ,0302 clinical medicine ,Bacterial Proteins ,Cell Line, Tumor ,Rho GTPases ,medicine ,Humans ,biology ,medicine.diagnostic_test ,Chemistry ,Cell Differentiation ,General Medicine ,Clostridium difficile ,Molecular biology ,Actins ,Staining ,oral squamous cell carcinoma ,stomatognathic diseases ,030104 developmental biology ,Cell culture ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,biology.protein ,Mouth Neoplasms - Abstract
Objective: This study evaluated the involvement of Rho GTPases proteins in the regulation of cytodifferentiation of the SCC-4 human oral squamous cell carcinoma cell line. Methods: Cytokeratin and vimentin immunofluorescence and F-actin staining, assays were performed with control cells and Clostridium difficile 1, 2 and 4 μg/mL Toxin A (Rho GTPases inhibitor) treated SCC-4 cells on three-dimensional MatrigelTM for 24 h. Samples were analyzed by using confocal laser microscopy. Significances were p
- Published
- 2020
218. Studies from Iowa State University Describe New Findings in Hematopoietic Stem Cells (Nod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases)
- Subjects
Immunotherapy -- Reports -- Research ,G proteins -- Research -- Reports ,Hematopoietic stem cells -- Transplantation -- Reports -- Research ,Stem cell research -- Research -- Reports ,Health ,Iowa State University -- Reports - Abstract
2023 DEC 13 (NewsRx) -- By a News Reporter-Staff News Editor at Immunotherapy Weekly -- Investigators publish new report on hematopoietic stem cells. According to news reporting from Iowa State [...]
- Published
- 2023
219. Rho GTPases in primary brain tumor malignancy and invasion
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Khalil, Bassem D. and El-Sibai, Mirvat
- Published
- 2012
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220. Interaction between Rho GTPases and 14-3-3 Proteins.
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Brandwein, Daniel and Zhixiang Wang
- Subjects
- *
RHO GTPases , *PROTEIN structure , *GUANOSINE diphosphate , *GUANOSINE triphosphatase , *CELL migration , *PHOSPHORYLATION - Abstract
The Rho GTPase family accounts for as many as 20 members. Among them, the archetypes RhoA, Rac1, and Cdc42 have been the most well-characterized. Like all members of the small GTPases superfamily, Rho proteins act as molecular switches to control cellular processes by cycling between active, GTP-bound and inactive, GDP-bound states. The 14-3-3 family proteins comprise seven isoforms. They exist as dimers (homo- or hetero-dimer) in cells. They function by binding to Ser/Thr phosphorylated intracellular proteins, which alters the conformation, activity, and subcellular localization of their binding partners. Both 14-3-3 proteins and Rho GTPases regulate cell cytoskeleton remodeling and cell migration, which suggests a possible interaction between the signaling pathways regulated by these two groups of proteins. Indeed, more and more emerging evidence indicates the mutual regulation of these two signaling pathways. There have been many documented reviews of 14-3-3 protein and Rac1 separately, but there is no reviewregarding the interaction andmutual regulation of these two groups of proteins. Thus, in this article we thoroughly review all the reported interactions between the signaling pathways regulated by 14-3-3 proteins and Rho GTPases (mostly Rac1). [ABSTRACT FROM AUTHOR]
- Published
- 2017
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221. Key role of Rho GTPases in motor disorders associated with neurodevelopmental pathologies
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Evelyne Bloch-Gallego and David Anderson
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Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Molecular Biology - Abstract
Growing evidence suggests that Rho GTPases and molecules involved in their signaling pathways play a major role in the development of the central nervous system (CNS). Whole exome sequencing (WES) and de novo examination of mutations, including SNP (Single Nucleotide Polymorphism) in genes coding for the molecules of their signaling cascade, has allowed the recent discovery of dominant autosomic mutations and duplication or deletion of candidates in the field of neurodevelopmental diseases (NDD). Epidemiological studies show that the co-occurrence of several of these neurological pathologies may indeed be the rule. The regulators of Rho GTPases have often been considered for cognitive diseases such as intellectual disability (ID) and autism. But, in a remarkable way, mild to severe motor symptoms are now reported in autism and other cognitive NDD. Although a more abundant litterature reports the involvement of Rho GTPases and signaling partners in cognitive development, molecular investigations on their roles in central nervous system (CNS) development or degenerative CNS pathologies also reveal their role in embryonic and perinatal motor wiring through axon guidance and later in synaptic plasticity. Thus, Rho family small GTPases have been revealed to play a key role in brain functions including learning and memory but their precise role in motor development and associated symptoms in NDD has been poorly scoped so far, despite increasing clinical data highlighting the links between cognition and motor development. Indeed, early impairements in fine or gross motor performance is often an associated feature of NDDs, which then impact social communication, cognition, emotion, and behavior. We review here recent insights derived from clinical developmental neurobiology in the field of Rho GTPases and NDD (autism spectrum related disorder (ASD), ID, schizophrenia, hypotonia, spastic paraplegia, bipolar disorder and dyslexia), with a specific focus on genetic alterations affecting Rho GTPases that are involved in motor circuit development.
- Published
- 2022
222. Uncovering the secret life of Rho GTPases
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Jenna A Perry and Amy Shaub Maddox
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RhoGTPase ,RhoGDI ,Cdc42 ,Rho ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
New methods to directly visualize Rho GTPases reveal how a protein called RhoGDI regulates the activity of these 'molecular switches' at the plasma membrane.
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- 2019
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223. Direct multiplex imaging and optogenetics of Rho GTPases enabled by near-infrared FRET
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Shcherbakova, Daria M., Cox Cammer, Natasha, Huisman, Tsipora M., Verkhusha, Vladislav V., and Hodgson, Louis
- Published
- 2018
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224. Roles of Rho GTPases in Intracellular Transport and Cellular Transformation
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Ji-Long Chen, Mark Stamnes, Yifan Huang, Xiaojuan Chi, and Song Wang
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Rho GTPases ,vesicle trafficking ,viral transport ,cellular transformation ,actin cytoskeleton ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Rho family GTPases belong to the Ras GTPase superfamily and transduce intracellular signals known to regulate a variety of cellular processes, including cell polarity, morphogenesis, migration, apoptosis, vesicle trafficking, viral transport and cellular transformation. The three best-characterized Rho family members are Cdc42, RhoA and Rac1. Cdc42 regulates endocytosis, the transport between the endoplasmic reticulum and Golgi apparatus, post-Golgi transport and exocytosis. Cdc42 influences trafficking through interaction with Wiskott-Aldrich syndrome protein (N-WASP) and the Arp2/3 complex, leading to changes in actin dynamics. Rac1 mediates endocytic and exocytic vesicle trafficking by interaction with its effectors, PI3kinase, synaptojanin 2, IQGAP1 and phospholipase D1. RhoA participates in the regulation of endocytosis through controlling its downstream target, Rho kinase. Interestingly, these GTPases play important roles at different stages of viral protein and genome transport in infected host cells. Importantly, dysregulation of Cdc42, Rac1 and RhoA leads to numerous disorders, including malignant transformation. In some cases, hyperactivation of Rho GTPases is required for cellular transformation. In this article, we review a number of findings related to Rho GTPase function in intracellular transport and cellular transformation.
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- 2013
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225. ARHGEF5 binds Drebrin and affects α-tubulin acetylation to direct neuronal morphogenesis and migration during mouse brain development.
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Ji-ye Kim, Hee-Gon Hwang, Hye-Jin Jeon, Seung Il Kim, Min-kyu Kim, and Jeong-Yoon Kim
- Subjects
NEURAL development ,GUANINE nucleotide exchange factors ,ACETYLATION ,RHO GTPases ,CELL physiology ,MORPHOGENESIS - Abstract
Rho guanine nucleotide exchange factors (Rho GEFs) activate Rho GTPases, which act as molecular switches regulating various essential cellular functions. This study investigated the role of ARHGEF5, a Rho GEF known for its involvement in cell migration and invasion processes, in the context of brain development. We found that ARHGEF5 is essential for dendrite development during the early stages of neuronal growth. We also discovered that ARHGEF5 binds to Drebrin E, which is vital for coordinating actin and microtubule dynamics, and facilitates the interaction between Drebrin E and Cyclin-dependent kinase 5, which phosphorylates Drebrin E. Notably, ARHGEF5 deficiency resulted in a decrease in acetylated α-tubulin levels, and the expression of an α-tubulin acetylation mimetic mutant (K40Q) rescued the defects in dendrite development and neuronal migration, suggesting ARHGEF5’s role in modulating microtubule stability. Additionally, ARHGEF5 was shown to influence Golgi positioning in the leading processes of migrating cortical neurons during brain development. Our study suggests that ARHGEF5 plays a crucial role in integrating cytoskeletal dynamics with neuronal morphogenesis and migration processes during brain development. [ABSTRACT FROM AUTHOR]
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- 2024
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226. Lipogenic signalling modulates prostate cancer cell adhesion and migration via modification of Rho GTPases
- Abstract
Fatty acid synthase (FASN) is commonly overexpressed in prostate cancer and associated with tumour progression. FASN is responsible for de novo synthesis of the fatty acid palmitate; the building block for protein palmitoylation. Recent work has suggested that alongside its established role in promoting cell proliferation FASN may also promote invasion. We now find depletion of FASN expression increases prostate cancer cell adhesiveness, impairs HGF-mediated cell migration and reduces 3D invasion. These changes in motility suggest that FASN can mediate actin cytoskeletal remodelling; a process known to be downstream of Rho family GTPases. Here, we demonstrate that modulation of FASN expression specifically impacts on the palmitoylation of the atypical GTPase RhoU. Impaired RhoU activity in FASN depleted cells leads to reduced adhesion turnover downstream of paxillin serine phosphorylation, which is rescued by addition of exogenous palmitate. Moreover, canonical Cdc42 expression is dependent on the palmitoylation status of RhoU. Thus we uncover a novel relationship between FASN, RhoU and Cdc42 that directly influences cell migration potential. These results provide compelling evidence that FASN activity directly promotes cell migration and supports FASN as a potential therapeutic target in metastatic prostate cancer.
- Published
- 2020
- Full Text
- View/download PDF
227. Lipogenic signalling modulates prostate cancer cell adhesion and migration via modification of Rho GTPases
- Abstract
Fatty acid synthase (FASN) is commonly overexpressed in prostate cancer and associated with tumour progression. FASN is responsible for de novo synthesis of the fatty acid palmitate; the building block for protein palmitoylation. Recent work has suggested that alongside its established role in promoting cell proliferation FASN may also promote invasion. We now find depletion of FASN expression increases prostate cancer cell adhesiveness, impairs HGF-mediated cell migration and reduces 3D invasion. These changes in motility suggest that FASN can mediate actin cytoskeletal remodelling; a process known to be downstream of Rho family GTPases. Here, we demonstrate that modulation of FASN expression specifically impacts on the palmitoylation of the atypical GTPase RhoU. Impaired RhoU activity in FASN depleted cells leads to reduced adhesion turnover downstream of paxillin serine phosphorylation, which is rescued by addition of exogenous palmitate. Moreover, canonical Cdc42 expression is dependent on the palmitoylation status of RhoU. Thus we uncover a novel relationship between FASN, RhoU and Cdc42 that directly influences cell migration potential. These results provide compelling evidence that FASN activity directly promotes cell migration and supports FASN as a potential therapeutic target in metastatic prostate cancer.
- Published
- 2020
- Full Text
- View/download PDF
228. Lipogenic signalling modulates prostate cancer cell adhesion and migration via modification of Rho GTPases
- Abstract
Fatty acid synthase (FASN) is commonly overexpressed in prostate cancer and associated with tumour progression. FASN is responsible for de novo synthesis of the fatty acid palmitate; the building block for protein palmitoylation. Recent work has suggested that alongside its established role in promoting cell proliferation FASN may also promote invasion. We now find depletion of FASN expression increases prostate cancer cell adhesiveness, impairs HGF-mediated cell migration and reduces 3D invasion. These changes in motility suggest that FASN can mediate actin cytoskeletal remodelling; a process known to be downstream of Rho family GTPases. Here, we demonstrate that modulation of FASN expression specifically impacts on the palmitoylation of the atypical GTPase RhoU. Impaired RhoU activity in FASN depleted cells leads to reduced adhesion turnover downstream of paxillin serine phosphorylation, which is rescued by addition of exogenous palmitate. Moreover, canonical Cdc42 expression is dependent on the palmitoylation status of RhoU. Thus we uncover a novel relationship between FASN, RhoU and Cdc42 that directly influences cell migration potential. These results provide compelling evidence that FASN activity directly promotes cell migration and supports FASN as a potential therapeutic target in metastatic prostate cancer.
- Published
- 2020
- Full Text
- View/download PDF
229. Lipogenic signalling modulates prostate cancer cell adhesion and migration via modification of Rho GTPases
- Abstract
Fatty acid synthase (FASN) is commonly overexpressed in prostate cancer and associated with tumour progression. FASN is responsible for de novo synthesis of the fatty acid palmitate; the building block for protein palmitoylation. Recent work has suggested that alongside its established role in promoting cell proliferation FASN may also promote invasion. We now find depletion of FASN expression increases prostate cancer cell adhesiveness, impairs HGF-mediated cell migration and reduces 3D invasion. These changes in motility suggest that FASN can mediate actin cytoskeletal remodelling; a process known to be downstream of Rho family GTPases. Here, we demonstrate that modulation of FASN expression specifically impacts on the palmitoylation of the atypical GTPase RhoU. Impaired RhoU activity in FASN depleted cells leads to reduced adhesion turnover downstream of paxillin serine phosphorylation, which is rescued by addition of exogenous palmitate. Moreover, canonical Cdc42 expression is dependent on the palmitoylation status of RhoU. Thus we uncover a novel relationship between FASN, RhoU and Cdc42 that directly influences cell migration potential. These results provide compelling evidence that FASN activity directly promotes cell migration and supports FASN as a potential therapeutic target in metastatic prostate cancer.
- Published
- 2020
- Full Text
- View/download PDF
230. Lipogenic signalling modulates prostate cancer cell adhesion and migration via modification of Rho GTPases
- Abstract
Fatty acid synthase (FASN) is commonly overexpressed in prostate cancer and associated with tumour progression. FASN is responsible for de novo synthesis of the fatty acid palmitate; the building block for protein palmitoylation. Recent work has suggested that alongside its established role in promoting cell proliferation FASN may also promote invasion. We now find depletion of FASN expression increases prostate cancer cell adhesiveness, impairs HGF-mediated cell migration and reduces 3D invasion. These changes in motility suggest that FASN can mediate actin cytoskeletal remodelling; a process known to be downstream of Rho family GTPases. Here, we demonstrate that modulation of FASN expression specifically impacts on the palmitoylation of the atypical GTPase RhoU. Impaired RhoU activity in FASN depleted cells leads to reduced adhesion turnover downstream of paxillin serine phosphorylation, which is rescued by addition of exogenous palmitate. Moreover, canonical Cdc42 expression is dependent on the palmitoylation status of RhoU. Thus we uncover a novel relationship between FASN, RhoU and Cdc42 that directly influences cell migration potential. These results provide compelling evidence that FASN activity directly promotes cell migration and supports FASN as a potential therapeutic target in metastatic prostate cancer.
- Published
- 2020
- Full Text
- View/download PDF
231. EMT induces cell-cycle-dependent changes of Rho GTPases and downstream effectors
- Author
-
Hosseini, Kamran, primary, Frenzel, Annika, additional, and Fischer-Friedrich, Elisabeth, additional
- Published
- 2023
- Full Text
- View/download PDF
232. Immunohistological study of small Rho GTPases and β-catenin during regeneration of the rat submandibular gland
- Author
-
Shiratsuchi, Hiroshi, Shimizu, Osamu, Saito, Tadahito, Mashimo, Takayuki, and Yonehara, Yoshiyuki
- Published
- 2012
- Full Text
- View/download PDF
233. The role of Rho GTPases in regulation of macrophage motility and morphology
- Author
-
Wheeler, Ann
- Subjects
571.633 - Abstract
Rho GTPases are important regulators of cell motility and morphology. Mammals have three highly homologous Rho proteins, RhoA, RhoB and RhoC. The aim of this thesis was to determine whether individual isoforms of Rho have unique functions in the regulation of cell motility using primary bone marrow-derived macrophages (BMM) as a model system. BMMs were shown to express RhoA, RhoB but not RhoC. BMMs were analysed to determine the role of RhoA and RhoB in motility and morphology. A comparison between RhoA and RhoB-null was carried out using a combination of RhoB-null BMMs, and BMM treated with the pan Rho inhibitor C3-transferase and the Rho kinase inhibitor Y27632. RhoB-null BMMs moved faster and had a smaller spread area than wild-types. Whereas BMM treated with C3-transferase and Y27632 had reduced migration. The RhoB-null BMMs did not change shape following CSF-1 withdrawal unlike wild-type cells. Analysis of BMM spreading and adhesion revealed that deletion of RhoB caused defects in the initial stages of cell spreading and adhesion. Interestingly in RhoB-null BMMs the GTPase activity of RhoA and Rac1 and phosphorylation of their targets LIMK and MLC was decreased less in response to withdrawal of CSF-1 than in wildtype cells. This suggests that RhoB may be acting as a 'brake' for RhoA activity.
- Published
- 2005
234. Opto-RhoGEFs, an optimized optogenetic toolbox to reversibly control Rho GTPase activity on a global to subcellular scale, enabling precise control over vascular endothelial barrier strength.
- Author
-
Mahlandt, Eike K., Palacios Martínez, Sebastián, Arts, Janine J. G., Tol, Simon, van Buul, Jaap D., and Goedhart, Joachim
- Subjects
- *
GUANOSINE triphosphatase , *RHO GTPases , *TIGHT junctions , *CELL size , *ADHERENS junctions , *ENDOTHELIAL cells , *ENDOTHELIUM , *CADHERINS , *GLYCOCALYX - Abstract
The inner layer of blood vessels consists of endothelial cells, which form the physical barrier between blood and tissue. This vascular barrier is tightly regulated and is defined by cell-cell contacts through adherens and tight junctions. To investigate the signaling that regulates vascular barrier strength, we focused on Rho GTPases, regulators of the actin cytoskeleton and known to control junction integrity. To manipulate Rho GTPase signaling in a temporal and spatial manner we applied optogenetics. Guanine-nucleotide exchange factor (GEF) domains from ITSN1, TIAM1, and p63RhoGEF, activating Cdc42, Rac, and Rho, respectively, were integrated into the optogenetic recruitment tool improved light-induced dimer (iLID). This tool allows for Rho GTPase activation at the subcellular level in a reversible and non-invasive manner by recruiting a GEF to a specific area at the plasma membrane, The membrane tag of iLID was optimized and a HaloTag was applied to gain more flexibility for multiplex imaging. The resulting optogenetically recruitable RhoGEFs (Opto-RhoGEFs) were tested in an endothelial cell monolayer and demonstrated precise temporal control of vascular barrier strength by a cell-cell overlap-dependent, VE-cadherin-independent, mechanism. Furthermore, Opto-RhoGEFs enabled precise optogenetic control in endothelial cells over morphological features such as cell size, cell roundness, local extension, and cell contraction. In conclusion, we have optimized and applied the optogenetic iLID GEF recruitment tool, that is Opto-RhoGEFs, to study the role of Rho GTPases in the vascular barrier of the endothelium and found that membrane protrusions at the junction region can rapidly increase barrier integrity independent of VE-cadherin. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
235. Rho GTPases: Anti- or pro-neoplastic targets?
- Author
-
Zandvakili, I, Lin, Y, Morris, J C, and Zheng, Y
- Published
- 2017
- Full Text
- View/download PDF
236. Cross-talk between Rho GTPases and PI3K in the neutrophil.
- Author
-
McCormick, Barry, Chu, Julia Y., and Vermeren, Sonja
- Subjects
- *
NEUTROPHILS , *RHO GTPases , *GUANINE nucleotide exchange factors , *MYCOSES , *BACTERIAL diseases - Abstract
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]
- Published
- 2019
- Full Text
- View/download PDF
237. Mechanism of cell-intrinsic adaptation to Adams-Oliver Syndrome gene DOCK6 disruption highlights ubiquitin-like modifier ISG15 as a regulator of RHO GTPases.
- Author
-
Cerikan, Berati and Schiebel, Elmar
- Subjects
- *
RHO GTPases , *GUANINE nucleotide exchange factors , *ENDOPLASMIC reticulum , *ERROR functions , *SIGNAL recognition particle receptor , *PHYSIOLOGICAL adaptation - Abstract
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]
- Published
- 2019
- Full Text
- View/download PDF
238. Rho GTPases in Keratinocyte adhesion and differentiation
- Author
-
Liebig, Timo Christian
- Subjects
571.6 - Published
- 2008
239. Research Reports from Uppsala University Provide New Insights into Cancer (The Role of Fast-Cycling Atypical RHO GTPases in Cancer)
- Subjects
Oncology, Experimental ,G proteins -- Research ,Cancer -- Research ,Physical fitness -- Research ,Health - Abstract
2022 MAY 14 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Data detailed on cancer have been presented. According to news reporting out [...]
- Published
- 2022
240. Interaction between Rho GTPases and 14-3-3 Proteins
- Author
-
Daniel Brandwein and Zhixiang Wang
- Subjects
Rho GTPases ,14-3-3 protein ,Rac1 ,interaction ,guanine nucleotide exchange factors (GEFs) ,GTPase-activating proteins (GAPs) ,phosphorylation ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The Rho GTPase family accounts for as many as 20 members. Among them, the archetypes RhoA, Rac1, and Cdc42 have been the most well-characterized. Like all members of the small GTPases superfamily, Rho proteins act as molecular switches to control cellular processes by cycling between active, GTP-bound and inactive, GDP-bound states. The 14-3-3 family proteins comprise seven isoforms. They exist as dimers (homo- or hetero-dimer) in cells. They function by binding to Ser/Thr phosphorylated intracellular proteins, which alters the conformation, activity, and subcellular localization of their binding partners. Both 14-3-3 proteins and Rho GTPases regulate cell cytoskeleton remodeling and cell migration, which suggests a possible interaction between the signaling pathways regulated by these two groups of proteins. Indeed, more and more emerging evidence indicates the mutual regulation of these two signaling pathways. There have been many documented reviews of 14-3-3 protein and Rac1 separately, but there is no review regarding the interaction and mutual regulation of these two groups of proteins. Thus, in this article we thoroughly review all the reported interactions between the signaling pathways regulated by 14-3-3 proteins and Rho GTPases (mostly Rac1).
- Published
- 2017
- Full Text
- View/download PDF
241. Nε-Fatty acylation of Rho GTPases by a MARTX toxin effector.
- Author
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Yan Zhou, Chunfeng Huang, Li Yin, Muyang Wan, Xiaofei Wang, Lin Li, Yanhua Liu, Zhao Wang, Panhan Fu, Ni Zhang, She Chen, Xiaoyun Liu, Feng Shao, and Yongqun Zhu
- Subjects
- *
ACYLATION , *RHO GTPases , *LYSINE , *C-terminal residues , *INOSITOL , *CYSTEINE proteinases - Abstract
The multifunctional autoprocessing repeats-in-toxin (MARTX) toxins are a family of large toxins that are extensively distributed in bacterial pathogens. MARTX toxins are autocatalytically cleaved to multiple effector domains, which are released into host cells to modulate the host signaling pathways. The Rho guanosine triphosphatase (GTPase) inactivation domain (RID), a conserved effector domain of MARTX toxins, is implicated in cell rounding by disrupting the host actin cytoskeleton.We found that the RID is an Nε-fatty acyltransferase that covalently modifies the lysine residues in the C-terminal polybasic region of Rho GTPases. The resulting fatty acylation inhibited Rho GTPases and disrupted Rho GTPase–mediated signaling in the host. Thus, RID can mediate the lysine Nε-fatty acylation of mammalian proteins and represents a family of toxins that harbor N-fatty acyltransferase activities in bacterial pathogens. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
242. Role of Rho GTPases and PTEN in the migration of human glioma cells
- Author
-
Raftopoulou, Myrto
- Subjects
616.9948 - Abstract
Rho GTPases play a key role in regulating the migration of many cell types including astrocytes. Astrocytcs are relatively poor migrating cells, whereas, gliomas, can be highly invasive, infiltrating the surrounding tissue and spreading difftisely in the brain due, in part, to their highly motile behaviour. This thesis investigates the aberrant migration of three human glioma cell lines (U373, U138, U87) and, using microinjection techniques, it is shown that the small GTPase Rac is essential for the migration of astrocytes as well as for the three glioma cell lines. In agreement with a higher rate of migration, it was demonstrated that the level of active Rac (Rac-GTP) is higher in U373 than in astrocytes. Surprisingly, however, the levels of Rac-GTP in the more motile cell lines, U138 and U87, are much lower than U373 cells. Rac activity in cells can be stimulated through increases in the levels of PI(3,4,5)P3 generated by the enzymeP I 3- kinase. PI(3,4,5)P3le vels are negatively controlled by the dual specificity phosphatase PTEN, which dephosphorylates PI(3,4,5)P3- In in vitro assays,P TEN has also been shown to have protein phosphatase activity. All three glioma cell lines lack PTEN. This work demonstrates that re-expression of wtPTEN inhibits the migration of all three glioma cell lines, without affecting the migration of astrocytes. Moreover, data is presented showing that the protein, not the lipid, phosphatase activity of PTEN, is essential for inhibiting migration. Most unexpectedly, however, additional mutagenesis studies reveal that it is the C2 domain of PTEN that mediatest he inhibitory effect on the migration of these tumour cell lines, and that in the full-length protein, the phosphorylation of residue Tbr383 controls the anti-migratory activity of the C2 domain. Finally, using the carboxy terminus of PTEN as bait to screen a brain yeast two-hybrid library, new potential binding partners of PTEN are identified.
- Published
- 2003
243. The involvement of Rho GTPases in plexin mediated signal transduction
- Author
-
Turner, Laura
- Subjects
572.7 - Abstract
Plexins are a family of conserved transmembrane proteins. Together with neuropilins, they act as receptors for the semaphorin family of growth cone guidance molecules. Whilst it is clear that guidance involves cytoskeletal changes, little is known of the mechanisms via which plexins regulate growth cone morphology. Hints suggesting the involvement of Rho GTPases stem from observations of localised actin rearrangements elicited by plexins and semaphorins. This feeling is consolidated by the demonstration of the Rac dependent nature of plexin induced cellular responses. To investigate plexin mediated signal transduction, a heterologous assay for semaphorin induced collapse has been developed and characterised. Studies using jasplakinolide indicate that Sema3A-Fc induced collapse requires actin dissassembly. Interestingly, a similar collapsed phenotype is observed in cells treated with latrunculin A. It is possible that Sema3A-Fc and latrunculin A may utilise comparable intracellular machinery to achieve similar morphological outcomes. Experiments using GTPase mutants demonstrated that Sema3A-Fc induced collapse required Rac and Cdc42, but not RhoA. In addition, Sema3A-Fc stimulation led to Rac activation prior to morphological collapse. Interestingly, collapse induced by constitutively active Plexin-Al did not require Rac. This suggests that Rac may act upstream of Plexin-Al, perhaps regulating the activity of Plexin-Al itself Evidence that Plexin-Al interacts directly with Rac.GTP supports this theory. A putative inter-or intramolecular interaction was identified within the cytoplasmic tails of Plexin-Al and Plexin-Bl. As the critical residues required for these interactions are also essential for Rac binding, these interactions and the association between Rac and plexin may be mutually exclusive. Finally, the cytoplasmic tail of Plexin-Al was shown to dimerise, but antibody mediated clustering of Plexin-Al was not sufficient to induce morphological collapse. In the light of these results, Rac may regulate plexin activity by modulating either conformational changes or receptor aggregation states in response to semaphorin stimulation.
- Published
- 2003
244. Adverse clinical outcomes and immunosuppressive microenvironment of RHO-GTPase activation pattern in hepatocellular carcinoma
- Author
-
Yang, Qi, Zhuo, Zewei, Qiu, Xinqi, Luo, Ruibang, Guo, Kehang, Wu, Huihuan, Jiang, Rui, Li, Jingwei, Lian, Qizhou, Chen, Pengfei, Sha, Weihong, and Chen, Hao
- Published
- 2024
- Full Text
- View/download PDF
245. Molecular basis and current insights of atypical Rho small GTPase in cancer
- Author
-
Huang, Hua, Wang, Sijia, Guan, Yifei, Ren, Jing, and Liu, Xinhui
- Published
- 2024
- Full Text
- View/download PDF
246. Rho GTPases in Retinal Vascular Diseases
- Author
-
Akiyoshi Uemura and Yoko Fukushima
- Subjects
angiogenesis ,cell–cell junction ,cell migration ,endothelial cell ,retina ,Rho GTPase ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The Rho family of small GTPases (Rho GTPases) act as molecular switches that transduce extrinsic stimuli into cytoskeletal rearrangements. In vascular endothelial cells (ECs), Cdc42, Rac1, and RhoA control cell migration and cell–cell junctions downstream of angiogenic and inflammatory cytokines, thereby regulating vascular formation and permeability. While these Rho GTPases are broadly expressed in various types of cells, RhoJ is enriched in angiogenic ECs. Semaphorin 3E (Sema3E) releases RhoJ from the intracellular domain of PlexinD1, by which RhoJ induces actin depolymerization through competition with Cdc42 for their common effector proteins. RhoJ further mediates the Sema3E-induced association of PlexinD1 with vascular endothelial growth factor receptor (VEGFR) 2 and the activation of p38. Upon stimulation with VEGF-A, RhoJ facilitates the formation of a holoreceptor complex comprising VEGFR2, PlexinD1, and neuropilin-1, leading to the prevention of VEGFR2 degradation and the maintenance of intracellular signal transduction. These pleiotropic roles of RhoJ are required for directional EC migration in retinal angiogenesis. This review highlights the latest insights regarding Rho GTPases in the field of vascular biology, as it will be informative to consider their potential as targets for the treatment of aberrant angiogenesis and hyperpermeability in retinal vascular diseases.
- Published
- 2021
- Full Text
- View/download PDF
247. Rho GTPases: functions and association with cancer
- Author
-
Ellenbroek, Saskia I. J. and Collard, John G.
- Published
- 2007
- Full Text
- View/download PDF
248. Clostridium difficile toxin A-induced apoptosis is p53-independent but depends on glucosylation of Rho GTPases
- Author
-
Nottrott, Stefanie, Schoentaube, Janett, Genth, Harald, Just, Ingo, and Gerhard, Ralf
- Published
- 2007
- Full Text
- View/download PDF
249. Methods to Study the Roles of Rho GTPases in Platelet Function
- Author
-
Rivero, Francisco, primary and Calaminus, Simon, additional
- Published
- 2018
- Full Text
- View/download PDF
250. Methods to Study the Roles of Rho GTPases in Dendritic Tree Complexity
- Author
-
Schulz, Jana, primary and Schumacher, Stefan, additional
- Published
- 2018
- Full Text
- View/download PDF
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