1,439 results on '"RHO GTPases"'
Search Results
2. Emerging roles for Mitochondrial Rho GTPases in tumor biology
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Boulton, Dillon P. and Caino, M. Cecilia
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- 2024
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3. Tanshinone IIA modulates cancer cell morphology and movement via Rho GTPases-mediated actin cytoskeleton remodeling
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Liang, En-yu, Huang, Meng-he, Chen, Ying-ting, Zhang, Peng-wei, Shen, Yan, Tu, Xiao-xin, Chen, Wei-ye, Wang, Yi, Yan, Jun, Wang, Hong-yu, Ke, Pei-feng, and Huang, Xian-zhang
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- 2024
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4. Publisher Correction: Patterning of the cell cortex by Rho GTPases
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Bement, William M., Goryachev, Andrew B., Miller, Ann L., and von Dassow, George
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- 2024
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5. A computational analysis of the role of integrins and Rho-GTPases in the emergence and disruption of apical-basal polarization in renal epithelial cells.
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Maria J Hagelaars, Milica Nikolic, Maud Vermeulen, Sylvia Dekker, Carlijn V C Bouten, and Sandra Loerakker
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Biology (General) ,QH301-705.5 - Abstract
Apical-basal polarization in renal epithelial cells is crucial to renal function and an important trigger for tubule formation in kidney development. Loss of polarity can induce epithelial-to-mesenchymal transition (EMT), which can lead to kidney pathologies. Understanding the relative and combined roles of the involved proteins and their interactions that govern epithelial polarity may provide insights for controlling the process of polarization via chemical or mechanical manipulations in an in vitro or in vivo setting. Here, we developed a computational framework that integrates several known interactions between integrins, Rho-GTPases Rho, Rac and Cdc42, and polarity complexes Par and Scribble, to study their mutual roles in the emergence of polarization. The modeled protein interactions were shown to induce the emergence of polarized distributions of Rho-GTPases, which in turn led to the accumulation of apical and basal polarity complexes Par and Scribble at their respective poles, effectively recapitulating polarization. Our multiparametric sensitivity analysis suggested that polarization depends foremost on the mutual inhibition between Rac and Rho. Next, we used the computational framework to investigate the role of integrins and GTPases in the generation and disruption of polarization. We found that a minimum concentration of integrins is required to catalyze the process of polarization. Furthermore, loss of polarization was found to be only inducible via complete degradation of the Rho-GTPases Rho and Cdc42, suggesting that polarization is fairly stable once it is established. Comparison of our computational predictions against data from in vitro experiments in which we induced EMT in renal epithelial cells while quantifying the relative Rho-GTPase levels, displayed that EMT coincides with a large reduction in the Rho-GTPase Rho. Collectively, these results demonstrate the essential roles of integrins and Rho-GTPases in the establishment and disruption of apical-basal polarity and thereby provide handles for the in vitro or in vivo regulation of polarity.
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- 2024
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6. A computational analysis of the role of integrins and Rho-GTPases in the emergence and disruption of apical-basal polarization in renal epithelial cells.
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Hagelaars, Maria J., Nikolic, Milica, Vermeulen, Maud, Dekker, Sylvia, Bouten, Carlijn V. C., and Loerakker, Sandra
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EPITHELIAL cells , *KIDNEY tubules , *KIDNEY development , *EPITHELIAL-mesenchymal transition , *PROTEIN-protein interactions - Abstract
Apical-basal polarization in renal epithelial cells is crucial to renal function and an important trigger for tubule formation in kidney development. Loss of polarity can induce epithelial-to-mesenchymal transition (EMT), which can lead to kidney pathologies. Understanding the relative and combined roles of the involved proteins and their interactions that govern epithelial polarity may provide insights for controlling the process of polarization via chemical or mechanical manipulations in an in vitro or in vivo setting. Here, we developed a computational framework that integrates several known interactions between integrins, Rho-GTPases Rho, Rac and Cdc42, and polarity complexes Par and Scribble, to study their mutual roles in the emergence of polarization. The modeled protein interactions were shown to induce the emergence of polarized distributions of Rho-GTPases, which in turn led to the accumulation of apical and basal polarity complexes Par and Scribble at their respective poles, effectively recapitulating polarization. Our multiparametric sensitivity analysis suggested that polarization depends foremost on the mutual inhibition between Rac and Rho. Next, we used the computational framework to investigate the role of integrins and GTPases in the generation and disruption of polarization. We found that a minimum concentration of integrins is required to catalyze the process of polarization. Furthermore, loss of polarization was found to be only inducible via complete degradation of the Rho-GTPases Rho and Cdc42, suggesting that polarization is fairly stable once it is established. Comparison of our computational predictions against data from in vitro experiments in which we induced EMT in renal epithelial cells while quantifying the relative Rho-GTPase levels, displayed that EMT coincides with a large reduction in the Rho-GTPase Rho. Collectively, these results demonstrate the essential roles of integrins and Rho-GTPases in the establishment and disruption of apical-basal polarity and thereby provide handles for the in vitro or in vivo regulation of polarity. Author summary: Apical-basal polarization of renal epithelial cells lies at the foundation of the kidney's biological function and is the catalyst for tubulogenesis during kidney development. Although individual parts of the polarization pathway have been extensively studied before, a deep understanding of the combined and relative roles of the different proteins and/or protein interactions that lead to the emergence of polarization remains lacking due to the complexity of the various and integrated pathways. To dissect the complexity, we constructed a computational model that integrates known mechanisms of the polarization pathway. We found that the emergence of polarization is heavily dependent on a specific subset of the interactions between the involved proteins (i.e. integrins, Rho-GTPases, and polarity proteins Par and Scribble). Specifically, we concluded from our model that polarization could only be initiated when the number of integrins exceeded a threshold value, while polarization could only be disrupted in our model by complete degradation of certain Rho-GTPases. Collectively, these results indicate that apical-basal polarization is a stable process once it has emerged. Our findings help in deepening the understanding of the polarization pathway and provide new insights for regulating apical-basal polarization. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Testing models of cell cortex wave generation by Rho GTPases.
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Chomchai D, Leda M, Golding A, von Dassow G, Bement WM, and Goryachev AB
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The Rho GTPases pattern the cell cortex in a variety of fundamental cell-morphogenetic processes including division, wound repair, and locomotion. It has recently become apparent that this patterning arises from the ability of the Rho GTPases to self-organize into static and migrating spots, contractile pulses, and propagating waves in cells from yeasts to mammals
1 . These self-organizing Rho GTPase patterns have been explained by a variety of theoretical models which require multiple interacting positive and negative feedback loops. However, it is often difficult, if not impossible, to discriminate between different models simply because the available experimental data do not simultaneously capture the dynamics of multiple molecular concentrations and biomechanical variables at fine spatial and temporal resolution. Specifically, most studies typically provide either the total Rho GTPase signal or the Rho GTPase activity as reported by various sensors, but not both. Therefore, it remains largely unknown how membrane accumulation of Rho GTPases (i.e., Rho membrane enrichment) is related to Rho activity. Here we dissect the dynamics of RhoA by simultaneously imaging both total RhoA and active RhoA in the regime of acute cortical excitability2 , characterized by pronounced waves of Rho activity and F-actin polymerization3-5 . We find that within nascent waves, accumulation of active RhoA precedes that of total RhoA, and we exploit this finding to distinguish between two popular theoretical models previously used to explain propagating cortical Rho waves.- Published
- 2024
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8. Testing models of cell cortex wave generation by Rho GTPases
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Chomchai, Dominic A, primary, Leda, Marcin, additional, Golding, Adriana E, additional, von Dassow, George, additional, Bement, William M, additional, and Goryachev, Andrew B, additional
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- 2024
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9. Understanding P-Rex regulation: structural breakthroughs and emerging perspectives.
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Jones, Gareth D. and Ellisdon, Andrew M.
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GUANINE nucleotide exchange factors , *RHO GTPases , *PROTEIN-protein interactions , *CANCER invasiveness , *GUANOSINE triphosphatase - Abstract
Rho GTPases are a family of highly conserved G proteins that regulate numerous cellular processes, including cytoskeleton organisation, migration, and proliferation. The 20 canonical Rho GTPases are regulated by ~85 guanine nucleotide exchange factors (GEFs), with the largest family being the 71 Diffuse B-cell Lymphoma (Dbl) GEFs. Dbl GEFs promote GTPase activity through the highly conserved Dbl homology domain. The specificity of GEF activity, and consequently GTPase activity, lies in the regulation and structures of the GEFs themselves. Dbl GEFs contain various accessory domains that regulate GEF activity by controlling subcellular localisation, protein interactions, and often autoinhibition. This review focuses on the two phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3)-dependent Rac exchangers (P-Rex), particularly the structural basis of P-Rex1 autoinhibition and synergistic activation. First, we discuss structures that highlight the conservation of P-Rex catalytic and phosphoinositide binding activities. We then explore recent breakthroughs in uncovering the structural basis for P-Rex1 autoinhibition and detail the proposed minimal two-step model of how PI(3,4,5)P3 and Gβγ synergistically activate P-Rex1 at the membrane. Additionally, we discuss the further layers of P-Rex regulation provided by phosphorylation and P-Rex2-PTEN coinhibitory complex formation, although these mechanisms remain incompletely understood. Finally, we leverage the available data to infer how cancer-associated mutations in P-Rex2 destabilise autoinhibition and evade PTEN coinhibitory complex formation, leading to increased P-Rex2 GEF activity and driving cancer progression and metastasis. [ABSTRACT FROM AUTHOR]
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- 2024
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10. Transient Structural Properties of the Rho GDP‐Dissociation Inhibitor.
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Medina Gomez, Sara, Visco, Ilaria, Merino, Felipe, Bieling, Peter, and Linser, Rasmus
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RHO GTPases , *PEPTIDES , *MOLECULAR dynamics , *NUCLEAR magnetic resonance spectroscopy , *SURFACE interactions - Abstract
Rho GTPases, master spatial regulators of a wide range of cellular processes, are orchestrated by complex formation with guanine nucleotide dissociation inhibitors (RhoGDIs). These have been thought to possess an unstructured N‐terminus that inhibits nucleotide exchange of their client upon binding/folding. Via NMR analyses, molecular dynamics simulations, and biochemical assays, we reveal instead pertinent structural properties transiently maintained both, in the presence and absence of the client, imposed onto the terminus context‐specifically by modulating interactions with the surface of the folded C‐terminal domain. These observations revise the long‐standing textbook picture of the GTPases' mechanism of membrane extraction. Rather than by a disorder‐to‐order transition upon binding of an inhibitory peptide, the intricate and highly selective extraction process of RhoGTPases is orchestrated via a dynamic ensemble bearing preformed transient structural properties, suitably modulated by the specific surrounding along the multi‐step process. [ABSTRACT FROM AUTHOR]
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- 2024
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11. 3048 – NOD1-DEPENDENT NF-KB ACTIVATION INITIATES HEMATOPOIETIC STEM CELL SPECIFICATION IN RESPONSE TO SMALL RHO GTPASES
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Cheng, Xiaoyi, Barakat, Radwa, Pavani, Giulia, Usha, Masuma, Calderon, Rodolfo, Snella, Elizabeth, Gorden, Abigail, Zhang, Yudi, Gadue, Paul, French, Deborah, Dorman, Karin, Fidanza, Antonella, Campbell, Clyde, and Espin-Palazon, Raquel
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- 2024
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12. The mevalonate pathway contributes to breast primary tumorigenesis and lung metastasis.
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Conde, Javier, Fernández‐Pisonero, Isabel, Lorenzo‐Martín, L. Francisco, García‐Gómez, Rocío, Casar, Berta, Crespo, Piero, and Bustelo, Xosé R.
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NUCLEOTIDE exchange factors , *RHO GTPases , *BREAST cancer , *GENE expression , *DISEASE relapse , *BREAST - Abstract
The mevalonate pathway plays an important role in breast cancer and other tumor types. However, many issues remain obscure as yet regarding its mechanism of regulation and action. In the present study, we report that the expression of mevalonate pathway enzymes is mediated by the RHO guanosine nucleotide exchange factors VAV2 and VAV3 in a RAC1‐ and sterol regulatory element‐binding factor (SREBF)‐dependent manner in breast cancer cells. Furthermore, in vivo tumorigenesis experiments indicated that the two most upstream steps of this metabolic pathway [3‐hydroxy‐3‐methylglutaryl‐coenzyme A synthase 1 (HMGCS1) and 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR)] are important for primary tumorigenesis, angiogenesis, and cell survival in breast cancer cells. HMGCR, but not HMGCS1, is also important for the extravasation and subsequent fitness of breast cancer cells in the lung parenchyma. Genome‐wide expression analyses revealed that HMGCR influences the expression of gene signatures linked to proliferation, metabolism, and immune responses. The HMGCR‐regulated gene signature predicts long‐term tumor recurrence but not metastasis in cohorts of nonsegregated and chemotherapy‐resistant breast cancer patients. These results reveal a hitherto unknown, VAV‐catalysis‐dependent mechanism involved in the regulation of the mevalonate pathway in breast cancer cells. They also identify specific mevalonate‐pathway‐dependent processes that contribute to the malignant features of breast cancer cells. [ABSTRACT FROM AUTHOR]
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- 2024
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13. TRANSPLANTE DE CÉLULAS ENDOTELIAIS COMO UMA ALTERNATIVA AO TRANSPLANTE DE CÓRNEA.
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Meira Valadares, Nara Maria, Ribeiro Sternick, Letícia, Rubião Pimenta, Clara, Samarane Castro, Clara, and Duarte Coutinho, Camila Hostalácio
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RHO GTPases ,CORNEAL transplantation ,CORNEAL dystrophies ,VISUAL acuity ,CORNEA - Abstract
Copyright of Revista Foco (Interdisciplinary Studies Journal) is the property of Revista Foco and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2024
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14. Testing models of cell cortex wave generation by Rho GTPases
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G proteins -- Models ,Cells -- Models ,Biological sciences ,Health - Abstract
2024 MAY 14 (NewsRx) -- By a News Reporter-Staff News Editor at Life Science Weekly -- According to news reporting based on a preprint abstract, our journalists obtained the following [...]
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- 2024
15. RhoU forms homo-oligomers to regulate cellular responses.
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Clayton, Natasha S., Hodge, Richard G., Infante, Elvira, Alibhai, Dominic, Zhou, Felix, and Ridley, Anne J.
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RHO GTPases , *GENE expression , *CELL migration , *ISOPRENYLATION , *CELL cycle proteins - Abstract
RhoU is an atypical member of the Rho family of small G-proteins, which has N- and C-terminal extensions compared to the classic Rho GTPases RhoA, Rac1 and Cdc42, and associates with membranes through C-terminal palmitoylation rather than prenylation. RhoU mRNA expression is upregulated in prostate cancer and is considered a marker for disease progression. Here, we show that RhoU overexpression in prostate cancer cells increases cell migration and invasion. To identify RhoU targets that contribute to its function, we found that RhoU homodimerizes in cells. We map the region involved in this interaction to the C-terminal extension and show that C-terminal palmitoylation is required for self-association. Expression of the isolated C-terminal extension reduces RhoU-induced activation of p21-activated kinases (PAKs), which are known downstream targets for RhoU, and induces cell morphological changes consistent with inhibiting RhoU function. Our results show for the first time that the activity of a Rho family member is stimulated by self-association, and this is important for its activity. [ABSTRACT FROM AUTHOR]
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- 2024
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16. RhoB plays a central role in hyperosmolarity‐induced cell shrinkage in renal cells.
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Centrone, Mariangela, Saltarella, Ilaria, D'Agostino, Mariagrazia, Ranieri, Marianna, Venneri, Maria, Di Mise, Annarita, Simone, Laura, Pisani, Francesco, Valenti, Giovanna, Frassanito, Maria A., and Tamma, Grazia
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RHO GTPases , *FLUORESCENCE resonance energy transfer , *CELL size , *CELL morphology - Abstract
The small Rho GTP‐binding proteins are important cell morphology, function, and apoptosis regulators. Unlike other Rho proteins, RhoB can be subjected to either geranylgeranylation (RhoB‐GG) or farnesylation (RhoB‐F), making that the only target of the farnesyltransferase inhibitor (FTI). Fluorescence resonance energy transfer experiments revealed that RhoB is activated by hyperosmolarity. By contrast, hyposmolarity did not affect RhoB activity. Interestingly, treatment with farnesyltransferase inhibitor‐277 (FTI‐277) decreased the cell size. To evaluate whether RhoB plays a role in volume reduction, renal collecting duct MCD4 cells and Human Kidney, HK‐2 were transiently transfected with RhoB‐wildtype‐Enhance Green Fluorescence Protein (RhoB‐wt‐EGFP) and RhoB‐CLLL‐EGFP which cannot undergo farnesylation. A calcein‐based fluorescent assay revealed that hyperosmolarity caused a significant reduction of cell volume in mock and RhoB‐wt‐EGFP‐expressing cells. By contrast, cells treated with FTI‐277 or expressing the RhoB‐CLLL‐EGFP mutant did not properly respond to hyperosmolarity with respect to mock and RhoB‐wt‐EGFP expressing cells. These findings were further confirmed by 3D‐LSCM showing that RhoB‐CLLL‐EGFP cells displayed a significant reduction in cell size compared to cells expressing RhoB‐wt‐EGFP. Moreover, flow cytometry analysis revealed that RhoB‐CLLL‐EGFP expressing cells as well as FTI‐277‐treated cells showed a significant increase in cell apoptosis. Together, these data suggested that: (i) RhoB is sensitive to hyperosmolarity and not to hyposmolarity; (ii) inhibition of RhoB farnesylation associates with an increase in cell apoptosis, likely suggesting that RhoB might be a paramount player controlling apoptosis by interfering with responses to cell volume change. [ABSTRACT FROM AUTHOR]
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- 2024
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17. Impacts of in‐vitro zebularine treatment on genome‐wide DNA methylation and transcriptomic profiles in Salix purpurea L.
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Khodaeiaminjan, Mortaza, Gomes, Carolina, Pagano, Andrea, Kruszka, Dariusz, Sulima, Paweł, Przyborowski, Jerzy Andrzej, Krajewski, Paweł, and Paiva, Jorge Almiro Pinto
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DNA methylation , *RHO GTPases , *GENE expression , *RENEWABLE energy sources , *WILLOWS , *LIGNOCELLULOSE , *WOOD chemistry - Abstract
Renewable energy resources such as biomass are crucial for a sustainable global society. Trees are a major source of lignocellulosic biomass, which can vary in response to different environmental factors owing to epigenetic regulation, such as DNA C‐methylation. To investigate the effects of DNA methylation on plant development and wood formation, and its impacts on gene expression, with a focus on secondary cell wall (SCW)‐associated genes, Salix purpurea plantlets were cloned from buds derived from a single hybrid tree for both treatment and control conditions. For the treatment condition, buds were exposed to 50 μM zebularine in vitro and a combined strategy of whole‐genome bisulfite sequencing (WGBS) and RNA‐seq was employed to examine the methylome and transcriptome profiles of different tissues collected at various time points under both conditions. Transcriptomic and methylome data revealed that most of the promoter and gene body demethylation had no marked effects on the expression profiles of genes. Nevertheless, gene expression tended to decrease with the increased methylation levels of genes with highly methylated promoters. Results indicated that demethylation is less evident in centromeric regions and sex chromosomes. Promoters of secondary cell wall‐associated genes, such as 4‐coumarate‐CoA ligase‐like and Rac‐like GTP‐binding protein RHO, were differentially methylated in the secondary xylem samples collected from two‐month potted treated plants compared to control samples. Our results provide novel insights into DNA methylation and gene expression landscapes and a basis for investigating the epigenetic regulation of wood formation in S. purpurea as a model plant for bioenergy species. [ABSTRACT FROM AUTHOR]
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- 2024
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18. A rho-type GTPase activating protein affects the growth and development of Cordyceps cicadae.
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Li, Xueqian, Zou, Yu, Shrivastava, Neeraj, Bao, Jiandong, Lin, Fu-Cheng, and Wang, Hongkai
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CICADAS ,GUANOSINE triphosphatase ,CORDYCEPS ,RHO GTPases ,EUKARYOTIC cells ,ADENOSINES - Abstract
Cordyceps cicadae is recognized for its medicinal properties, attributed to bioactive constituents like polysaccharides and adenosine, which have been shown to improve kidney and liver functions and possess anti-tumor properties. Rho GTPase activating proteins (Rho GAPs) serve as inhibitory regulators of Rho GTPases in eukaryotic cells by accelerating the GTP hydrolysis of Rho GTPases, leading to their inactivation. In this study, we explored the function of the CcRga8 gene in C. cicadae, which encodes a Rho-type GTPase activating protein. Our study found that the knockout of CcRga8 resulted in a decrease in polysaccharide levels and an increase in adenosine concentration. Furthermore, the mutants exhibited altered spore yield and morphology, fruiting body development, decreased infectivity, reduced resistance to hyperosmotic stress, oxidative conditions, and cell wall inhibitors. These findings suggest that CcRga8 plays a crucial role in the development, stress response, and bioactive compound production of C. cicadae. [ABSTRACT FROM AUTHOR]
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- 2024
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19. Phloridzin Docosahexaenoate, an Omega-3 Fatty Acid Ester of a Flavonoid Precursor, Inhibits Angiogenesis by Suppressing Endothelial Cell Proliferation, Migration, and Differentiation.
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Fernando, Wasundara, MacLean, Emma, Monro, Susan, Power Coombs, Melanie R., Marcato, Paola, Rupasinghe, H. P. Vasantha, and Hoskin, David W.
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VASCULAR endothelial growth factors ,FATTY acid esters ,RHO GTPases ,NEOVASCULARIZATION inhibitors ,THORACIC aorta ,NEOVASCULARIZATION ,CYTOSKELETAL proteins - Abstract
Angiogenesis is a normal physiological process that also contributes to diabetic retinopathy-related complications and facilitates tumor metastasis by promoting the hematogenic dissemination of malignant cells from solid tumors. Here, we investigated the in vitro, ex vivo, and in vivo anti-angiogenic activity of phloridzin docosahexaenoate (PZ-DHA), a novel ω-3 fatty acid ester of a flavonoid precursor. Human umbilical vein endothelial cells (HUVEC) and human dermal microvascular endothelial cells (HMVEC) treated with a sub-cytotoxic concentration of PZ-DHA to assess in vitro anti-angiogenic activity showed impaired tubule formation on a Matrigel matrix. Ex vivo angiogenesis was measured using rat thoracic aortas, which exhibited reduced vessel sprouting and tubule formation in the presence of PZ-DHA. Female BALB/c mice bearing VEGF
165 - and basic fibroblast growth factor-containing Matrigel plugs showed a significant reduction in blood vessel development following PZ-DHA treatment. PZ-DHA inhibited HUVEC and HMVEC proliferation, as well as the migration of HUVECs in gap closure and trans-well cell migration assays. PZ-DHA inhibited upstream and downstream components of the Akt pathway and vascular endothelial growth factor (VEGF165 )-induced overexpression of small molecular Rho GTPases in HUVECs, suggesting a decrease in actin cytoskeletal-mediated stress fiber formation and migration. Taken together, these findings reveal the potential of combined food biomolecules in PZ-DHA to inhibit angiogenesis. [ABSTRACT FROM AUTHOR]- Published
- 2024
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20. Emerging roles of deubiquitinating enzymes in actin cytoskeleton and tumor metastasis.
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Xue, Ying, Xue, Cong, and Song, Wei
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DEUBIQUITINATING enzymes ,MICROFILAMENT proteins ,RHO GTPases ,TUMOR proteins ,CYTOSKELETON - Abstract
Background: Metastasis accounts for the majority of cancer-related deaths. Actin dynamics and actin-based cell migration and invasion are important factors in cancer metastasis. Metastasis is characterized by actin polymerization and depolymerization, which are precisely regulated by molecular changes involving a plethora of actin regulators, including actin-binding proteins (ABPs) and signalling pathways, that enable cancer cell dissemination from the primary tumour. Research on deubiquitinating enzymes (DUBs) has revealed their vital roles in actin dynamics and actin-based migration and invasion during cancer metastasis. Conclusion: Here, we review how DUBs drive tumour metastasis by participating in actin rearrangement and actin-based migration and invasion. We summarize the well-characterized and essential actin cytoskeleton signalling molecules related to DUBs, including Rho GTPases, Src kinases, and ABPs such as cofilin and cortactin. Other DUBs that modulate actin-based migration signalling pathways are also discussed. Finally, we discuss and address therapeutic opportunities and ongoing challenges related to DUBs with respect to actin dynamics. [ABSTRACT FROM AUTHOR]
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- 2024
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21. 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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22. 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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23. 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
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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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24. Signal flow in the NMDA receptor–dependent phosphoproteome regulates postsynaptic plasticity for aversive learning.
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Funahashi, Yasuhiro, Ahammad, Rijwan Uddin, Zhang, Xinjian, Hossen, Emran, Kawatani, Masahiro, Nakamuta, Shinichi, Yoshimi, Akira, Wu, Minhua, Wang, Huanhuan, Wu, Mengya, Li, Xu, Faruk, Md Omar, Shohag, Md Hasanuzzaman, Lin, You-Hsin, Tsuboi, Daisuke, Nishioka, Tomoki, Kuroda, Keisuke, Amano, Mutsuki, Noda, Yukihiko, and Yamada, Kiyofumi
- Subjects
RHO-associated kinases ,SCAFFOLD proteins ,NUCLEUS accumbens ,PROTEIN kinases ,RHO GTPases ,DENDRITIC spines - Abstract
Structural plasticity of dendritic spines in the nucleus accumbens (NAc) is crucial for learning from aversive experiences. Activation of NMDA receptors (NMDARs) stimulates Ca
2+ -dependent signaling that leads to changes in the actin cytoskeleton, mediated by the Rho family of GTPases, resulting in postsynaptic remodeling essential for learning. We investigated how phosphorylation events downstream of NMDAR activation drive the changes in synaptic morphology that underlie aversive learning. Large-scale phosphoproteomic analyses of protein kinase targets in mouse striatal/accumbal slices revealed that NMDAR activation resulted in the phosphorylation of 194 proteins, including RhoA regulators such as ARHGEF2 and ARHGAP21. Phosphorylation of ARHGEF2 by the Ca2+ -dependent protein kinase CaMKII enhanced its RhoGEF activity, thereby activating RhoA and its downstream effector Rho-associated kinase (ROCK/Rho-kinase). Further phosphoproteomic analysis identified 221 ROCK targets, including the postsynaptic scaffolding protein SHANK3, which is crucial for its interaction with NMDARs and other postsynaptic scaffolding proteins. ROCK-mediated phosphorylation of SHANK3 in the NAc was essential for spine growth and aversive learning. These findings demonstrate that NMDAR activation initiates a phosphorylation cascade crucial for learning and memory. Editor's summary: A component of the strengthened synaptic transmission that occurs in learning and memory is the growth of protrusions on neurons called dendritic spines, which requires activation of the NMDAR family of receptors in the nucleus accumbens. Funahashi et al. delineated the signaling pathway downstream of NMDARs that mediated aversive learning, which enables the identification, prediction, and avoidance of dangerous situations. The authors characterized the proteins phosphorylated in response to NMDAR activation and the kinases responsible. Dendritic spine growth and aversive learning were attenuated when the cytoskeleton-regulating kinase ROCK was pharmacologically inhibited or genetically ablated or when the ROCK-mediated phosphorylation of a specific substrate, the scaffolding protein SHANK3, was blocked in the nucleus accumbens. Thus, the phosphorylation of SHANK3 by ROCK is crucial for the changes in the neuronal actin cytoskeleton that support aversive learning. —Wei Wong [ABSTRACT FROM AUTHOR]- Published
- 2024
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25. Atypical RhoUV GTPases in development and disease
- Author
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Woo, Stephanie and Strasser, Leesa
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Genetics ,GTP-Binding Proteins ,rho GTP-Binding Proteins ,Signal Transduction ,Cell Adhesion ,EMT ,Rho GTPases ,RhoU ,RhoV ,cancer ,embryogenesis ,Medical Biochemistry and Metabolomics ,Biochemistry & Molecular Biology ,Biochemistry and cell biology - Abstract
RhoU and RhoV are members of the Rho family of small GTPases that comprise their own subfamily. RhoUV GTPases are classified as atypical due to the kinetics of their GTP/GDP binding cycles. They also possess unique N- and C-termini that regulate their subcellular localization and activity. RhoU and RhoV have been linked to cytoskeletal regulation, cell adhesion, and cell migration. They each exhibit distinct expression patterns during embryonic development and diseases such as cancer metastasis, suggesting they have specialized functions. In this review, we will discuss the known functions of RhoU and RhoV, with a focus on their roles in early development, organogenesis, and disease.
- Published
- 2024
26. Improved Cellulase Production of Trichoderma reesei by Regulating Mycelium Morphology.
- Author
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Jiang, Fangting, Tian, Jiudong, Yuan, Jie, Wang, Shengjie, Bao, Tongtong, Chen, Qiuhui, Gao, Le, Li, Jinyang, and Ma, Lijuan
- Subjects
TRICHODERMA reesei ,CELLULASE ,RHO GTPases ,CELL cycle proteins ,PLANT biomass ,MYCELIUM - Abstract
The small GTPases of the Rho family are known to regulate various biological processes in filamentous fungi. In this study, we investigated the impact of deleting Rho proteins on the growth and cellulase production of Trichoderma reesei. Our findings revealed that deletion of cdc42 led to the most severe growth defect and impaired cellulase production. Conversely, overexpression of cdc42 resulted in a hyperbranched phenotype, significantly enhancing cellulase production. Furthermore, the cdc42-overexpressing (OCdc42) strain showed an increased expression of multiple cellulase genes and Rho GTPase genes. Analysis of the secretome in the OCdc42 strain unveiled an increased abundance and diversity of extracellular proteins compared to the parent strain. These discoveries provide valuable insights into the functionality of Rho GTPases in T. reesei and offer potential targets for engineering fungi to improve plant biomass deconstruction in biorefineries. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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27. 490P Inhibiting glioma cells' migration: Exploring Rho-GTPases as a potential therapeutic target.
- Author
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Rolle, I.G., Del Mestre, P., Manini, I., Mastantuono, S., Skrap, M., Vindigni, M., Di Loreto, C., Magistrato, A., and Cesselli, D.
- Published
- 2024
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28. ROCK1 is a multifunctional factor maintaining the primordial follicle reserve and follicular development in mice.
- Author
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Tuo Zhang, Huan Lin, Tianhe Ren, Meina He, Wenying Zheng, Yuntong Tong, Bangming Jin, Kaiyun Xie, Ankang Deng, Shiyu Liu, Yuqian Chen, Guoqiang Xu, Tengxiang Chen, Wei Pan, and Ziwen Xiao
- Subjects
OVARIAN follicle ,HIPPO signaling pathway ,OVARIAN reserve ,PREMATURE ovarian failure ,RHO-associated kinases ,RHO GTPases - Abstract
The follicle is the basic structural and functional unit of the ovary in female mammals. The excessive depletion of follicles will lead to diminished ovarian reserve or even premature ovarian failure, resulting in diminished ovarian oogenesis and endocrine function. Excessive follicular depletion is mainly due to loss of primordial follicles. Our analysis of published human ovarian single-cell sequencing results by others revealed a significant increase in rho-associated protein kinase 1 (ROCK1) expression during primordial follicle development. However, the role of ROCK1 in primordial follicle development and maintenance is not clear. This study revealed a gradual increase in ROCK1 expression during primordial follicle activation. Inhibition of ROCK1 resulted in reduced primordial follicle activation, decreased follicular reserve, and delayed development of growing follicles. This effect may be achieved through the HIPPO pathway. The present study indicates that ROCK1 is a key molecule for primordial follicular reserve and follicular development. NEW & NOTEWORTHY: ROCK1, one of the Rho GTPases, plays an important role in primordial follicle reserve and follicular development. ROCK1 was primarily expressed in the cytoplasm of oocytes and granulosa cell in mice. Inhibition of ROCK1 significantly reduced the primordial follicle reserve and delayed growing follicle development. ROCK1 regulates primordial follicular reserve and follicle development through the HIPPO signaling pathway. These findings shed new lights on the physiology of sustaining female reproduction. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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29. Adverse clinical outcomes and immunosuppressive microenvironment of RHO-GTPase activation pattern in hepatocellular carcinoma
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Qi Yang, Zewei Zhuo, Xinqi Qiu, Ruibang Luo, Kehang Guo, Huihuan Wu, Rui Jiang, Jingwei Li, Qizhou Lian, Pengfei Chen, Weihong Sha, and Hao Chen
- Subjects
Rho GTPases ,Hepatocellular carcinoma ,Pan-cancer ,Immune infiltration ,Single-cell transcriptome ,Medicine - Abstract
Abstract Background Emerging evidence suggests that Rho GTPases play a crucial role in tumorigenesis and metastasis, but their involvement in the tumor microenvironment (TME) and prognosis of hepatocellular carcinoma (HCC) is not well understood. Methods We aim to develop a tumor prognosis prediction system called the Rho GTPases-related gene score (RGPRG score) using Rho GTPase signaling genes and further bioinformatic analyses. Results Our work found that HCC patients with a high RGPRG score had significantly worse survival and increased immunosuppressive cell fractions compared to those with a low RGPRG score. Single-cell cohort analysis revealed an immune-active TME in patients with a low RGPRG score, with strengthened communication from T/NK cells to other cells through MIF signaling networks. Targeting these alterations in TME, the patients with high RGPRG score have worse immunotherapeutic outcomes and decreased survival time in the immunotherapy cohort. Moreover, the RGPRG score was found to be correlated with survival in 27 other cancers. In vitro experiments confirmed that knockdown of the key Rho GTPase-signaling biomarker SFN significantly inhibited HCC cell proliferation, invasion, and migration. Conclusions This study provides new insight into the TME features and clinical use of Rho GTPase gene pattern at the bulk-seq and single-cell level, which may contribute to guiding personalized treatment and improving clinical outcome in HCC.
- Published
- 2024
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30. Streptococcus pneumoniae infection of lung epithelial cells induces internalization of surface GPI-anchored proteins through pneumolysin-mediated activation of host Rho GTPases (Updated April 27, 2024).
- Subjects
STREPTOCOCCUS pneumoniae ,STREPTOCOCCAL diseases ,RHO GTPases ,EPITHELIAL cells ,LUNG infections ,SEROTYPES - Abstract
A recent study investigated the effects of Streptococcus pneumoniae infection on lung epithelial cells. The study found that the bacteria's toxin, pneumolysin, caused a reduction in the expression of CD73, a protein involved in inflammation modulation. Additionally, the toxin led to the internalization of glycosylphosphatidylinositol anchored proteins (GPI-APs) through the activation of host Rho GTPases. This internalization process may serve as a rapid innate repair response to cell damage induced by the toxin. The findings suggest that this mechanism could help bacteria evade host defenses. However, it is important to note that this study has not yet undergone peer review. [Extracted from the article]
- Published
- 2024
31. The Role of LIM Kinase 1 in Memory Processes.
- Author
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Nikitina, E. A., Zalomaeva, E. S., Medvedeva, A. V., Zhuravlev, A. V., and Savvateeva-Popova, E. V.
- Subjects
BRAIN damage ,RHO GTPases ,NEURODEGENERATION ,GENE expression ,DROSOPHILA - Abstract
Modern concepts hold that intellectual problems in neurological brain damage are based on active forgetting, which is regulated by actin remodeling signal cascades dependent on small GTPases Rac and Rho. The key enzyme in these cascades is LIM kinase 1 (LIMK1). Changes in limk1 gene expression lead to neurocognitive pathologies. There is a need to create and validate simple animal models for rapid screening and testing of targeted therapeutic agents altering the protein–protein interactions of GTPases and components of signal cascades. One opportunity for this is provided by Drosophila, mutant strains of which allow the key points of the intersections of biochemical and neural networks which accompany active forgetting to be identifi ed. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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32. VAV2 orchestrates the interplay between regenerative proliferation and ribogenesis in both keratinocytes and oral squamous cell carcinoma
- Author
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Natalia Fernández-Parejo, L. Francisco Lorenzo-Martín, Juana M. García-Pedrero, Juan P. Rodrigo, Mercedes Dosil, and Xosé R. Bustelo
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Guanosine nucleotide exchange factors ,RHO GTPases ,RAC1 ,RHOA ,PAK1 ,ROCK ,Medicine ,Science - Abstract
Abstract VAV2 is an activator of RHO GTPases that promotes and maintains regenerative proliferation-like states in normal keratinocytes and oral squamous cell carcinoma (OSCC) cells. Here, we demonstrate that VAV2 also regulates ribosome biogenesis in those cells, a program associated with poor prognosis of human papilloma virus-negative (HPV−) OSCC patients. Mechanistically, VAV2 regulates this process in a catalysis-dependent manner using a conserved pathway comprising the RAC1 and RHOA GTPases, the PAK and ROCK family kinases, and the c-MYC and YAP/TAZ transcription factors. This pathway directly promotes RNA polymerase I activity and synthesis of 47S pre-rRNA precursors. This process is further consolidated by the upregulation of ribosome biogenesis factors and the acquisition of the YAP/TAZ-dependent undifferentiated cell state. Finally, we show that RNA polymerase I is a therapeutic Achilles’ heel for both keratinocytes and OSCC patient-derived cells endowed with high VAV2 catalytic activity. Collectively, these findings highlight the therapeutic potential of modulating VAV2 and the ribosome biogenesis pathways in both preneoplastic and late progression stages of OSCC.
- Published
- 2024
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33. PAK2 is necessary for myelination in the peripheral nervous system.
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Hu, Bo, Moiseev, Daniel, Schena, Isabella, Faezov, Bulat, Dunbrack, Roland, Chernoff, Jonathan, and Li, Jun
- Subjects
PERIPHERAL nervous system ,MYELINATION ,SCHWANN cells ,SCIATIC nerve ,RHO GTPases - Abstract
Myelination enables electrical impulses to propagate on axons at the highest speed, encoding essential life functions. The Rho family GTPases, RAC1 and CDC42, have been shown to critically regulate Schwann cell myelination. P21-activated kinase 2 (PAK2) is an effector of RAC1/CDC42, but its specific role in myelination remains undetermined. We produced a Schwann cell-specific knockout mouse of Pak2 (scPak2
−/− ) to evaluate PAK2's role in myelination. Deletion of Pak2 , specifically in mouse Schwann cells, resulted in severe hypomyelination, slowed nerve conduction velocity and behaviour dysfunctions in the scPak2−/− peripheral nerve. Many Schwann cells in scPak2−/− sciatic nerves were arrested at the stage of axonal sorting. These abnormalities were rescued by reintroducing Pak2 , but not the kinase-dead mutation of Pak2 , via lentivirus delivery to scPak2−/− Schwann cells in vivo. Moreover, ablation of Pak2 in Schwann cells blocked the promyelinating effect driven by neuregulin-1, prion protein and inactivated RAC1/CDC42. Conversely, the ablation of Pak2 in neurons exhibited no phenotype. Such PAK2 activity can also be either enhanced or inhibited by different myelin lipids. We have identified a novel promyelinating factor, PAK2, that acts as a critical convergence point for multiple promyelinating signalling pathways. The promyelination by PAK2 is Schwann cell-autonomous. Myelin lipids, identified as inhibitors or activators of PAK2, may be utilized to develop therapies for repairing abnormal myelin in peripheral neuropathies. [ABSTRACT FROM AUTHOR]- Published
- 2024
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34. The cytoskeleton adaptor protein Sorbs1 controls the development of lymphatic and venous vessels in zebrafish.
- Author
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Veloso, Alexandra, Bleuart, Anouk, Conrard, Louise, Orban, Tanguy, Bruyr, Jonathan, Cabochette, Pauline, Germano, Raoul F. V., Schevenels, Giel, Bernard, Alice, Zindy, Egor, Demeyer, Sofie, Vanhollebeke, Benoit, Dequiedt, Franck, and Martin, Maud
- Subjects
ADAPTOR proteins ,BRACHYDANIO ,RHO GTPases ,ENDOTHELIAL cells ,NEOVASCULARIZATION ,CYTOSKELETON - Abstract
Background: Lymphangiogenesis, the formation of lymphatic vessels, is tightly linked to the development of the venous vasculature, both at the cellular and molecular levels. Here, we identify a novel role for Sorbs1, the founding member of the SoHo family of cytoskeleton adaptor proteins, in vascular and lymphatic development in the zebrafish. Results: We show that Sorbs1 is required for secondary sprouting and emergence of several vascular structures specifically derived from the axial vein. Most notably, formation of the precursor parachordal lymphatic structures is affected in sorbs1 mutant embryos, severely impacting the establishment of the trunk lymphatic vessel network. Interestingly, we show that Sorbs1 interacts with the BMP pathway and could function outside of Vegfc signaling. Mechanistically, Sorbs1 controls FAK/Src signaling and subsequently impacts on the cytoskeleton processes regulated by Rac1 and RhoA GTPases. Inactivation of Sorbs1 altered cell-extracellular matrix (ECM) contacts rearrangement and cytoskeleton dynamics, leading to specific defects in endothelial cell migratory and adhesive properties. Conclusions: Overall, using in vitro and in vivo assays, we identify Sorbs1 as an important regulator of venous and lymphatic angiogenesis independently of the Vegfc signaling axis. These results provide a better understanding of the complexity found within context-specific vascular and lymphatic development. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
35. Cardiomyocytes, cardiac endothelial cells and fibroblasts contribute to anthracycline-induced cardiac injury through RAS-homologous small GTPases RAC1 and CDC42
- Author
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Pelin Kücük, Lena Abbey, Joachim Schmitt, Christian Henninger, and Gerhard Fritz
- Subjects
Anthracyclines ,Cardiotoxicity ,RHO GTPases ,DNA damage ,DNA damage response ,Therapeutics. Pharmacology ,RM1-950 - Abstract
The clinical use of the DNA damaging anticancer drug doxorubicin (DOX) is limited by irreversible cardiotoxicity, which depends on the cumulative dose. The RAS-homologous (RHO) small GTPase RAC1 contributes to DOX-induced DNA damage formation and cardiotoxicity. However, the pathophysiological relevance of other RHO GTPases than RAC1 and different cardiac cell types (i.e., cardiomyocytes, non-cardiomyocytes) for DOX-triggered cardiac damage is unclear. Employing diverse in vitro and in vivo models, we comparatively investigated the level of DOX-induced DNA damage in cardiomyocytes versus non-cardiomyocytes (endothelial cells and fibroblasts), in the presence or absence of selected RHO GTPase inhibitors. Non-cardiomyocytes exhibited the highest number of DOX-induced DNA double-strand breaks (DSB), which were efficiently repaired in vitro. By contrast, rather low levels of DSB were formed in cardiomyocytes, which however remained largely unrepaired. Moreover, DOX-induced apoptosis was detected only in non-cardiomyocytes but not in cardiomyocytes. Pharmacological inhibitors of RAC1 and CDC42 most efficiently attenuated DOX-induced DNA damage in all cell types examined in vitro. Consistently, immunohistochemical analyses revealed that the RAC1 inhibitor NSC23766 and the pan-RHO GTPase inhibitor lovastatin reduced the level of DOX-induced residual DNA damage in both cardiomyocytes and non-cardiomyocytes in vivo. Overall, we conclude that endothelial cells, fibroblasts and cardiomyocytes contribute to the pathophysiology of DOX-induced cardiotoxicity, with RAC1- and CDC42-regulated signaling pathways being especially relevant for DOX-stimulated DSB formation and DNA damage response (DDR) activation. Hence, we suggest dual targeting of RAC1/CDC42-dependent mechanisms in multiple cardiac cell types to mitigate DNA damage-dependent cardiac injury evoked by DOX-based anticancer therapy.
- Published
- 2024
- Full Text
- View/download PDF
36. Molecular and cellular mechanisms of teneurin signaling in synaptic partner matching.
- Author
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Xu, Chuanyun, Li, Zhuoran, Lyu, Cheng, Hu, Yixin, McLaughlin, Colleen N., Wong, Kenneth Kin Lam, Xie, Qijing, Luginbuhl, David J., Li, Hongjie, Udeshi, Namrata D., Svinkina, Tanya, Mani, D.R., Han, Shuo, Li, Tongchao, Li, Yang, Guajardo, Ricardo, Ting, Alice Y., Carr, Steven A., Li, Jiefu, and Luo, Liqun
- Subjects
- *
MEMBRANE proteins , *RHO GTPases , *DENDRITES , *PROTEOMICS , *F-actin - Abstract
In developing brains, axons exhibit remarkable precision in selecting synaptic partners among many non-partner cells. Evolutionarily conserved teneurins are transmembrane proteins that instruct synaptic partner matching. However, how intracellular signaling pathways execute teneurins' functions is unclear. Here, we use in situ proximity labeling to obtain the intracellular interactome of a teneurin (Ten-m) in the Drosophila brain. Genetic interaction studies using quantitative partner matching assays in both olfactory receptor neurons (ORNs) and projection neurons (PNs) reveal a common pathway: Ten-m binds to and negatively regulates a RhoGAP, thus activating the Rac1 small GTPases to promote synaptic partner matching. Developmental analyses with single-axon resolution identify the cellular mechanism of synaptic partner matching: Ten-m signaling promotes local F-actin levels and stabilizes ORN axon branches that contact partner PN dendrites. Combining spatial proteomics and high-resolution phenotypic analyses, this study advanced our understanding of both cellular and molecular mechanisms of synaptic partner matching. [Display omitted] • In situ spatial proteomics reveals the intracellular interactome of a teneurin • Ten-m signals via a RhoGAP and Rac1 GTPase to regulate synaptic partner matching • Single-axon analyses reveal a stabilization-upon-contact model for partner matching • Ten-m signaling promotes F-actin in axon branches contacting partner dendrites Synaptic partner matching in the fly olfactory circuit is achieved by selectively stabilizing axon branches by partner dendrites. Synaptic partner matching molecule Ten-m regulates this process by binding to and negatively regulating a RhoGAP, which in turn activates the Rac1 small GTPase to promote actin polymerization. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
37. The cytoskeleton adaptor protein Sorbs1 controls the development of lymphatic and venous vessels in zebrafish
- Author
-
Alexandra Veloso, Anouk Bleuart, Louise Conrard, Tanguy Orban, Jonathan Bruyr, Pauline Cabochette, Raoul F. V. Germano, Giel Schevenels, Alice Bernard, Egor Zindy, Sofie Demeyer, Benoit Vanhollebeke, Franck Dequiedt, and Maud Martin
- Subjects
Sorbs1 ,Lymphangiogenesis ,BMP signaling ,Vegfc ,Angiogenesis ,Rho GTPases ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background Lymphangiogenesis, the formation of lymphatic vessels, is tightly linked to the development of the venous vasculature, both at the cellular and molecular levels. Here, we identify a novel role for Sorbs1, the founding member of the SoHo family of cytoskeleton adaptor proteins, in vascular and lymphatic development in the zebrafish. Results We show that Sorbs1 is required for secondary sprouting and emergence of several vascular structures specifically derived from the axial vein. Most notably, formation of the precursor parachordal lymphatic structures is affected in sorbs1 mutant embryos, severely impacting the establishment of the trunk lymphatic vessel network. Interestingly, we show that Sorbs1 interacts with the BMP pathway and could function outside of Vegfc signaling. Mechanistically, Sorbs1 controls FAK/Src signaling and subsequently impacts on the cytoskeleton processes regulated by Rac1 and RhoA GTPases. Inactivation of Sorbs1 altered cell-extracellular matrix (ECM) contacts rearrangement and cytoskeleton dynamics, leading to specific defects in endothelial cell migratory and adhesive properties. Conclusions Overall, using in vitro and in vivo assays, we identify Sorbs1 as an important regulator of venous and lymphatic angiogenesis independently of the Vegfc signaling axis. These results provide a better understanding of the complexity found within context-specific vascular and lymphatic development.
- Published
- 2024
- Full Text
- View/download PDF
38. Connecting the ends: signaling via receptor tyrosine kinases and cytoskeletal degradation in neurodegeneration
- Author
-
Priyanka Sengupta, Russa Das, Piyali Majumder, and Debashis Mukhopadhyay
- Subjects
receptor tyrosine kinase signaling ,nuclear translocation ,cytoskeletal remodeling ,crosstalk ,rho gtpases ,neurodegeneration ,rho/rac/cdc42 ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Receptor tyrosine kinases (RTKs) are known to perform versatile roles in disease landscapes, which determine the fate of the cell. Although much has been discussed from the perspective of proliferation, this review focuses on the impact of RTK-mediated signaling and its role in cytoskeletal degradation, the penultimate stage of cellular degeneration. In the case of degenerative diseases such as Alzheimer’s disease (AD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), age-related macular degeneration (AMD), and type 2 diabetes mellitus (T2DM), RTK signaling has been reported to be perturbed in several studies. The implications of downstream signaling via these receptors through canonical and noncanonical pathways alter the status of actin filaments that provide structural integrity to cells. Degenerative signaling leads to the altered status of rat sarcoma (Ras), Ras homologous (Rho), Ras-related C3 botulinum toxin substrate (Rac), and cell division control protein 42 (Cdc42), the best-characterized components of the cytoskeleton remodeling machinery. RTKs, along with their diverse adaptor partners and other membrane receptors, affect the functionality of Rho family guanosine triphosphate hydrolases (GTPases), which are discussed in this review. To conclude, this review focuses on therapeutic strategies targeting RTKs and Rho GTPase-mediated pathways that can be more effective due to their combined multifactorial impact on neurodegenerative cascades.
- Published
- 2024
- Full Text
- View/download PDF
39. Newcastle disease virus activates diverse signaling pathways via Src to facilitate virus entry into host macrophages.
- Author
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Qiankai Shi, Ran Zhao, Linna Chen, Tianyi Liu, Tao Di, Chunwei Zhang, Zhiying Zhang, Fangfang Wang, Zongxi Han, Junfeng Sun, and Shengwang Liu
- Subjects
- *
NEWCASTLE disease virus , *CELLULAR signal transduction , *RHO GTPases , *CELL cycle proteins , *PROTEIN-tyrosine kinases , *MYOSIN , *CYTOSKELETAL proteins , *COATED vesicles - Abstract
As an intrinsic cellular mechanism responsible for the internalization of extracellular ligands and membrane components, caveolae-mediated endocytosis (CavME) is also exploited by certain pathogens for endocytic entry [e.g., Newcastle disease virus (NDV) of paramyxovirus]. However, the molecular mechanisms of NDVinduced CavME remain poorly understood. Herein, we demonstrate that sialic acid-containing gangliosides, rather than glycoproteins, were utilized by NDV as receptors to initiate the endocytic entry of NDV into HD11 cells. The binding of NDV to gangliosides induced the activation of a non-receptor tyrosine kinase, Src, leading to the phosphorylation of caveolin-1 (Cav1) and dynamin-2 (Dyn2), which contributed to the endocytic entry of NDV. Moreover, an inoculation of cells with NDV-induced actin cytoskeletal rearrangement through Src to facilitate NDV entry via endocytosis and direct fusion with the plasma membrane. Subsequently, unique members of the Rho GTPases family, RhoA and Cdc42, were activated by NDV in a Src-dependent manner. Further analyses revealed that RhoA and Cdc42 regulated the activities of specific effectors, cofilin and myosin regulatory light chain 2, responsible for actin cytoskeleton rearrangement, through diverse intracellular signaling cascades. Taken together, our results suggest that an inoculation of NDV-induced Src-mediated cellular activation by binding to ganglioside receptors. This process orchestrated NDV endocytic entry by modulating the activities of caveolae-associated Cav1 and Dyn2, as well as specific Rho GTPases and downstream effectors. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
40. Salmonella engages CDC42 effector protein 1 for intracellular invasion.
- Author
-
Bandyopadhyay, Sheila, Zhang, Xiao, Ascura, Andrea, Edelblum, Karen L., Bonder, Edward M., and Gao, Nan
- Subjects
CELL cycle proteins ,SALMONELLA diseases ,SALMONELLA ,INTESTINAL infections ,RHO GTPases ,SALMONELLA typhimurium - Abstract
Human enterocytes are primary targets of infection by invasive bacterium Salmonella Typhimurium, and studies using nonintestinal epithelial cells established that S. Typhimurium activates Rho family GTPases, primarily CDC42, to modulate the actin cytoskeletal network for invasion. The host intracellular protein network that engages CDC42 and influences the pathogen's invasive capacity are relatively unclear. Here, proteomic analyses of canonical and variant CDC42 interactomes identified a poorly characterized CDC42 interacting protein, CDC42EP1, whose intracellular localization is rapidly redistributed and aggregated around the invading bacteria. CDC42EP1 associates with SEPTIN‐7 and Villin, and its relocalization and bacterial engagement depend on host CDC42 and S. Typhimurium's capability of activating CDC42. Unlike CDC42, CDC42EP1 is not required for S. Typhimurium's initial cellular entry but is found to associate with Salmonella‐containing vacuoles after long‐term infections, indicating a contribution to the pathogen's intracellular growth and replication. These results uncover a new host regulator of enteric Salmonella infections, which may be targeted to restrict bacterial load at the primary site of infection to prevent systemic spread. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
41. Molecular dissection of PI3Kβ synergistic activation by receptor tyrosine kinases, GβGγ, and Rho-family GTPases
- Author
-
Benjamin R Duewell, Naomi E Wilson, Gabriela M Bailey, Sarah E Peabody, and Scott D Hansen
- Subjects
phosphoinositide 3-kinase ,phosphatidylinositol phosphate lipids ,Rho GTPases ,GPCRs ,receptor tyrosine kinases ,G-proteins ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Phosphoinositide 3-kinase (PI3K) beta (PI3Kβ) is functionally unique in the ability to integrate signals derived from receptor tyrosine kinases (RTKs), G-protein coupled receptors, and Rho-family GTPases. The mechanism by which PI3Kβ prioritizes interactions with various membrane-tethered signaling inputs, however, remains unclear. Previous experiments did not determine whether interactions with membrane-tethered proteins primarily control PI3Kβ localization versus directly modulate lipid kinase activity. To address this gap in our knowledge, we established an assay to directly visualize how three distinct protein interactions regulate PI3Kβ when presented to the kinase in a biologically relevant configuration on supported lipid bilayers. Using single molecule Total Internal Reflection Fluorescence (TIRF) Microscopy, we determined the mechanism controlling PI3Kβ membrane localization, prioritization of signaling inputs, and lipid kinase activation. We find that auto-inhibited PI3Kβ prioritizes interactions with RTK-derived tyrosine phosphorylated (pY) peptides before engaging either GβGγ or Rac1(GTP). Although pY peptides strongly localize PI3Kβ to membranes, stimulation of lipid kinase activity is modest. In the presence of either pY/GβGγ or pY/Rac1(GTP), PI3Kβ activity is dramatically enhanced beyond what can be explained by simply increasing membrane localization. Instead, PI3Kβ is synergistically activated by pY/GβGγ and pY/Rac1 (GTP) through a mechanism consistent with allosteric regulation.
- Published
- 2024
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42. 流体剪切力调控血脑屏障的力学生物学机制研究.
- Author
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杜聆语, 许博闻, 程 琳, 岳红燕, 张怀奕, and 沈 阳
- Subjects
BLOOD-brain barrier ,ENDOTHELIAL cells ,RATS ,PROTEINS - Abstract
Copyright of Journal of Sichuan University (Medical Science Edition) is the property of Editorial Board of Journal of Sichuan University (Medical Sciences) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2024
43. Harnessing homeostatically active RhoC at cell junctions preserves human endothelial barrier function during inflammation (Updated June 27, 2024).
- Subjects
CELL junctions ,INFLAMMATION ,RHO GTPases ,ADHERENS junctions ,CELL contraction - Abstract
A preprint abstract from biorxiv.org discusses the potential use of RhoC, a protein involved in cell contraction, as a therapy for strengthening endothelial barriers during inflammation. The study found that activating RhoC, along with two other similar proteins, enhanced the homeostatic endothelial barrier function and preserved the microvascular endothelium in response to inflammatory challenges. The researchers identified a specific region within RhoC that determines its barrier-protective function. This research has not yet undergone peer review. [Extracted from the article]
- Published
- 2024
44. C-terminal CDC42 variants in autoinflammatory patients specifically trigger actin defects and NF-kB hyperactivation.
- Subjects
CELL cycle proteins ,NF-kappa B ,ACTIN ,RHO GTPases ,CYTOSKELETON - Abstract
A recent preprint abstract discusses the findings of a study on CDC42 variants in autoinflammatory patients. The study aimed to investigate whether four CDC42 variants, specifically those located in the C-terminal region, share common signaling alterations. The results showed that the C-terminal variants exhibited aberrant subcellular localizations and functional alterations, including a reduction in actin filament polymerization and increased NF-kB nuclear translocation and phosphorylation. However, there was no causal relationship found between these two events. The study suggests that CDC42 patients should not necessarily be classified among actinopathies and highlights the potential for more personalized therapeutic interventions based on the functional defects observed. [Extracted from the article]
- Published
- 2024
45. Harnessing homeostatically active RhoC at cell junctions preserves human endothelial barrier function during inflammation.
- Subjects
CELL junctions ,INFLAMMATION ,RHO GTPases ,CELL contraction ,CYTOLOGY - Abstract
A preprint abstract from biorxiv.org discusses the role of the GTPase RhoC in preserving endothelial barrier function during inflammation. The study found that activating RhoC, along with RhoA and RhoB, using a chimeric recombinant toxin, enhanced microvascular endothelial barrier function in response to inflammatory challenges. RhoC was found to have a unique barrier-protective function, in contrast to the permeability-inducing function of RhoA and RhoB. The study suggests that harnessing the activity of RhoC could be a potential therapy for strengthening endothelial barriers during pathological inflammation. However, it is important to note that this preprint has not been peer-reviewed. [Extracted from the article]
- Published
- 2024
46. Findings from Georgetown University Provide New Insights into Medulloblastoma (Mdb-37. Rac1 Inhibition For The Treatment of Medulloblastoma).
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MEDULLOBLASTOMA ,HEDGEHOG signaling proteins ,REPORTERS & reporting ,RHO GTPases - Abstract
A recent study conducted by researchers at Georgetown University explores potential new therapies for the treatment of medulloblastoma, a type of brain cancer. The study focuses on the role of the small GTPase Rac1 in regulating the GLI1/GLI2/UHRF1/DNMT1 complex, which is involved in the epigenetic regulation of medulloblastoma. The researchers found that a brain penetrant Rac1 inhibitor called GYS32661 effectively inhibits the interaction between GLI1 and UHRF1, disrupting early events in the Hedgehog signaling pathway. Additionally, GYS32661 inhibits actin polymerization, suggesting it may have a dual mechanism of inhibiting Shh signaling and cellular migration. The compound shows promise as a potential clinical candidate for the treatment of medulloblastoma. [Extracted from the article]
- Published
- 2024
47. Molecular and cellular consequences of mevalonate kinase deficiency.
- Author
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Politiek, Frouwkje A., Turkenburg, Marjolein, Henneman, Linda, Ofman, Rob, and Waterham, Hans R.
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- *
MEVALONATE kinase , *METABOLIC reprogramming , *RHO GTPases , *CYTOSKELETON , *CELL cycle - Abstract
Mevalonate kinase deficiency (MKD) is an autosomal recessive metabolic disorder associated with recurrent autoinflammatory episodes. The disorder is caused by bi-allelic loss-of-function variants in the MVK gene, which encodes mevalonate kinase (MK), an early enzyme in the isoprenoid biosynthesis pathway. To identify molecular and cellular consequences of MKD, we studied primary fibroblasts from severely affected patients with mevalonic aciduria (MKD-MA) and more mildly affected patients with hyper IgD and periodic fever syndrome (MKD-HIDS). As previous findings indicated that the deficient MK activity in MKD impacts protein prenylation in a temperature-sensitive manner, we compared the subcellular localization and activation of the small Rho GTPases RhoA, Rac1 and Cdc42 in control, MKD-HIDS and MKD-MA fibroblasts cultured at physiological and elevated temperatures. This revealed a temperature-induced altered subcellular localization and activation in the MKD cells. To study if and how the temperature-induced ectopic activation of these signalling proteins affects cellular processes, we performed comparative transcriptome analysis of control and MKD-MA fibroblasts cultured at 37 °C or 40 °C. This identified cell cycle and actin cytoskeleton organization as respectively most down- and upregulated gene clusters. Further studies confirmed that these processes were affected in fibroblasts from both patients with MKD-MA and MKD-HIDS. Finally, we found that, similar to immune cells, the MK deficiency causes metabolic reprogramming in MKD fibroblasts resulting in increased expression of genes involved in glycolysis and the PI3K/Akt/mTOR pathway. We postulate that the ectopic activation of small GTPases causes inappropriate signalling contributing to the molecular and cellular aberrations observed in MKD. • Enhanced temperature causes ectopic activation of Rho GTPases in MKD fibroblasts. • Cell cycle-related genes are downregulated in MKD fibroblasts. • Actin cytoskeleton-related genes are upregulated in MKD fibroblasts. • MKD affects cell cycle progression and actin cytoskeleton dynamics. • The expression of glycolytic genes is increased in MKD fibroblasts. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
48. RhoGDI1 regulates cell-cell junctions in polarized epithelial cells.
- Author
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Wibbe, Nicolina, Steinbacher, Tim, Tellkamp, Frederik, Beckmann, Niklas, Brinkmann, Frauke, Stecher, Manuel, Gerke, Volker, Niessen, Carien M., and Ebnet, Klaus
- Subjects
GUANINE nucleotide exchange factors ,TIGHT junctions ,GTPASE-activating protein ,CELL migration ,CELL receptors - Abstract
Cell-cell contact formation of polarized epithelial cells is a multi-step process that involves the co-ordinated activities of Rho family small GTPases. Consistent with the central role of Rho GTPases, a number of Rho guanine nucleotide exchange factors (GEFs) and Rho GTPase-activating proteins (GAPs) have been identified at cell-cell junctions at various stages of junction maturation. As opposed to RhoGEFs and RhoGAPs, the role of Rho GDP dissociation inhibitors (GDIs) during cell-cell contact formation is poorly understood. Here, we have analyzed the role of RhoGDI1/ARHGDIA, a member of the RhoGDI family, during cell-cell contact formation of polarized epithelial cells. Depletion of RhoGDI1 delays the development of linear cellcell junctions and the formation of barrier-forming tight junctions. In addition, RhoGDI1 depletion impairs the ability of cells to stop migration in response to cell collision and increases the migration velocity of collectively migrating cells. We also find that the cell adhesion receptor JAM-A promotes the recruitment of RhoGDI1 to cell-cell contacts. Our findings implicate RhoGDI1 in various processes involving the dynamic reorganization of cell-cell junctions. [ABSTRACT FROM AUTHOR]
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- 2024
- Full Text
- View/download PDF
49. Differential Regulation of Hemichannels and Gap Junction Channels by RhoA GTPase and Actin Cytoskeleton: A Comparative Analysis of Cx43 and Cx26.
- Author
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Jara, Oscar, Maripillán, Jaime, Momboisse, Fanny, Cárdenas, Ana María, García, Isaac E., and Martínez, Agustín D.
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CELL membrane formation ,CYTOSKELETON ,GUANOSINE triphosphatase ,MEMBRANE proteins ,BIOLOGICAL transport - Abstract
Connexins (Cxs) are transmembrane proteins that assemble into gap junction channels (GJCs) and hemichannels (HCs). Previous researches support the involvement of Rho GTPases and actin microfilaments in the trafficking of Cxs, formation of GJCs plaques, and regulation of channel activity. Nonetheless, it remains uncertain whether distinct types of Cxs HCs and GJCs respond differently to Rho GTPases or changes in actin polymerization/depolymerization dynamics. Our investigation revealed that inhibiting RhoA, a small GTPase that controls actin polymerization, or disrupting actin microfilaments with cytochalasin B (Cyto-B), resulted in reduced GJCs plaque size at appositional membranes and increased transport of HCs to non-appositional plasma membrane regions. Notably, these effects were consistent across different Cx types, since Cx26 and Cx43 exhibited similar responses, despite having distinct trafficking routes to the plasma membrane. Functional assessments showed that RhoA inhibition and actin depolymerization decreased the activity of Cx43 GJCs while significantly increasing HC activity. However, the functional status of GJCs and HCs composed of Cx26 remained unaffected. These results support the hypothesis that RhoA, through its control of the actin cytoskeleton, facilitates the transport of HCs to appositional cell membranes for GJCs formation while simultaneously limiting the positioning of free HCs at non-appositional cell membranes, independently of Cx type. This dynamic regulation promotes intercellular communications and reduces non-selective plasma membrane permeability through a Cx-type dependent mechanism, whereby the activity of Cx43 HCs and GJCs are differentially affected but Cx26 channels remain unchanged. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
50. Short-Term and Long-Term Fluvastatin Inhibit Effects of Thrombospondin-1 on Human Vascular Smooth Muscle Cells.
- Author
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Maier, Kristopher, Helkin, Alex, Stein, Jeffrey J., Yuan, Helen L., Seymour, Keri, Ryabtsev, Boris, Iwuchukwu, Chinenye, and Gahtan, Vivian
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- *
FOCAL adhesion kinase , *VASCULAR smooth muscle , *RHO GTPases , *STATINS (Cardiovascular agents) , *FLUVASTATIN - Abstract
Vascular smooth muscle cells are important in intimal hyperplasia. Thrombospondin-1 is a matricellular protein involved in the vascular injury response. Statins are cholesterol lowering drugs that have beneficial cardiovascular effects. Statis have been shown to inhibit smooth muscle migration through the mevalonate pathway. This effect is thought to be mediated by small G protein Ras and Rho turnover which requires many hours. While many patients undergoing treatment for vascular disease are on statins, many are not. Thus immediate pretreatment with statins before surgery may be beneficial. We hypothesized that statins have effects independent of the mevalonate pathway and thus have an immediate effect.Human vascular smooth muscle cells were pretreated for 20 h (long-term) or 20 min (short-term) with fluvastatin, or mevalonolactone plus fluvastatin. Thrombospondin-1-induced migration, activation of p42/p44 extracellular signal-regulated kinase, c-Src, focal adhesion kinase and PI3 kinase was determined. The effect of fluvastatin on thrombospondin-1-induced expression of
THBS1 ,FOS ,HAS2 andTGFB2 was examined.Both treatments inhibited thrombospondin-1-induced chemotaxis back to the control group. Mevalonolactone reversed the long-term statin effect by increasing migration but had no effect on the short-term statin response. p42/p44 extracellular signal-regulated kinase was activated by thrombospondin-1 and both treatments augmented activation. Neither treatment affected c-Src activity, but both inhibited focal adhesion kinase and PI3 kinase activity. Only long-term statin treatment inhibitedTHBS1 expression while both treatments inhibitedFOS andTGFB2 expression. Neither treatment affectedHAS2 .FOS knockdown inhibited thrombospondin-1-inducedHAS2 but notTGFβ2 gene expression.Long-term fluvastatin inhibited thrombospondin-1-induced chemotaxis through the mevalonate pathway while short-term fluvastatin inhibited chemotaxis through an alternate mechanism. Short-term stains have immediate effects independent of the mevalonate pathway. Acute local treatment with statins followed by longer term therapy may limit the vascular response to injury. [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF
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