Journal articles: 'Rac1 signalling'

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Whalley, Katherine. "RAC1 signalling remodels dendrites." Nature Reviews Neuroscience 13, no. 6 (May 10, 2012): 361. http://dx.doi.org/10.1038/nrn3261.

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Payapilly, Aishwarya, and Angeliki Malliri. "Compartmentalisation of RAC1 signalling." Current Opinion in Cell Biology 54 (October 2018): 50–56. http://dx.doi.org/10.1016/j.ceb.2018.04.009.

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Takenaka, Nobuyuki, Yukio Sumi, Keiko Matsuda, Junko Fujita, Tetsuya Hosooka, Tetsuya Noguchi, Atsu Aiba, and Takaya Satoh. "Role for RalA downstream of Rac1 in skeletal muscle insulin signalling." Biochemical Journal 469, no. 3 (July 23, 2015): 445–54. http://dx.doi.org/10.1042/bj20150218.

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The small GTPase RalA is required for Rac1-mediated glucose uptake and activated by Rac1 in mouse skeletal muscle fibres. This might be the first demonstration of the involvement of RalA in Rac1-mediated insulin signalling in mature skeletal muscle.

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Dilasser, Florian, Lindsay Rose, Dorian Hassoun, Martin Klein, Morgane Rousselle, Carole Brosseau, Christophe Guignabert, et al. "Essential role of smooth muscle Rac1 in severe asthma-associated airway remodelling." Thorax 76, no. 4 (February 4, 2021): 326–34. http://dx.doi.org/10.1136/thoraxjnl-2020-216271.

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BackgroundSevere asthma is a chronic lung disease characterised by inflammation, airway hyperresponsiveness (AHR) and airway remodelling. The molecular mechanisms underlying uncontrolled airway smooth muscle cell (aSMC) proliferation involved in pulmonary remodelling are still largely unknown. Small G proteins of the Rho family (RhoA, Rac1 and Cdc42) are key regulators of smooth muscle functions and we recently demonstrated that Rac1 is activated in aSMC from allergic mice. The objective of this study was to assess the role of Rac1 in severe asthma-associated airway remodelling.Methods and resultsImmunofluorescence analysis in human bronchial biopsies revealed an increased Rac1 activity in aSMC from patients with severe asthma compared with control subjects. Inhibition of Rac1 by EHT1864 showed that Rac1 signalling controlled human aSMC proliferation induced by mitogenic stimuli through the signal transducer and activator of transcription 3 (STAT3) signalling pathway. In vivo, specific deletion of Rac1 in SMC or pharmacological inhibition of Rac1 by nebulisation of NSC23766 prevented AHR and aSMC hyperplasia in a mouse model of severe asthma. Moreover, the Rac1 inhibitor prevented goblet cell hyperplasia and epithelial cell hypertrophy whereas treatment with corticosteroids had less effect. Nebulisation of NSC23766 also decreased eosinophil accumulation in the bronchoalveolar lavage of asthmatic mice.ConclusionThis study demonstrates that Rac1 is overactive in the airways of patients with severe asthma and is essential for aSMC proliferation. It also provides evidence that Rac1 is causally involved in AHR and airway remodelling. Rac1 may represent as an interesting target for treating both AHR and airway remodelling of patients with severe asthma.

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Fan, Minghua, Yongping Xu, Fanzhen Hong, Xiaolin Gao, Gang Xin, Haijie Hong, Lihua Dong, and Xingbo Zhao. "Rac1/β-Catenin Signalling Pathway Contributes to Trophoblast Cell Invasion by Targeting Snail and MMP9." Cellular Physiology and Biochemistry 38, no. 4 (2016): 1319–32. http://dx.doi.org/10.1159/000443076.

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Background/Aims: Preeclampsia is an idiopathic and serious complication during gestation in which placental trophoblast cells differentiate into several functional subtypes, including highly invasive extravillous trophoblasts (EVTs). Although the cause and pathogenesis of preeclampsia have remained unclear, numerous studies have suggested that the inadequacy of EVT invasion leads to imperfect uterine spiral artery remodelling, which plays a crucial role in the development of preeclampsia. Rac1, or Ras-related C3 botulinum toxin substrate 1, was found to be a key regulator of the migration, invasion uand apoptosis of various tumour cells. Because EVTs share similar invasive and migratory biological behaviours with malignant cells, this study aimed to determine whether the Rac1 signalling pathway affects trophoblast invasion and is thus involved in the pathogenesis of preeclampsia. Methods: We measured the activity of Rac1 and its downstream targets, β-catenin, Snail and MMP9 in placental tissues from patients experiencing a normal pregnancy and those with preeclampsia. Furthermore, we treated HTR-8/SVneo cells with a shRNA Rac1 vector and the β-catenin inhibitor IWP-2 and explored Rac1 signalling pathway activation as well as the effects of Snail and β-catenin on trophoblast invasion. Results: In placental samples from patients experiencing a normal pregnancy and those with preeclampsia, active Rac1 levels and MMP9 protein and mRNA levels were significantly decreased in term pregnancy samples compared to early pregnancy samples. Lower levels were found in preeclampsia samples than in normal term pregnancy samples, and these levels significantly declined in severe preeclampsia samples compared with mild preeclampsia samples. Further analyses demonstrated that both Rac1 shRNA and the β-catenin inhibitor significantly suppressed MMP9 and Snail activation in trophoblasts, thus impairing trophoblast invasion. Notably, silencing Rac1 down-regulated the expression of β-catenin in HTR-8/SVneo cells, demonstrating that β-catenin is a downstream effector of Rac1 in trophoblast invasion. Conclusion: Our data suggest that Rac1-mediated activation of β-catenin might regulate Snail and MMP9 expression subsequently promoting trophoblast invasion in pregnancy.

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Tkachuk, Natalia, Hermann Haller, Inna Dumler, and Ioulia Kiian. "Urokinase-induced migration of human vascular smooth muscle cells requires coupling of the small GTPases RhoA and Rac1 to the Tyk2/PI3-K signalling pathway." Thrombosis and Haemostasis 89, no. 05 (2003): 904–14. http://dx.doi.org/10.1055/s-0037-1613478.

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SummaryUrokinase-type plasminogen activator (uPA) facilitates cell migration by localizing proteolisys on the cell surface and by inducing intracellular signalling pathways. In human vascular smooth muscle cell (VSMC) uPA stimulates migration via the uPA receptor (uPAR) signalling complex containing the Janus kinase Tyk2 and phosphatidylinositol 3-kinase (PI3-K). We report that active GTP-bound forms of small GTPases RhoA and Rac1, but not Cdc42, are directly associated with Tyk2 and PI3-K in an uPA/uPAR-dependent fashion. Endogenous RhoA, but not Rac1 or Cdc42, was significantly activated in response to uPA. RhoA activation was abolished by cell treatment with two unrelated, structurally distinct, specific inhibitors of PI3-K, wortmannin, and LY294002. Downstream of RhoA, phosphorylation of myosin light chain (MLC) was dramatically upregulated by uPA in a Rho kinase- and PI3-K-dependent manner. Thus, selective Rho kinase inhibitor Y27632 and PI3-K inhibitors wortmannin and LY294002 prevented the uPA-induced stimulation of MLC phosphorylation. Rho kinase inhibition also decreased uPA-stimulated VSMC migration as observed in a Boyden chamber. VSMC immunocytochemical staining demonstrated redistribution of RhoA and Rac1 active forms to the newly formed leading edge of migrating cell. VSMC microinjection with antibodies to either Rho or Rac1 decreased uPA-stimulated cell migration, indicating the involvement of both GTPases in the migration process. Our results provide evidence that the small GTPases RhoA and Rac1, together with Rho kinase, are necessary to mediate the uPA/uPAR-directed migration via the Tyk2/PI3-K signalling complex in human VSMC.

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Neagoe, Raluca A. I., Elizabeth E. Gardiner, David Stegner, Bernhard Nieswandt, Steve P. Watson, and Natalie S. Poulter. "Rac Inhibition Causes Impaired GPVI Signalling in Human Platelets through GPVI Shedding and Reduction in PLCγ2 Phosphorylation." International Journal of Molecular Sciences 23, no. 7 (March 29, 2022): 3746. http://dx.doi.org/10.3390/ijms23073746.

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Rac1 is a small Rho GTPase that is activated in platelets upon stimulation with various ligands, including collagen and thrombin, which are ligands for the glycoprotein VI (GPVI) receptor and the protease-activated receptors, respectively. Rac1-deficient murine platelets have impaired lamellipodia formation, aggregation, and reduced PLCγ2 activation, but not phosphorylation. The objective of our study is to investigate the role of Rac1 in GPVI-dependent human platelet activation and downstream signalling. Therefore, we used human platelets stimulated using GPVI agonists (collagen and collagen-related peptide) in the presence of the Rac1-specific inhibitor EHT1864 and analysed platelet activation, aggregation, spreading, protein phosphorylation, and GPVI clustering and shedding. We observed that in human platelets, the inhibition of Rac1 by EHT1864 had no significant effect on GPVI clustering on collagen fibres but decreased the ability of platelets to spread or aggregate in response to GPVI agonists. Additionally, in contrast to what was observed in murine Rac1-deficient platelets, EHT1864 enhanced GPVI shedding in platelets and reduced the phosphorylation levels of PLCγ2 following GPVI activation. In conclusion, Rac1 activity is required for both human and murine platelet activation in response to GPVI-ligands, but Rac1’s mode of action differs between the two species.

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Williams, M. J. "Rac1 signalling in the Drosophila larval cellular immune response." Journal of Cell Science 119, no. 10 (May 15, 2006): 2015–24. http://dx.doi.org/10.1242/jcs.02920.

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Moshfegh, Yasmin, Jose Javier Bravo-Cordero, Veronika Miskolci, John Condeelis, and Louis Hodgson. "A Trio–Rac1–Pak1 signalling axis drives invadopodia disassembly." Nature Cell Biology 16, no. 6 (May 25, 2014): 571–83. http://dx.doi.org/10.1038/ncb2972.

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Chiu, Tim T., Thomas E. Jensen, Lykke Sylow, Erik A. Richter, and Amira Klip. "Rac1 signalling towards GLUT4/glucose uptake in skeletal muscle." Cellular Signalling 23, no. 10 (October 2011): 1546–54. http://dx.doi.org/10.1016/j.cellsig.2011.05.022.

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Yin, Qianran, Dehua Jiang, Lei Li, Yu Yang, Pei wu, Yuanyuan Luo, Rongli Yang, and Dongye Li. "LPS Promotes Vascular Smooth Muscle Cells Proliferation Through the TLR4/Rac1/Akt Signalling Pathway." Cellular Physiology and Biochemistry 44, no. 6 (2017): 2189–200. http://dx.doi.org/10.1159/000486024.

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Background/Aims: Lipopolysaccharide (LPS) is a potent activator of vascular smooth muscle cells (VSMCs) proliferation, but the underlying mechanism remains unknown. In this study, we knocked down Toll-like receptor 4 (TLR4) and Ras-related C3 botulinum toxin substrate 1 (Rac1) expression using small interfering RNA (siRNA) in order to investigate the effects and possible mechanisms of LPS-induced VSMCs proliferation. Methods: VSMCs proliferation was monitored by 5-ethynyl-2’-deoxyuridine staining, and Rac1 activity was measured via Glutathione S-transferase pull-down assay. mRNAs encoding proliferating cell nuclear antigen (PCNA), smooth muscle 22α (SM22α), myosin heavy chain (MYH) and transient receptor potential channel 1 (TRPC1) were detected by qRT-PCR. The expression of total Akt, p-Akt (308), p-Akt (473), SM22α, MYH and TRPC1 protein was analysed by Western blot. Results: Treatment with TLR4 siRNA (siTLR4) or Rac1 siRNA (siRac1) significantly decreased LPS-induced VSMCs proliferation. Moreover, LPS-induced activation of Rac1 through TLR4 was observed. Western blot analysis revealed that transfection with siTLR4 or siRac1 inhibited LPS-induced Akt phosphorylation. We discovered that LPS stimulated VSMCs proliferation via phenotypic modulation and that this effect was partially inhibited by pre-treatment with siTLR4 or siRac1. Further, TLR4 and Rac1 are involved in LPS-induced activation of TRPC1. Conclusion: This study suggests that LPS exerts an effect on VSMCs proliferation and that the TLR4/Rac1/Akt signalling pathway mediates this effect.

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Hoppe, Sven, Mario Schelhaas, Verena Jaeger, Timo Liebig, Philipp Petermann, and Dagmar Knebel-Mörsdorf. "Early herpes simplex virus type 1 infection is dependent on regulated Rac1/Cdc42 signalling in epithelial MDCKII cells." Journal of General Virology 87, no. 12 (December 1, 2006): 3483–94. http://dx.doi.org/10.1099/vir.0.82231-0.

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The aim of this study was to understand how molecular determinants of epithelial cells influence initial infection by herpes simplex virus type 1 (HSV-1). Upon infection of the epithelial MDCKII cell line, enhanced association of virus particles with cells forming actin protrusions was observed, suggesting a putative role of actin dynamics in HSV-1 infection. Thus, the impact of the small Rho-like GTPases Rac1, Cdc42 and RhoA acting as key regulators of actin dynamics was addressed. Endogenous Rac1 and Cdc42 were temporarily activated at 15 and 30 min after HSV-1 infection. When constitutively active Cdc42 or Rac1 mutants were expressed transiently, a significant decrease in infectivity was observed, whereas expression of RhoA mutants had no influence. Furthermore, dominant-negative Cdc42 led to decreased infectivity, whereas dominant-negative Rac1 had no effect. So far, the study of potential effectors indicated that Rac1/Cdc42 mutants inhibited infectivity independently of p21-activated kinase (Pak1). The inhibitory effect of Rac1/Cdc42 mutant expression on HSV-1 infection was characterized further and it was found that binding, internalization and transport of HSV-1 were not affected by expression of Rac1/Cdc42 mutants. Thus, these results provide the first evidence for a role of Rac1/Cdc42 signalling during early HSV-1 infection and suggest a mechanism relying on virus-induced regulation of Rac1/Cdc42 activities.

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Abdullah, Jafri Malin, Zulkifli Mustafa, and Aini Ideris. "Newcastle Disease Virus Interaction in Targeted Therapy against Proliferation and Invasion Pathways of Glioblastoma Multiforme." BioMed Research International 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/386470.

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Glioblastoma multiforme (GBM), or grade IV glioma, is one of the most lethal forms of human brain cancer. Current bioscience has begun to depict more clearly the signalling pathways that are responsible for high-grade glioma initiation, migration, and invasion, opening the door for molecular-based targeted therapy. As such, the application of viruses such as Newcastle disease virus (NDV) as a novel biological bullet to specifically target aberrant signalling in GBM has brought new hope. The abnormal proliferation and aggressive invasion behaviour of GBM is reported to be associated with aberrant Rac1 protein signalling. NDV interacts with Rac1 upon viral entry, syncytium induction, and actin reorganization of the infected cell as part of the replication process. Ultimately, intracellular stress leads the infected glioma cell to undergo cell death. In this review, we describe the characteristics of malignant glioma and the aberrant genetics that drive its aggressive phenotype, and we focus on the use of oncolytic NDV in GBM-targeted therapy and the interaction of NDV in GBM signalling that leads to inhibition of GBM proliferation and invasion, and subsequently, cell death.

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Kim, Hugh, Colin D. White, Zhigang Li, and David B. Sacks. "Salmonella enterica serotype Typhimurium usurps the scaffold protein IQGAP1 to manipulate Rac1 and MAPK signalling." Biochemical Journal 440, no. 3 (November 28, 2011): 309–18. http://dx.doi.org/10.1042/bj20110419.

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Salmonella enterica serotype Typhimurium invades eukaryotic cells by re-arranging the host-cell cytoskeleton. However, the precise mechanisms by which Salmonella induces cytoskeletal changes remain undefined. IQGAP1 (IQ motif-containing GTPase-activating protein 1) is a scaffold protein that binds multiple proteins including actin, the Rho GTPases Rac1 and Cdc42 (cell division cycle 42), and components of the MAPK (mitogen-activated protein kinase) pathway. We have shown previously that optimal invasion of Salmonella into HeLa cells requires IQGAP1. In the present paper, we use IQGAP1-null MEFs (mouse embryonic fibroblasts) and selected well-characterized IQGAP1 mutant constructs to dissect the molecular determinants of Salmonella invasion. Knockout of IQGAP1 expression reduced Salmonella invasion into MEFs by 75%. Reconstituting IQGAP1-null MEFs with wild-type IQGAP1 completely rescued invasion. By contrast, reconstituting IQGAP1-null cells with mutant IQGAP1 constructs that specifically lack binding to either Cdc42 and Rac1 (termed IQGAP1ΔMK24), actin, MEK [MAPK/ERK (extracellular-signal-regulated kinase) kinase] or ERK only partially restored Salmonella entry. Cell-permeant inhibitors of Rac1 activation or MAPK signalling reduced Salmonella invasion into control cells by 50%, but had no effect on bacterial entry into IQGAP1-null MEFs. Importantly, the ability of IQGAP1ΔMK24 to promote Salmonella invasion into IQGAP1-null cells was abrogated by chemical inhibition of MAPK signalling. Collectively, these results imply that the scaffolding function of IQGAP1, which integrates Rac1 and MAPK signalling, is usurped by Salmonella to invade fibroblasts and suggest that IQGAP1 may be a potential therapeutic target for Salmonella pathogenesis.

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Tebar, Francesc, Albert Chavero, Neus Agell, Albert Lu, Carles Rentero, Carlos Enrich, and Thomas Grewal. "Pleiotropic Roles of Calmodulin in the Regulation of KRas and Rac1 GTPases: Functional Diversity in Health and Disease." International Journal of Molecular Sciences 21, no. 10 (May 23, 2020): 3680. http://dx.doi.org/10.3390/ijms21103680.

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Calmodulin is a ubiquitous signalling protein that controls many biological processes due to its capacity to interact and/or regulate a large number of cellular proteins and pathways, mostly in a Ca2+-dependent manner. This complex interactome of calmodulin can have pleiotropic molecular consequences, which over the years has made it often difficult to clearly define the contribution of calmodulin in the signal output of specific pathways and overall biological response. Most relevant for this review, the ability of calmodulin to influence the spatiotemporal signalling of several small GTPases, in particular KRas and Rac1, can modulate fundamental biological outcomes such as proliferation and migration. First, direct interaction of calmodulin with these GTPases can alter their subcellular localization and activation state, induce post-translational modifications as well as their ability to interact with effectors. Second, through interaction with a set of calmodulin binding proteins (CaMBPs), calmodulin can control the capacity of several guanine nucleotide exchange factors (GEFs) to promote the switch of inactive KRas and Rac1 to an active conformation. Moreover, Rac1 is also an effector of KRas and both proteins are interconnected as highlighted by the requirement for Rac1 activation in KRas-driven tumourigenesis. In this review, we attempt to summarize the multiple layers how calmodulin can regulate KRas and Rac1 GTPases in a variety of cellular events, with biological consequences and potential for therapeutic opportunities in disease settings, such as cancer.

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O'Neill, L. A. J., J. S. Matthews, E. Pålsson, C. Jeffries, P. Brennan, and D. A. Cantrell. "29 INTERLEUKIN 1 SIGNALLING: SYNERGY WITH RAC1 AND PI3 KINASE." Biochemical Society Transactions 25, no. 4 (November 1, 1997): S578. http://dx.doi.org/10.1042/bst025s578.

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Moshfegh, Yasmin, Jose Javier Bravo-Cordero, Veronika Miskolci, John Condeelis, and Louis Hodgson. "Erratum: A Trio–Rac1–Pak1 signalling axis drives invadopodia disassembly." Nature Cell Biology 17, no. 3 (February 27, 2015): 350. http://dx.doi.org/10.1038/ncb3123.

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Sarner, Shula, Robert Kozma, Sohail Ahmed, and Louis Lim. "Phosphatidylinositol 3-Kinase, Cdc42, and Rac1 Act Downstream of Ras in Integrin-Dependent Neurite Outgrowth in N1E-115 Neuroblastoma Cells." Molecular and Cellular Biology 20, no. 1 (January 1, 2000): 158–72. http://dx.doi.org/10.1128/mcb.20.1.158-172.2000.

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ABSTRACT Ras and Rho family GTPases have been ascribed important roles in signalling pathways determining cellular morphology and growth. Here we investigated the roles of the GTPases Ras, Cdc42, Rac1, and Rho and that of phosphatidylinositol 3-kinase (PI 3-kinase) in the pathway leading from serum starvation to neurite outgrowth in N1E-115 neuroblastoma cells. Serum-starved cells grown on a laminin matrix exhibited integrin-dependent neurite outgrowth. Expression of dominant negative mutants of Ras, PI 3-kinase, Cdc42, or Rac1 all blocked this neurite outgrowth, while constitutively activated mutants of Ras, PI 3-kinase, or Cdc42 were each sufficient to promote outgrowth even in the presence of serum. A RasH40C;G12V double mutant which binds preferentially to PI 3-kinase also promoted neurite formation. Activated RasG12V-induced outgrowth required PI 3-kinase activity, but activated PI 3-kinase-induced outgrowth did not require Ras activity. Although activated Rac1 by itself did not induce neurites, neurite outgrowth induced by activated Cdc42G12Vwas Rac1 dependent. Cdc42G12V-induced neurites appeared to lose their normal polarization, almost doubling the average number of neurites produced by a single cell. Outgrowth induced by activated Ras or PI 3-kinase required both Cdc42 and Rac1 activity, but Cdc42G12V-induced outgrowth did not need Ras or PI 3-kinase activity. Active RhoG14V reduced outgrowth promoted by RasG12V. Finally, expression of dominant negative Jun N-terminal kinase or extracellular signal-regulated kinase did not inhibit outgrowth, suggesting these pathways are not essential for this process. Our results suggest a hierarchy of signalling where Ras signals through PI 3-kinase to Cdc42 and Rac1 activation (and Rho inactivation), culminating in neurite outgrowth. Thus, in the absence of serum factors, Ras may initiate cell cycle arrest and terminal differentiation in N1E-115 neuroblastoma cells.

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Sturge, Justin, Jocelyne Hamelin, and Gareth E. Jones. "N-WASP activation by a β1-integrin-dependent mechanism supports PI3K-independent chemotaxis stimulated by urokinase-type plasminogen activator." Journal of Cell Science 115, no. 4 (February 15, 2002): 699–711. http://dx.doi.org/10.1242/jcs.115.4.699.

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Urokinase-type plasminogen activator (uPA)-uPA receptor (uPAR) and epidermal growth factor (EGF)-EGF receptor (EGFR) expression is highly correlated with breast cancer metastasis. Phosphoinositide 3-kinase (PI3K),small Rho GTPases, such as Cdc42 and Rac1, and neuronal Wiskott Aldrich syndrome protein (N-WASP) are key effectors that regulate dynamic changes in the actin cytoskeleton and cell migration. uPA- and EGF-stimulated chemotaxis,cytoskeletal rearrangements and activation of Cdc42, Rac1 and N-WASP were studied in the highly metastatic human breast cancer cell line MDA MB 231. These studies reveal that divergent signalling occurs downstream of PI3K. The activity of PI3K was not necessary for uPA-induced chemotactic responses, but those induced by EGF were entirely dependent upon PI3K. Furthermore,PI3K-independent chemotactic signalling by uPA was shown to involve disruption of an interaction between β1-integrins and N-WASP and translocation of N-WASP to the actin cytoskeleton.

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Nagase, Miki, and Toshiro Fujita. "Role of Rac1–mineralocorticoid-receptor signalling in renal and cardiac disease." Nature Reviews Nephrology 9, no. 2 (January 8, 2013): 86–98. http://dx.doi.org/10.1038/nrneph.2012.282.

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KIM, Byung-Chul, and Jae-Hong KIM. "Exogenous C2-ceramide activates c-fos serum response element via Rac-dependent signalling pathway." Biochemical Journal 330, no. 2 (March 1, 1998): 1009–14. http://dx.doi.org/10.1042/bj3301009.

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Ceramide is an important regulatory molecule implicated in a variety of biological processes in response to stress and cytokines. To understand the signal transduction pathway of ceramide to the nucleus, in the present study, we examined whether C2-ceramide, a cell permeable ceramide, activates c-fos serum response element (SRE). Treatment of Rat-2 fibroblast cells with C2-ceramide caused the stimulation of c-fos SRE-dependent reporter gene activity in a dose- and time-dependent manner by transient transfection analysis. Next, we examined the role of Rho family GTPases in the ceramide-induced signalling to SRE activation. By reporter gene analysis following transient transfections with various plasmids expressing a dominant negative mutant form of Cdc42, Rac1 or RhoA, C2-ceramide-induced SRE activation was shown to be selectively repressed by pEXV-RacN17 encoding a dominant negative mutant of Rac1, suggesting that Rac activity is essential for the signalling cascade of ceramide to the nucleus. In a further study to analyse the downstream mediator of Rac in the ceramide-signalling pathway, we observed that either pretreatment with mepacrine, a potent and specific inhibitor of phospholipase A2, or co-transfection with antisense cytosolic phospholipase A2 (cPLA2) oligonucleotide repressed the C2-ceramide-induced SRE activation selectively, implying a critical role of cPLA2 in C2-ceramide-induced signalling to nucleus. Consistent with these results, the translocation of cPLA2 protein as well as the release of arachidonic acid, a principal product of phospholipase A2, was rapidly induced by the addition of C2-ceramide in a Rac-dependent manner. Together, our findings suggest the critical role of ‘Rac and subsequent activation of phospholipase A2’ in ceramide-signalling to nucleus.

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Guillemot, J. C., P. Montcourrier, E. Vivier, J. Davoust, and P. Chavrier. "Selective control of membrane ruffling and actin plaque assembly by the Rho GTPases Rac1 and CDC42 in FcepsilonRI-activated rat basophilic leukemia (RBL-2H3) cells." Journal of Cell Science 110, no. 18 (September 15, 1997): 2215–25. http://dx.doi.org/10.1242/jcs.110.18.2215.

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Engagement of the high affinity IgE receptor (FcepsilonRI) in mast cells elicits a series of intracellular signalling events including cytoskeletal reorganization and granule exocytosis. To analyze the coupling of receptor activation to specific cytoskeletal responses, we expressed dominant negative mutant forms of the Rho GTPases CDC42 and Rac1 in rat RBL-2H3 tumor mast cells. We show here that dominant inhibition of CDC42 function decreases cell adhesion, interferes with Fc(epsilon)RI-induced actin plaque assembly and reduced the recruitment of vinculin at the cell-substratum interface, while the inhibitory Rac1 mutant abolishes Fc(epsilon)RI-mediated membrane ruffling. The expression of trans-dominant inhibitory forms of either CDC42 or Rac1 significantly inhibited antigen-induced degranulation. Altogether, our results demonstrate that CDC42 and Rac1 control distinct pathways downstream of FcepsilonRI engagement leading either to the induction of actin plaques, or to the production of membrane ruffles. These two pathways are critically involved during the degranulation response induced by Fc(epsilon)RI aggregation.

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Maltas, Joe, Hannah Reed, Andrew Porter, and Angeliki Malliri. "Mechanisms and consequences of dysregulation of the Tiam family of Rac activators in disease." Biochemical Society Transactions 48, no. 6 (November 16, 2020): 2703–19. http://dx.doi.org/10.1042/bst20200481.

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The Tiam family proteins — Tiam1 and Tiam2/STEF — are Rac1-specific Guanine Nucleotide Exchange Factors (GEFs) with important functions in epithelial, neuronal, immune and other cell types. Tiam GEFs regulate cellular migration, proliferation and survival, mainly through activating and directing Rac1 signalling. Dysregulation of the Tiam GEFs is significantly associated with human diseases including cancer, immunological and neurological disorders. Uncovering the mechanisms and consequences of dysregulation is therefore imperative to improving the diagnosis and treatment of diseases. Here we compare and contrast the subcellular localisation and function of Tiam1 and Tiam2/STEF, and review the evidence for their dysregulation in disease.

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Brandes, Vanessa, Ilona Schelle, Sophie Brinkmann, Florian Schulz, Janett Schwarz, Ralf Gerhard, and Harald Genth. "Protection from Clostridium difficile toxin B-catalysed Rac1/Cdc42 glucosylation by tauroursodeoxycholic acid-induced Rac1/Cdc42 phosphorylation." Biological Chemistry 393, no. 1-2 (January 1, 2012): 77–84. http://dx.doi.org/10.1515/bc-2011-198.

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Abstract Toxin A (TcdA) and toxin B (TcdB) are the major virulence factors of Clostridium difficile-associated diarrhoea (CDAD). TcdA and TcdB mono-glucosylate small GTPases of the Rho family, thereby causing actin re-organisation in colonocytes, resulting in the loss of colonic barrier function. The hydrophilic bile acid tauroursodeoxycholic acid (TUDCA) is an approved drug for the treatment of cholestasis and biliary cirrhosis. In this study, TUDCA-induced activation of Akt1 is presented to increase cellular levels of pS71-Rac1/Cdc42 in human hepatocarcinoma (HepG2) cells, showing for the first time that bile acid signalling affects the activity of Rho proteins. Rac1/Cdc42 phosphorylation, in turn, protects Rac1/Cdc42 from TcdB-catalysed glucosylation and reduces the TcdB-induced cytopathic effects in HepG2 cells. The results of this study indicate that TUDCA may prove useful as a therapeutic agent for the treatment of CDAD.

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Ham, Sun Ah, Jung Seok Hwang, Taesik Yoo, Hanna Lee, Eun Sil Kang, Chankyu Park, Jae-Wook Oh, et al. "Ligand-activated PPARδ inhibits UVB-induced senescence of human keratinocytes via PTEN-mediated inhibition of superoxide production." Biochemical Journal 444, no. 1 (April 26, 2012): 27–38. http://dx.doi.org/10.1042/bj20111832.

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UV radiation-mediated photodamage to the skin has been implicated in premature aging and photoaging-related skin cancer and melanoma. Little is known about the cellular events that underlie premature senescence, or how to impede these events. In the present study we demonstrate that PPARδ (peroxisome-proliferator-activated receptor δ) regulates UVB-induced premature senescence of normal keratinocytes. Activation of PPARδ by GW501516, a specific ligand of PPARδ, significantly attenuated UVB-mediated generation of ROS (reactive oxygen species) and suppressed senescence of human keratinocytes. Ligand-activated PPARδ up-regulated the expression of PTEN (phosphatase and tensin homologue deleted on chromosome 10) and suppressed the PI3K (phosphatidylinositol 3-kinase)/Akt pathway. Concomitantly, translocation of Rac1 to the plasma membrane, which leads to the activation of NADPH oxidases and generation of ROS, was significantly attenuated. siRNA (small interfering RNA)-mediated knockdown of PTEN abrogated the effects of PPARδ on cellular senescence, on PI3K/Akt/Rac1 signalling and on generation of ROS in keratinocytes exposed to UVB. Finally, when HR-1 hairless mice were treated with GW501516 before exposure to UVB, the number of senescent cells in the skin was significantly reduced. Thus ligand-activated PPARδ confers resistance to UVB-induced cellular senescence by up-regulating PTEN and thereby modulating PI3K/Akt/Rac1 signalling to reduce ROS generation in keratinocytes.

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Zamudio-Meza, Horacio, Aída Castillo-Alvarez, César González-Bonilla, and Isaura Meza. "Cross-talk between Rac1 and Cdc42 GTPases regulates formation of filopodia required for dengue virus type-2 entry into HMEC-1 cells." Journal of General Virology 90, no. 12 (December 1, 2009): 2902–11. http://dx.doi.org/10.1099/vir.0.014159-0.

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Infection with dengue virus type-2 (DENV-2) begins with virus adherence to cell surface receptors. In endothelial cells (HMEC-1), a cell model for DENV-2 infection, α5β3 integrin has been identified as a putative receptor for the virus. Previous work had suggested that the actin cytoskeleton of HMEC-1 cells plays an important role in virus entry and infection. In the present work, fixed and living HMEC-1 cells expressing enhanced green fluorescent protein–actin were monitored for actin reorganization after virus inoculation, utilizing fluorescence and time lapse microscopy. Cell infection and production of infective viruses were quantified using an anti-E protein antibody and by measuring the p.f.u. ml−1. Specific drugs that antagonize actin organization and regulate actin-signalling pathways were tested in viral adhesion and infection assays, as were the expression of dominant-negative Rac1 and Cdc42 proteins. Disorganization of actin precluded infection, while microtubule depolymerization had no effect. Activation of Rac1 and Cdc42 signalling, which occurs upon virus binding, induced reorganization of actin to form filopodia in the cellular periphery. Formation of filopodia was a requirement for virus entry and further cell infection. Expression of the dominant-negative proteins Rac1 and Cdc42 confirmed the role of these GTPases in the actin reorganization that is required to form filopodia. In addition, inhibition of the ATPase activity of myosin II greatly decreased infection, suggesting its participation in filopodial stability. We show here, for the first time, that internalization of DENV-2 into endothelial cells requires viral induction of dynamic filopodia regulated by Rac1 and Cdc42 cross-talk and myosin II motor activities.

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Tan, Bai, Saintigny, and Darido. "mTOR Signalling in Head and Neck Cancer: Heads Up." Cells 8, no. 4 (April 9, 2019): 333. http://dx.doi.org/10.3390/cells8040333.

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The mammalian target of rapamycin (mTOR) signalling pathway is a central regulator of metabolism in all cells. It senses intracellular and extracellular signals and nutrient levels, and coordinates the metabolic requirements for cell growth, survival, and proliferation. Genetic alterations that deregulate mTOR signalling lead to metabolic reprogramming, resulting in the development of several cancers including those of the head and neck. Gain-of-function mutations in EGFR, PIK3CA, and HRAS, or loss-of-function in p53 and PTEN are often associated with mTOR hyperactivation, whereas mutations identified from The Cancer Genome Atlas (TCGA) dataset that potentially lead to aberrant mTOR signalling are found in the EIF4G1, PLD1, RAC1, and SZT2 genes. In this review, we discuss how these mutant genes could affect mTOR signalling and highlight their impact on metabolic processes, as well as suggest potential targets for therapeutic intervention, primarily in head and neck cancer.

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Pesaresi, M. G., I. Amori, C. Giorgi, A. Ferri, P. Fiorenzo, F. Gabanella, A. M. Salvatore, et al. "Mitochondrial redox signalling by p66Shc mediates ALS-like disease through Rac1 inactivation." Human Molecular Genetics 20, no. 21 (August 9, 2011): 4196–208. http://dx.doi.org/10.1093/hmg/ddr347.

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FLEMING, Ian N., Ian H. BATTY, Alan R. PRESCOTT, Alex GRAY, Gursant S. KULAR, Hazel STEWART, and C. Peter DOWNES. "Inositol phospholipids regulate the guanine-nucleotide-exchange factor Tiam1 by facilitating its binding to the plasma membrane and regulating GDP/GTP exchange on Rac1." Biochemical Journal 382, no. 3 (September 7, 2004): 857–65. http://dx.doi.org/10.1042/bj20040916.

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Binding of the Rac1-specific guanine-nucleotide-exchange factor, Tiam1, to the plasma membrane requires the N-terminal pleckstrin homology domain. In the present study, we show that membrane-association is mediated by binding of PtdIns(4,5)P2 to the pleckstrin homology domain. Moreover, in 1321N1 astrocytoma cells, translocation of Tiam1 to the cytosol, following receptor-mediated stimulation of PtdIns(4,5)P2 breakdown, correlates with decreased Rac1-GTP levels, indicating that membrane-association is required for GDP/GTP exchange on Rac1. In addition, we show that platelet-derived growth factor activates Rac1 in vivo by increasing PtdIns(3,4,5)P3 concentrations, rather than the closely related lipid, PtdIns(3,4)P2. Finally, the data demonstrate that PtdIns(4,5)P2 and PtdIns(3,4,5)P3 bind to the same pleckstrin homology domain in Tiam1 and that soluble inositol phosphates appear to compete with lipids for this binding. Together, these novel observations provide strong evidence that distinct phosphoinositides regulate different functions of this enzyme, indicating that local concentrations of signalling lipids and the levels of cytosolic inositol phosphates will play crucial roles in determining its activity in vivo.

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GORIN, Yves, Jill M. RICONO, Brent WAGNER, Nam-Ho KIM, Basant BHANDARI, Goutam Ghosh CHOUDHURY, and Hanna E. ABBOUD. "Angiotensin II-induced ERK1/ERK2 activation and protein synthesis are redox-dependent in glomerular mesangial cells." Biochemical Journal 381, no. 1 (June 22, 2004): 231–39. http://dx.doi.org/10.1042/bj20031614.

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Angiotensin II (Ang II) stimulates hypertrophy of glomerular mesangial cells. The signalling mechanism by which Ang II exerts this effect is not precisely known. Downstream potential targets of Ang II are the extracellular-signal-regulated kinases 1 and 2 (ERK1/ERK2). We demonstrate that Ang II activates ERK1/ERK2 via the AT1 receptor. Arachidonic acid (AA) mimics the action of Ang II on ERK1/ERK2 and phospholipase A2 inhibitors blocked Ang II-induced ERK1/ERK2 activation. The antioxidant N-acetylcysteine as well as the NAD(P)H oxidase inhibitors diphenylene iodonium and phenylarsine oxide abolished both Ang II- and AA-induced ERK1/ERK2 activation. Moreover, dominant-negative Rac1 (N17Rac1) blocks activation of ERK1/ERK2 in response to Ang II and AA, whereas constitutively active Rac1 resulted in an increase in ERK1/ERK2 activity. Antisense oligonucleotides for Nox4 NAD(P)H oxidase significantly reduce activation of ERK1/ERK2 by Ang II and AA. We also show that protein synthesis in response to Ang II and AA is inhibited by N17Rac1 or MEK (mitogen-activated protein kinase/ERK kinase) inhibitor. These results demonstrate that Ang II stimulates ERK1/ERK2 by AA and Nox4-derived reactive oxygen species, suggesting that these molecules act as downstream signal transducers of Ang II in the signalling pathway linking the Ang II receptor AT1 to ERK1/ERK2 activation. This pathway involving AA, Rac1, Nox4, reactive oxygen species and ERK1/ERK2 may play an important role in Ang II-induced mesangial cell hypertrophy.

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Alaridah, Nader, Nataliya Lutay, Erik Tenland, Anna Rönnholm, Oskar Hallgren, Manoj Puthia, Gunilla Westergren-Thorsson, and Gabriela Godaly. "Mycobacteria Manipulate G-Protein-Coupled Receptors to Increase Mucosal Rac1 Expression in the Lungs." Journal of Innate Immunity 9, no. 3 (December 24, 2016): 318–29. http://dx.doi.org/10.1159/000453454.

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Mycobacterium bovis bacille Calmette-Guérin (BCG) is currently the only approved vaccine against tuberculosis (TB). BCG mimics M. tuberculosis (Mtb) in its persistence in the body and is used as a benchmark to compare new vaccine candidates. BCG was originally designed for mucosal vaccination, but comprehensive knowledge about its interaction with epithelium is currently lacking. We used primary airway epithelial cells (AECs) and a murine model to investigate the initial events of mucosal BCG interactions. Furthermore, we analysed the impact of the G-protein-coupled receptors (GPCRs), CXCR1 and CXCR2, in this process, as these receptors were previously shown to be important during TB infection. BCG infection of AECs induced GPCR-dependent Rac1 up-regulation, resulting in actin redistribution. The altered distribution of the actin cytoskeleton involved the MAPK signalling pathway. Blocking of the CXCR1 or CXCR2 prior to infection decreased Rac1 expression, and increased epithelial transcriptional activity and epithelial cytokine production. BCG infection did not result in epithelial cell death as measured by p53 phosphorylation and annexin. This study demonstrated that BCG infection of AECs manipulated the GPCRs to suppress epithelial signalling pathways. Future vaccine strategies could thus be improved by targeting GPCRs.

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Zeng, Ni, Madhuri S. Salker, Shaqiu Zhang, Yogesh Singh, Bing Shi, Christos Stournaras, and Florian Lang. "1α,25(OH)2D3 Induces Actin Depolymerization in Endometrial Carcinoma Cells by Targeting RAC1 and PAK1." Cellular Physiology and Biochemistry 40, no. 6 (2016): 1455–64. http://dx.doi.org/10.1159/000453197.

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Background: Cell proliferation and motility require actin reorganization, which is under control of various signalling pathways including ras-related C3 botulinum toxin substrate 1 (RAC1), p21 protein-activated kinase 1 (PAK1) and actin related protein 2 (ARP2). Tumour cell proliferation is modified by 1α,25-Dihydroxy-Vitamin D3 (1α,25(OH)2D3), a steroid hormone predominantly known for its role in calcium and phosphorus metabolism. The present study explored whether 1α,25(OH)2D3 modifies actin cytoskeleton in Ishikawa cells, a well differentiated endometrial carcinoma cell line. Methods: To this end, actin cytoskeleton was visualized by confocal microscopy. Globular over filamentous actin ratio was determined utilizing Western blotting and flow cytometry, transcript levels by qRT-PCR and protein abundance by immunoblotting. Results: A 24 hour treatment with 1α,25(OH)2D3 (100 nM) significantly decreased RAC1 and PAK1 transcript levels and activity, decreased ARP2 protein levels and depolymerized actin. The effect of 1α,25(OH)2D3 on actin polymerization was mimicked by pharmacological inhibition of RAC1 and PAK1. Conclusions: 1α,25(OH)2D3 leads to disruption of RAC1 and PAK1 activity with subsequent actin depolymerization of endometrial carcinoma cells.

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Konopka, Anna, Andre Zeug, Anna Skupien, Beata Kaza, Franziska Mueller, Agnieszka Chwedorowicz, Evgeni Ponimaskin, Grzegorz M. Wilczynski, and Joanna Dzwonek. "Cleavage of Hyaluronan and CD44 Adhesion Molecule Regulate Astrocyte Morphology via Rac1 Signalling." PLOS ONE 11, no. 5 (May 10, 2016): e0155053. http://dx.doi.org/10.1371/journal.pone.0155053.

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Lassus, Patrice, Pierre Roux, Olivier Zugasti, Alexandre Philips, Philippe Fort, and Urszula Hibner. "Extinction of Rac1 and Cdc42Hs signalling defines a novel p53-dependent apoptotic pathway." Oncogene 19, no. 20 (May 2000): 2377–85. http://dx.doi.org/10.1038/sj.onc.1203553.

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Deng, Qing, Yan-Xiao Tian, and JianJun Liang. "Mangiferin inhibits cell migration and invasion through Rac1/WAVE2 signalling in breast cancer." Cytotechnology 70, no. 2 (February 17, 2018): 593–601. http://dx.doi.org/10.1007/s10616-017-0140-1.

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Maly, Karl, Georg Hechenberger, Kukka Strese, Ingeborg Tinhofer, Irene Wede, Wolfgang Doppler, and Hans H. Grunicke. "Regulation of calcium signalling by the small GTP-binding proteins Ras and Rac1." Advances in Enzyme Regulation 47, no. 1 (January 2007): 169–83. http://dx.doi.org/10.1016/j.advenzreg.2006.12.017.

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Li, Yu-Long, Ming Shao, and De-Li Shi. "Rac1 signalling coordinates epiboly movement by differential regulation of actin cytoskeleton in zebrafish." Biochemical and Biophysical Research Communications 490, no. 3 (August 2017): 1059–65. http://dx.doi.org/10.1016/j.bbrc.2017.06.165.

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ZHAO, Dezheng, Sabina KUHNT-MOORE, Huiyan ZENG, Amy PAN, Jack S. WU, Simos SIMEONIDIS, Mary P. MOYER, and Charalabos POTHOULAKIS. "Substance P-stimulated interleukin-8 expression in human colonic epithelial cells involves Rho family small GTPases." Biochemical Journal 368, no. 2 (December 1, 2002): 665–72. http://dx.doi.org/10.1042/bj20020950.

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Interaction of the neuropeptide substance P (SP) and its neurokinin-1 receptor (NK-1R) plays an important role in the pathophysiology of intestinal inflammation. SP is known to stimulate production of interleukin (IL)-6 and IL-8 in the U-373-MG human astrocytoma cell line via activation of p38 MAPK (mitogen-activated protein kinase) and nuclear factor (NF)-κB, respectively. However, the signalling mechanisms by which SP-NK-1R interaction induces NF-κB activation and IL-8 expression are still not clear. In this study we demonstrate that SP stimulates IL-8 secretion and IL-8 promoter activity in the NCM460 non-transformed human colonic epithelial cell line transfected with NK-1R cDNA. Our results indicate that inhibition of endogenous Rho family proteins (RhoA, Rac1 and Cdc42) by their respective dominant negative mutants significantly decreases SP-induced IL-8 secretion and IL-8 promoter activity. We also demonstrate that SP rapidly activates RhoA, Rac1 and Cdc42 and that co-expression of the dominant negative mutants of RhoA, Rac1 and Cdc42 in NK-1R cDNA-transfected NCM460 cells significantly inhibits SP-induced NF-κB-dependent gene expression. These results demonstrate that Rho family small GTPases RhoA, Rac1 and Cdc42 are novel signal transducers for SP-stimulated IL-8 expression.

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Nakamura, Fumihiko. "FilGAP and its close relatives: a mediator of Rho–Rac antagonism that regulates cell morphology and migration." Biochemical Journal 453, no. 1 (June 13, 2013): 17–25. http://dx.doi.org/10.1042/bj20130290.

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Cell migration, phagocytosis and cytokinesis are mechanically intensive cellular processes that are mediated by the dynamic assembly and contractility of the actin cytoskeleton. GAPs (GTPase-activating proteins) control activities of the Rho family proteins including Cdc42, Rac1 and RhoA, which are prominent upstream regulators of the actin cytoskeleton. The present review concerns a class of Rho GAPs, FilGAP (ARHGAP24 gene product) and its close relatives (ARHGAP22 and AHRGAP25 gene products). FilGAP is a GAP for Rac1 and a binding partner of FLNa (filamin A), a widely expressed F-actin (filamentous actin)-cross-linking protein that binds many different proteins that are important in cell regulation. Phosphorylation of FilGAP serine/threonine residues and binding to FLNa modulate FilGAP's GAP activity and, as a result, its ability to regulate cell protrusion and spreading. FLNa binds to FilGAP at F-actin-enriched sites, such as at the leading edge of the cell where Rac1 activity is controlled to inhibit actin assembly. FilGAP then dissociates from FLNa in actin networks by myosin-dependent mechanical deformation of FLNa's FilGAP-binding site to relocate at the plasma membrane by binding to polyphosphoinositides. Since actomyosin contraction is activated downstream of RhoA–ROCK (Rho-kinase), RhoA activity regulates Rac1 through FilGAP by signalling to the force-generating system. FilGAP and the ARHGAP22 gene product also act as mediators between RhoA and Rac1 pathways, which lead to amoeboid and mesenchymal modes of cell movements respectively. Therefore FilGAP and its close relatives are key regulators that promote the reciprocal inhibitory relationship between RhoA and Rac1 in cell shape changes and the mesenchymal–amoeboid transition in tumour cells.

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Barabutis, Nektarios, Christiana Dimitropoulou, Betsy Gregory, and John D. Catravas. "Wild-type p53 enhances endothelial barrier function by mediating RAC1 signalling and RhoA inhibition." Journal of Cellular and Molecular Medicine 22, no. 3 (January 24, 2018): 1792–804. http://dx.doi.org/10.1111/jcmm.13460.

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Bright, Michael D., Paul A. Clarke, Paul Workman, and Faith E. Davies. "Oncogenic RAC1 and NRAS drive resistance to endoplasmic reticulum stress through MEK/ERK signalling." Cellular Signalling 44 (April 2018): 127–37. http://dx.doi.org/10.1016/j.cellsig.2018.01.004.

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Chakraborty, Arijit, Syamal Roy, Shyam Sundar, and Malini Sen. "Wnt5a signaling antagonizes Leishmania donovani infection." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 200.20. http://dx.doi.org/10.4049/jimmunol.196.supp.200.20.

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Abstract Leishmania donovani, the causative agent for visceral leishmaniasis creates a niche within host immune cells to sustain itself. In light of the fact that Wnt5a utilizes a Rac1–NFκB circuitry for sustaining immune homeostasis in macrophages and alters actin assembly (Naskar.et.al 2014, Witze et.al 2008) we deciphered whether there is any influence of Wnt5a signaling on L. donovani infection. Upon infection of macrophages with L.donovani, we noted significant decrease in Wnt5a protein levels. Infection with both SAG sensitive and SAG resistant parasite strains yielded similar results. Interestingly, upon treatment of macrophages with recombinant Wnt5a prior to infection separately with SAG senstive and SAG resistant L.donovani, there was significant decrease in the intracellular load of both strains of parasite, as judged by microscopic analysis and expression of Leishmania specific genes (Amastin and G6PDH). Depleting Wnt5a from the macrophages by si-RNA in-vitro or by use of Inhibitor of Wnt Production (IWP2) in-vivo, on the other hand, led to an increase in parasite load. Using specific inhibitors of the Wnt5a signaling intermediates Rac1 and NFκB, we demonstrated that Wnt5a induced reduction in parasite load is due to Wnt5a dependent Rac1 activity but not NFκB signalling. In light of the known involvement of Rac1 in actin organization, the altered actin assembly of Wnt5a pre-treated macrophages, as evident from flow cytometric analysis corroborated the observed Rac1 mediated inhibition of L.donovani infection. Taken together, our results indicate that (i) Wnt5a signaling is detrimental to L. donovani infection and (ii) the parasite evades host immune response at least partly through obliteration of Wnt5a signaling.

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Hampson, Elizabeth, Elpida Tsonou, Martin J. Baker, David C. Hornigold, Roderick E. Hubbard, Andrew Massey, and Heidi C. E. Welch. "P-Rex1 Controls Sphingosine 1-Phosphate Receptor Signalling, Morphology, and Cell-Cycle Progression in Neuronal Cells." Cells 10, no. 9 (September 18, 2021): 2474. http://dx.doi.org/10.3390/cells10092474.

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P-Rex1 is a guanine-nucleotide exchange factor (GEF) that activates Rac-type small G proteins in response to the stimulation of a range of receptors, particularly G protein-coupled receptors (GPCRs), to control cytoskeletal dynamics and other Rac-dependent cell responses. P-Rex1 is mainly expressed in leukocytes and neurons. Whereas its roles in leukocytes have been studied extensively, relatively little is known about its functions in neurons. Here, we used CRISPR/Cas9-mediated P-Rex1 deficiency in neuronal PC12 cells that stably overexpress the GPCR S1PR1, a receptor for sphingosine 1-phosphate (S1P), to investigate the role of P-Rex1 in neuronal GPCR signalling and cell responses. We show that P-Rex1 is required for the S1P-stimulated activation of Rac1 and Akt, basal Rac3 activity, and constitutive cAMP production in PC12-S1PR1 cells. The constitutive cAMP production was not due to increased expression levels of major neuronal adenylyl cyclases, suggesting that P-Rex1 may regulate adenylyl cyclase activity. P-Rex1 was required for maintenance of neurite protrusions and spreading in S1P-stimulated PC12-S1PR1 cells, as well as for cell-cycle progression and proliferation. In summary, we identified novel functional roles of P-Rex1 in neuronal Rac, Akt and cAMP signalling, as well as in neuronal cell-cycle progression and proliferation.

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Wang, H., and M. G. Kazanietz. "The lipid second messenger diacylglycerol as a negative regulator of Rac signalling." Biochemical Society Transactions 34, no. 5 (October 1, 2006): 855–57. http://dx.doi.org/10.1042/bst0340855.

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We have established a novel role for the second messenger DAG (diacylglycerol), a product of PtdIns(4,5)P2 hydrolysis by PLC (phospholipase C). In addition to its well-known function as a protein kinase C activator, DAG produced by stimulation of the epidermal growth factor receptor causes the redistribution of the Rac-GAP (GTPase-activating protein) β2-chimaerin to the plasma membrane, where it associates with the active form of Rac1 and promotes the inactivation of this small G-protein. This represents the first example of a Rac-GAP regulated directly by DAG in response to the activation of a tyrosine kinase receptor, and suggests a previously unappreciated role for this lipid as a negative modulator of Rac signalling.

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Zhao, Z. S., T. Leung, E. Manser, and L. Lim. "Pheromone signalling in Saccharomyces cerevisiae requires the small GTP-binding protein Cdc42p and its activator CDC24." Molecular and Cellular Biology 15, no. 10 (October 1995): 5246–57. http://dx.doi.org/10.1128/mcb.15.10.5246.

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Pheromone signalling in Saccharomyces cerevisiae is mediated by the STE4-STE18 G-protein beta gamma subunits. A possible target for the subunits is Ste20p, whose structural homolog, the serine/threonine kinase PAK, is activated by GTP-binding p21s Cdc42 and Rac1. The putative Cdc42p-binding domain of Ste20p, expressed as a fusion protein, binds human and yeast GTP-binding Cdc42p. Cdc42p is required for alpha-factor-induced activation of FUS1.cdc24ts strains defective for Cdc42p GDP/GTP exchange show no pheromone induction at restrictive temperatures but are partially rescued by overexpression of Cdc42p, which is potentiated by Cdc42p12V mutants. Epistatic analysis indicates that CDC24 and CDC42 lie between STE4 and STE20 in the pathway. The two-hybrid system revealed that Ste4p interacts with Cdc24p. We propose that Cdc42p plays a pivotal role both in polarization of the cytoskeleton and in pheromone signalling.

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Hetmanski, Joseph H. R., Jean-Marc Schwartz, and Patrick T. Caswell. "Modelling GTPase dynamics to understand RhoA-driven cancer cell invasion." Biochemical Society Transactions 44, no. 6 (December 2, 2016): 1695–700. http://dx.doi.org/10.1042/bst20160184.

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Metastasis, initially driven by cells migrating and invading through the local environment, leads to most cancer-associated deaths. Cells can use a variety of modes to move in vitro, all of which depend on Rho GTPases at some level. While traditionally it was thought that Rac1 activity drives protrusive lamellipodia at the leading edge of a polarised cell while RhoA drives rear retraction, more recent work in 3D microenvironments has revealed a much more complicated picture of GTPase dynamics. In particular, RhoA activity can dominate the leading edge polymerisation of actin to form filopodial actin-spike protrusions that drive more invasive cell migration. We recently described a potential mechanism to abrogate this pro-invasive localised leading edge Rac1 to RhoA switch via manipulation of a negative feedback loop that was revealed by adopting a logical modelling approach. Both challenging dogma and taking a formal, mathematical approach to understanding signalling involved in motility may be vital to harnessing harmful cell migration and preventing metastasis in future research.

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Barros, P., A. J. Amaral, L. B. Abrantes, T. Oliveira, H. Louro, M. J. Silva, P. Jordan, M. Gama-Carvalho, and P. Matos. "Stimulation of RAC1/PAK1 signalling upregulates DNA damage repair genes via the BCL6/STAT5-switch." Annals of Oncology 28 (September 2017): v19—v20. http://dx.doi.org/10.1093/annonc/mdx361.069.

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Wang, Yanpeng, Jian Ma, Meng Wei, and Tianqing Peng. "RAC1 SIGNALLING MEDIATES DOXORUBICIN-INDUCED CARDIOTOXICITY THROUGH BOTH REACTIVE OXYGEN SPECIES DEPENDENT AND INDEPENDENT PATHWAYS." Heart 98, Suppl 2 (October 2012): E21.3—E22. http://dx.doi.org/10.1136/heartjnl-2012-302920a.47.

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Ma, Jian, Yanpeng Wang, Dong Zheng, Meng Wei, Huaxi Xu, and Tianqing Peng. "Rac1 signalling mediates doxorubicin-induced cardiotoxicity through both reactive oxygen species-dependent and -independent pathways." Cardiovascular Research 97, no. 1 (October 1, 2012): 77–87. http://dx.doi.org/10.1093/cvr/cvs309.

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Osada, Y., T. Sunatani, I. S. Kim, Y. Nakanishi, and A. Shiratsuchi. "Signalling Pathway Involving GULP, MAPK and Rac1 for SR-BI-Induced Phagocytosis of Apoptotic Cells." Journal of Biochemistry 145, no. 3 (January 4, 2009): 387–94. http://dx.doi.org/10.1093/jb/mvn176.

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Journal articles on the topic 'Rac1 signalling'

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