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Rho GTPases

Silvia P Sepúlveda-Ramírez, Leslie Toledo-Jacobo, John H Henson, Charles B Shuster
In the sea urchin embryo, gastrulation is characterized by the ingression and directed cell migration of primary mesenchyme cells (PMCs), as well as the primary invagination and convergent extension of the endomesoderm. Like all cell shape changes, individual and collective cell motility is orchestrated by Rho family GTPases and their modulation of the actomyosin cytoskeleton. And while endomesoderm specification has been intensively studied in echinoids, much less is known about the proximate regulators driving cell motility...
March 16, 2018: Developmental Biology
Jingxiao Wang, Xinjie Yang, Haibo Han, Limin Wang, Weiqian Bao, Shanshan Wang, Robert M Hoffman, Meng Yang, Hui Qi, Chao An, Kaiwen Hu
Objective: Triple-negative breast cancer (TNBC) is highly invasive and metastatic, which is in urgent need of transformative therapeutics. Tubeimu (TBM), the rhizome of Bolbostemma paniculatum (Maxim.) Franquet, is one of the Chinese medicinal herbs used for breast diseases since the ancient times. The present study evaluated the efficacy, especially the anti-metastatic effects of the dichloromethane extract of Tubeimu (ETBM) on TNBC orthotopic mouse models and cell lines. Methods: We applied real-time imaging on florescent orthotopic TNBC mice model and tested cell migration and invasion abilities with MDA-MB-231 cell line...
February 2018: Chinese Journal of Cancer Research, Chung-kuo Yen Cheng Yen Chiu
Verónica M Negrón-Pérez, Luana Teixeira Rodrigues, Gisele Zoccal Mingoti, Peter J Hansen
Rho-associated coiled-coil containing protein kinases (ROCK1 and ROCK2) are activated by binding to RHO GTPases and phosphorylate a variety of downstream targets including actinomyosin. In the mouse embryo, ROCK signaling acts to promote formation of trophectoderm (TE) and inhibit formation of the inner cell mass (ICM) by polarizing outer cells of the embryo to inactivate Hippo signaling (Kono et al., 2014; Mihajlović and Bruce, 2016). This article is protected by copyright. All rights reserved.
March 15, 2018: Molecular Reproduction and Development
Alexis Bonfim-Melo, Éden R Ferreira, Renato A Mortara
This study evaluated the participation of host cell Rho-family GTPases and their effector proteins in the actin-dependent invasion by Trypanosoma cruzi extracellular amastigotes (EAs). We observed that all proteins were recruited and colocalized with actin at EA invasion sites in live or fixed cells. EA internalization was inhibited in cells depleted in Rac1, N-WASP, and WAVE2. Time-lapse experiments with Rac1, N-WASP and WAVE2 depleted cells revealed that EA internalization kinetics is delayed even though no differences were observed in the proportion of EA-induced actin recruitment in these groups...
2018: Frontiers in Microbiology
Ryo Hatano, Ai Takeda, Yukiko Abe, Kotoku Kawaguchi, Itsuro Kazama, Mitsunobu Matsubara, Shinji Asano
Ezrin is highly expressed in glomerular podocytes and is reported to form a multi-protein complex with scaffold protein Na+ /H+ exchanger regulatory factor 2 (NHERF2) and podocalyxin, a major sialoprotein. Podocalyxin-knockout mice died within 24 h of birth with anuric renal failure, whereas NHERF2-knockout mice show no apparent changes in the glomerular functions. However, the physiological roles of ezrin in glomerular podocytes remain unclear. Here, we investigated the importance of ezrin in the regulation of glomerular podocyte function using ezrin-knockdown mice (Vil2kd/kd )...
March 14, 2018: Scientific Reports
Liya Pi, Chunhua Fu, Yuanquing Lu, Junmei Zhou, Marda Jorgensen, Vinayak Shenoy, Kenneth E Lipson, Edward W Scott, Andrew J Bryant
Chronic hypoxia frequently complicates the care of patients with interstitial lung disease, contributing to the development of pulmonary hypertension (PH), and premature death. Connective tissue growth factor (CTGF), a matricellular protein of the Cyr61/CTGF/Nov (CCN) family, is known to exacerbate vascular remodeling within the lung. We have previously demonstrated that vascular endothelial-cell specific down-regulation of CTGF is associated with protection against the development of PH associated with hypoxia, though the mechanism for this effect is unknown...
2018: Frontiers in Physiology
Jerry C Madukwe, Elisabeth E Garland-Kuntz, Angeline M Lyon, Alan V Smrcka
Phospholipase C (PLC) enzymes hydrolyze membrane phosphatidylinositol 4,5 bisphosphate (PIP2) and regulate Ca2+ and protein kinase signaling in virtually all mammalian cell types. Chronic activation of the PLCɛ isoform downstream of G protein-coupled receptors (GPCRs) contributes to the development of cardiac hypertrophy. We have previously shown that PLCε-catalyzed hydrolysis of Golgi-associated phosphatidylinositol 4-phosphate (PI4P) in cardiac myocytes depends on G protein βγ subunits released upon stimulation with endothelin-1...
March 13, 2018: Journal of Biological Chemistry
Richard T Amison, Shirin Jamshidi, Khondaker M Rahman, Clive P Page, Simon C Pitchford
Platelet P2Y1 receptor signaling via RhoGTPases is necessary for platelet-dependent leukocyte recruitment, where no platelet aggregation is observed. We investigated signaling cascades involved in distinct P2Y1 -dependent platelet activities in vitro, using specific inhibitors for phospholipase C (PLC) (U73122, to inhibit the canonical pathway), and RhoGTPases: Rac1 (NSC23766) and RhoA (ROCK inhibitor GSK429286). Human platelet rich plasma (for platelet aggregation) or isolated washed platelets (for chemotaxis assays) was treated with U73122, GSK429286 or NSC23766 prior to stimulation with adenosine diphosphate (ADP) or the P2Y1 specific agonist MRS2365...
March 10, 2018: European Journal of Pharmacology
Kiyoshi Takagi, Yasuhiro Miki, Yoshiaki Onodera, Takanori Ishida, Mika Watanabe, Hironobu Sasano, Takashi Suzuki
Rho GTPase activating protein 15 (ARHGAP15) is a recently identified GTPase activating protein which enhances intrinsic hydrolysis of GTP-bound Ras-related C3 botulinus toxin substrate (Rac1), resulting in inactivation of Rac1. Although a lot of studies have pointed out the pivotal roles of the Rac1 pathway in the progression of breast carcinomas, the clinical significance of ARHGAP15 has remained largely unknown in human breast carcinomas. Therefore, we immunolocalized ARHGAP15 in one hundred breast carcinoma tissues...
March 10, 2018: International Journal of Molecular Sciences
Michael Pablo, Samuel A Ramirez, Timothy C Elston
Polarity establishment, the spontaneous generation of asymmetric molecular distributions, is a crucial component of many cellular functions. Saccharomyces cerevisiae (yeast) undergoes directed growth during budding and mating, and is an ideal model organism for studying polarization. In yeast and many other cell types, the Rho GTPase Cdc42 is the key molecular player in polarity establishment. During yeast polarization, multiple patches of Cdc42 initially form, then resolve into a single front. Because polarization relies on strong positive feedback, it is likely that the amplification of molecular-level fluctuations underlies the generation of multiple nascent patches...
March 2018: PLoS Computational Biology
Virginia Tajadura-Ortega, Ritu Garg, Richard Allen, Claudia Owczarek, Michael D Bright, Samuel Kean, Aisyah Mohd-Noor, Anita Grigoriadis, Timothy C Elston, Klaus M Hahn, Anne J Ridley
BACKGROUND: Cell migration is essential for development and tissue repair, but it also contributes to disease. Rho GTPases regulate cell migration, but a comprehensive analysis of how each Rho signalling component affects migration has not been carried out. RESULTS: Through an RNA interference screen, and using a prostate cancer cell line, we find that approximately 25% of Rho network components alter migration. Some genes enhance migration while others decrease basal and/or hepatocyte growth factor-stimulated migration...
March 6, 2018: BMC Biology
Stéphanie Moortgat, Damien Lederer, Marie Deprez, Marga Buzatu, Philippe Clapuyt, Sébastien Boulanger, Valérie Benoit, Sandrine Mary, Agnès Guichet, Alban Ziegler, Estelle Colin, Dominique Bonneau, Isabelle Maystadt
Mutations in the oligophrenin 1 gene (OPHN1) have been identified in patients with X-linked intellectual disability (XLID) associated with cerebellar hypoplasia and ventriculomegaly, suggesting it could be a recognizable syndromic intellectual disability (ID). Affected individuals share additional clinical features including speech delay, seizures, strabismus, behavioral difficulties, and slight facial dysmorphism. OPHN1 is located in Xq12 and encodes a Rho-GTPase-activating protein involved in the regulation of the G-protein cycle...
March 3, 2018: European Journal of Medical Genetics
Eirini Nomikou, Melina Livitsanou, Christos Stournaras, Dimitris Kardassis
Rho GTPases are highly conserved proteins that play critical roles in many cellular processes including actin dynamics, vesicular trafficking, gene transcription, cell-cycle progression, and cell adhesion. The main mode of regulation of Rho GTPases is through guanine nucleotide binding (cycling between an active GTP-bound form and an inactive GDP-bound form), but transcriptional, post-transcriptional, and post-translational modes of Rho regulation have also been described. In the present review, we summarize recent progress on the mechanisms that control the expression of the three members of the Rho-like subfamily (RhoA, RhoB, and RhoC) at the level of gene transcription as well as their post-transcriptional regulation by microRNAs...
March 2, 2018: Cellular and Molecular Life Sciences: CMLS
Zhen Zhong, Laura Grasso, Caroline Sibilla, Tim J Stevens, Nicholas Barry, Anne Bertolotti
Protein aggregation is a hallmark of diverse neurodegenerative diseases. Multiple lines of evidence have revealed that protein aggregates can penetrate inside cells and spread like prions. How such aggregates enter cells remains elusive. Through a focused siRNA screen targeting genes involved in membrane trafficking, we discovered that mutant SOD1 aggregates, like viruses, exploit cofilin-1 to remodel cortical actin and enter cells. Upstream of cofilin-1, signalling from the RHO GTPase and the ROCK1 and LIMK1 kinases controls cofilin-1 activity to remodel actin and modulate aggregate entry...
March 15, 2018: EMBO Journal
Hongchi Yu, Min Gao, Yunlong Ma, Lijuan Wang, Yang Shen, Xiaoheng Liu
angiogenesis plays an important role in the development and progression of tumors, and it involves a series of signaling pathways contributing to the migration of endothelial cells for vascularization and to the invasion of cancer cells for secondary tumor formation. Among these pathways, the focal adhesion kinase (FAK) signaling cascade has been implicated in a variety of human cancers in connection with cell adhesion and migration events leading to tumor angiogenesis, metastasis and invasion. Therefore, the inhibition of FAK in endothelial and/or cancer cells is a potential target for anti‑angiogenic therapy...
February 23, 2018: International Journal of Molecular Medicine
Michela Manni, Sanjay Gupta, Edd Ricker, Yurii Chinenov, Sung Ho Park, Man Shi, Tania Pannellini, Rolf Jessberger, Lionel B Ivashkiv, Alessandra B Pernis
Age-associated B cells (ABCs) are a subset of B cells dependent on the transcription factor T-bet that accumulate prematurely in autoimmune settings. The pathways that regulate ABCs in autoimmunity are largely unknown. SWAP-70 and DEF6 (also known as IBP or SLAT) are the only two members of the SWEF family, a unique family of Rho GTPase-regulatory proteins that control both cytoskeletal dynamics and the activity of the transcription factor IRF4. Notably, DEF6 is a newly identified human risk variant for systemic lupus erythematosus...
February 26, 2018: Nature Immunology
Ilana L Stroke, Jeffrey J Letourneau, Teresa E Miller, Yan Xu, Igor Pechik, Diana R Savoly, Linh Ma, Laurie J Sturzenbecker, Joan Sabalski, Philip D Stein, Maria L Webb, David W Hilbert
Clostridium difficile infection (CDI) is the leading cause of hospital-acquired infectious diarrhea, with significant morbidity, mortality and associated healthcare costs. The major risk factor for CDI is antimicrobial therapy, which disrupts the normal gut microbiota and allows C. difficile to flourish. Treatment of CDI with antimicrobials is generally effective in the short-term, but recurrent infections are frequent and problematic, indicating that improved treatment options are necessary. Symptoms of disease are largely due to two homologous toxins, TcdA and TcdB, which are glucosyltransferases that inhibit host Rho GTPases...
February 26, 2018: Antimicrobial Agents and Chemotherapy
Yu-Ying Shang, Ying-Juan Ma, Lei Zhang, Li-Juan Wang, Xiao-Fan Wu, Xue-Ping Liu
Synapse dysfunction is an early hallmark of Alzheimer's disease (AD), and was considered to be closely related to memory loss. The molecular mechanisms that trigger synapse loss and dysfunction remain poorly understood. Increasing evidence shows a link between Rho GTPases and synapse plasticity. Rho GTPases play a role in controlling synapse function by regulating actin cytoskeleton and dendritic spines. Observations have suggested that phytochemicals, such as flavonoids, alleviate cognition impairment in AD...
February 23, 2018: Neuroreport
Yanmei Qi, Norbert Mair, Kai K Kummer, Michael G Leitner, María Camprubí-Robles, Michiel Langeslag, Michaela Kress
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid involved in numerous physiological and pathophysiological processes. We have previously reported a S1P-induced nocifensive response in mice by excitation of sensory neurons via activation of an excitatory chloride current. The underlying molecular mechanism for the S1P-induced chloride conductance remains elusive. In the present study, we identified two CLCN voltage-gated chloride channels, CLCN3 and CLCN5, which mediated a S1P-induced excitatory Cl- current in sensory neurons by combining RNA-seq, adenovirus-based gene silencing and whole-cell electrophysiological voltage-clamp recordings...
2018: Frontiers in Molecular Neuroscience
Shin-Young Park, Joong-Soo Han
Phospholipase D1 (PLD1) is generally accepted as playing an important role in the regulation of multiple cell functions, such as cell growth, survival, differentiation, membrane trafficking, and cytoskeletal organization. Recent findings suggest that PLD1 also plays an important role in the regulation of neuronal differentiation of neuronal cells. Moreover, PLD1-mediated signaling molecules dynamically regulate the neuronal differentiation of neural stem cells (NSCs). Rho family GTPases and Ca2+ -dependent signaling, in particular, are closely involved in PLD1-mediated neuronal differentiation of NSCs...
February 24, 2018: Journal of Molecular Neuroscience: MN
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