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Rho GTPases

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https://www.readbyqxmd.com/read/29774203/small-rho-gtpases-and-the-effector-vipa-mediate-the-invasion-of-epithelial-cells-by-filamentous-legionella-pneumophila
#1
Akriti Prashar, María Eugenia Ortiz, Stefanie Lucarelli, Elizabeth Barker, Zohreh Tabatabeiyazdi, Feras Shamoun, Deepa Raju, Costin Antonescu, Cyril Guyard, Mauricio R Terebiznik
Legionella pneumophila (Lp) exhibits different morphologies with varying degrees of virulence. Despite their detection in environmental sources of outbreaks and in respiratory tract secretions and lung autopsies from patients, the filamentous morphotype of Lp remains poorly studied. We previously demonstrated that filamentous Lp invades lung epithelial cells (LECs) and replicates intracellularly in a Legionella containing vacuole. Filamentous Lp activates β1integrin and E-cadherin receptors at the surface of LECs leading to the formation of actin-rich cell membrane structures we termed hooks and membrane wraps...
2018: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/29773874/mutations-in-six-nephrosis-genes-delineate-a-pathogenic-pathway-amenable-to-treatment
#2
Shazia Ashraf, Hiroki Kudo, Jia Rao, Atsuo Kikuchi, Eugen Widmeier, Jennifer A Lawson, Weizhen Tan, Tobias Hermle, Jillian K Warejko, Shirlee Shril, Merlin Airik, Tilman Jobst-Schwan, Svjetlana Lovric, Daniela A Braun, Heon Yung Gee, David Schapiro, Amar J Majmundar, Carolin E Sadowski, Werner L Pabst, Ankana Daga, Amelie T van der Ven, Johanna M Schmidt, Boon Chuan Low, Anjali Bansal Gupta, Brajendra K Tripathi, Jenny Wong, Kirk Campbell, Kay Metcalfe, Denny Schanze, Tetsuya Niihori, Hiroshi Kaito, Kandai Nozu, Hiroyasu Tsukaguchi, Ryojiro Tanaka, Kiyoshi Hamahira, Yasuko Kobayashi, Takumi Takizawa, Ryo Funayama, Keiko Nakayama, Yoko Aoki, Naonori Kumagai, Kazumoto Iijima, Henry Fehrenbach, Jameela A Kari, Sherif El Desoky, Sawsan Jalalah, Radovan Bogdanovic, Nataša Stajić, Hildegard Zappel, Assel Rakhmetova, Sharon-Rose Wassmer, Therese Jungraithmayr, Juergen Strehlau, Aravind Selvin Kumar, Arvind Bagga, Neveen A Soliman, Shrikant M Mane, Lewis Kaufman, Douglas R Lowy, Mohamad A Jairajpuri, Richard P Lifton, York Pei, Martin Zenker, Shigeo Kure, Friedhelm Hildebrandt
No efficient treatment exists for nephrotic syndrome (NS), a frequent cause of chronic kidney disease. Here we show mutations in six different genes (MAGI2, TNS2, DLC1, CDK20, ITSN1, ITSN2) as causing NS in 17 families with partially treatment-sensitive NS (pTSNS). These proteins interact and we delineate their roles in Rho-like small GTPase (RLSG) activity, and demonstrate deficiency for mutants of pTSNS patients. We find that CDK20 regulates DLC1. Knockdown of MAGI2, DLC1, or CDK20 in cultured podocytes reduces migration rate...
May 17, 2018: Nature Communications
https://www.readbyqxmd.com/read/29772566/the-epigenetic-factor-kdm2b-regulates-emt-and-small-gtpases-in-colon-tumor-cells
#3
Nefeli Zacharopoulou, Anna Tsapara, Galatea Kallergi, Evi Schmid, Saad Alkahtani, Saud Alarifi, Philip N Tsichlis, Sotirios C Kampranis, Christos Stournaras
BACKGROUND/AIMS: The epigenetic factor KDM2B is a histone demethylase expressed in various tumors. Recently, we have shown that KDM2B regulates actin cytoskeleton organization, small Rho GTPases signaling, cell-cell adhesion and migration of prostate tumor cells. In the present study, we addressed its role in regulating EMT and small GTPases expression in colon tumor cells. METHODS: We used RT-PCR for the transcriptional analysis of various genes, Western blotting for the assessment of protein expression and immunofluorescence microscopy for visualization of fluorescently labeled proteins...
May 14, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29768694/de-novo-variants-in-rhobtb2-an-atypical-rho-gtpase-gene-cause-epileptic-encephalopathy
#4
Hazrat Belal, Mitsuko Nakashima, Hiroshi Matsumoto, Kenji Yokochi, Mariko Taniguchi-Ikeda, Kazushi Aoto, Mohammed Badrul Amin, Azusa Maruyama, Hiroaki Nagase, Takeshi Mizuguchi, Satoko Miyatake, Noriko Miyake, Kazumoto Iijima, Shigeaki Nonoyama, Naomichi Matsumoto, Hirotomo Saitsu
By whole exome sequencing, we identified three de novo RHOBTB2 variants in three patients with epileptic encephalopathies (EEs). Interestingly, all three patients showed acute encephalopathy (febrile status epilepticus), with magnetic resonance imaging revealing hemisphere swelling or reduced diffusion in various brain regions. RHOBTB2 encodes Rho-related BTB domain-containing protein 2, an atypical Rho GTPase that is a substrate-specific adaptor or itself is a substrate for the Cullin-3 (CUL3)-based ubiquitin/proteasome complex...
May 16, 2018: Human Mutation
https://www.readbyqxmd.com/read/29757152/dynamic-seesaw-model-for-rapid-signaling-responses-in-eukaryotic-chemotaxis
#5
Shiliang Feng, Lvwen Zhou, ShouQin Lü, Yan Zhang
Directed movement of eukaryotic cells toward spatiotemporally varied chemotactic stimuli enables rapid intracellular signaling responses. While macroscopic cellular manifestation is shaped by balancing external stimuli strength with finite internal delays, the organizing principles of the underlying molecular mechanisms remain to be clarified. Here, we developed a novel modeling framework based on a simple seesaw mechanism to elucidate how cells repeatedly reverse polarity. As a key feature of the modeling, the bottom module of bidirectional molecular transport is successively controlled by three upstream modules of signal reception, initial signal processing, and Rho GTPase regulation...
May 14, 2018: Physical Biology
https://www.readbyqxmd.com/read/29749605/rho-signaling-research-history-current-status-and-future-directions
#6
Shuh Narumiya, Dean Thumkeo
One of the main research areas in biology from the mid-1980's through the 990's was the elucidation of signaling pathways governing cell responses. These studies brought, among other molecules, the small GTPase Rho to the epicenter. Rho signaling research has since expanded to all areas of biology and medicine. Here, we describe how Rho emerged as a key molecule governing cell morphogenesis and movement, how it was linked to actin reorganization, and how the study of Rho signaling has expanded from cultured cells to whole biological systems...
May 10, 2018: FEBS Letters
https://www.readbyqxmd.com/read/29746086/activation-of-rho-family-gtpases-by-small-molecules
#7
Charuta C Palsuledesai, Zurab Surviladze, Anna Waller, T Fabiola Miscioscia, Yuna Guo, Yang Wu, Jake Strouse, Elsa Romero, Virginia M Salas, Ramona Curpan, Susan Young, Mark Carter, Terry Foutz, Zhanna Galochkina, Harold Ames, Mark K Haynes, Bruce S Edwards, Orazio Nicolotti, Li Luo, Oleg Ursu, Cristian G Bologa, Tudor I Oprea, Angela Wandinger-Ness, Larry A Sklar
Ras and Ras-related small GTPases are key regulators of diverse cellular functions that impact cell growth, survival, motility, morphogenesis and differentiation. They are important targets for studies of disease mechanisms as well as drug discovery. Here, we report the characterization of small molecule agonists of one or more of six Rho, Rab and Ras family GTPases that were first identified through flow cytometry based, multi-plexed high throughput screening of 200,000 compounds. The activators were categorized into three distinct chemical families that are represented by three lead compounds having the highest activity...
May 10, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29746010/rho-kinase-rock-collaborates-with-pak-to-regulate-actin-polymerization-and-contraction-in-airway-smooth-muscle
#8
Wenwu Zhang, Bhupal P Bhetwal, Susan J Gunst
KEY POINTS: The mechanisms by which Rho kinase (ROCK) regulates airway smooth muscle contraction were determined in tracheal smooth muscle tissues. ROCK may mediate smooth muscle contraction by inhibiting myosin regulatory light chain (RLC) phosphatase. ROCK can also regulate F-actin dynamics during cell migration, and actin polymerization is critical for airway smooth muscle contraction. Our results show that ROCK does not regulate airway smooth muscle contraction by inhibiting myosin RLC phosphatase or by stimulating myosin RLC phosphorylation...
May 10, 2018: Journal of Physiology
https://www.readbyqxmd.com/read/29743277/small-gtpase-dependent-regulation-of-leukocyte-endothelial-interactions-in-inflammation
#9
REVIEW
Julia Y Chu, Barry McCormick, Sonja Vermeren
Inflammation is a complex biological response that serves to protect the body's tissues following harmful stimuli such as infection, irritation or injury and initiates tissue repair. At the start of an inflammatory response, pro-inflammatory mediators induce changes in the endothelial lining of the blood vessels and in leukocytes. This results in increased vascular permeability and increased expression of adhesion proteins, and promotes adhesion of leukocytes, especially neutrophils to the endothelium. Adhesion is a prerequisite for neutrophil extravasation and chemoattractant-stimulated recruitment to inflammatory sites, where neutrophils phagocytose and kill microbes, release inflammatory mediators and cross-talk with other immune cells to co-ordinate the immune response in preparation for tissue repair...
May 9, 2018: Biochemical Society Transactions
https://www.readbyqxmd.com/read/29738516/the-bacterial-toxin-cnf1-induces-activation-and-maturation-of-human-monocyte-derived-dendritic-cells
#10
Laura Gall-Mas, Alessia Fabbri, Martin R J Namini, Michael Givskov, Carla Fiorentini, Thorbjørn Krejsgaard
Cytotoxic necrotizing factor 1 (CNF1) is a bacterial protein toxin primarily expressed by pathogenic Escherichia coli strains, causing extraintestinal infections. The toxin is believed to enhance the invasiveness of E. coli by modulating the activity of Rho GTPases in host cells, but it has interestingly also been shown to promote inflammation, stimulate host immunity and function as a potent immunoadjuvant. The mechanisms underlying the immunostimulatory properties of CNF1 are, however, poorly characterized, and little is known about the direct effects of the toxin on immune cells...
May 8, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29734338/rit1-controls-actin-dynamics-via-complex-formation-with-rac1-cdc42-and-pak1
#11
Uta Meyer Zum Büschenfelde, Laura Isabel Brandenstein, Leonie von Elsner, Kristina Flato, Tess Holling, Martin Zenker, Georg Rosenberger, Kerstin Kutsche
RIT1 belongs to the RAS family of small GTPases. Germline and somatic RIT1 mutations have been identified in Noonan syndrome (NS) and cancer, respectively. By using heterologous expression systems and purified recombinant proteins, we identified the p21-activated kinase 1 (PAK1) as novel direct effector of RIT1. We found RIT1 also to directly interact with the RHO GTPases CDC42 and RAC1, both of which are crucial regulators of actin dynamics upstream of PAK1. These interactions are independent of the guanine nucleotide bound to RIT1...
May 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29733372/cnf1-like-deamidase-domains-common-lego-bricks-among-cancer-promoting-immunomodulatory-bacterial-virulence-factors
#12
Mengfei Ho, Amel Mettouchi, Brenda A Wilson, Emmanuel Lemichez
Alterations of the cellular proteome over time due to spontaneous or toxin-mediated enzymatic deamidation of glutamine (Gln) and asparagine (Asn) residues contribute to bacterial infection and might represent a source of aging-related diseases. Here, we put into perspective what is known about the mode of action of the CNF1 toxin from pathogenic E. coli, a paradigm of bacterial deamidases that activate Rho GTPases, to illustrate the importance of determining whether exposure to these factors are risk factors in the etiology age-related diseases, such as cancer...
May 3, 2018: Pathogens and Disease
https://www.readbyqxmd.com/read/29730655/tumor-suppressive-role-of-arhgap17-in-colon-cancer-through-wnt-%C3%AE-catenin-signaling
#13
Shengli Pan, Yingying Deng, Jun Fu, Yuhao Zhang, Zhijin Zhang, Xiaokun Ru, Xianju Qin
BACKGROUND/AIMS: A few Rho GTPase activating proteins (RhoGAPs) have been identified as tumor suppressors in a variety of human cancers. ARHGAP17, a member of RhoGAPs, has been reported to be involved in the maintenance of tight junction and epithelial barrier. The present study aimed to explore its expression in colon cancer and the possible function in colonic carcinogenesis. METHODS: The mRNA and protein expression was assessed by realtime PCR and immunoblotting, respectively...
April 28, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29728601/publisher-correction-direct-multiplex-imaging-and-optogenetics-of-rho-gtpases-enabled-by-near-infrared-fret
#14
Daria M Shcherbakova, Natasha Cox Cammer, Tsipora M Huisman, Vladislav V Verkhusha, Louis Hodgson
In the version of this article originally published, the values for time shown on the x axis of Figure 5c were incorrect. The error has been corrected in all versions of the paper.
May 4, 2018: Nature Chemical Biology
https://www.readbyqxmd.com/read/29720560/targeting-the-mevalonate-pathway-suppresses-vhl-deficient-cc-rcc-through-a-hif-dependent-mechanism
#15
Jordan M Thompson, Alejandro Alvarez, Monika K Singha, Matthew W Pavesic, Quy H Nguyen, Luke J Nelson, David A Fruman, Olga V Razorenova
Clear Cell Renal Cell Carcinoma (CC-RCC) is a devastating disease with limited therapeutic options available for advance stages. The objective of this study was to investigate HMG-CoA Reductase inhibitors, also known as statins, as potential therapeutics for CC-RCC. Importantly, treatment with statins was found to be synthetically lethal with the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in 90% of CC-RCC driving the disease. This effect has been confirmed in three different CC-RCC cell lines with three different lipophilic statins...
May 2, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29707151/high-levels-of-circulating-endothelial-progenitor-cells-in-patients-with-diabetic-retinopathy-are-positively-associated-with-arhgap22-expression
#16
Yu-Chuen Huang, Wen-Ling Liao, Jane-Ming Lin, Ching-Chu Chen, Shih-Ping Liu, Shih-Yin Chen, Yu-Ning Lin, Yu-Jie Lei, Huan-Ting Liu, Yu-Jen Chen, Fuu-Jen Tsai
Diabetic retinopathy (DR) is a common microvascular complication of diabetes. Circulating endothelial progenitor cells (EPCs) are derived from bone marrow and are characterized by pathological retinal neovascularization. Rho GTPase Activating Protein 22 ( ARHGAP22 ) is a DR susceptibility gene that interacts with its downstream regulatory protein ras-related C3 botulinum toxin substrate 1 (Rac1), to assist in endothelial cell angiogenesis and increasing capillary permeability. The aim of this study was to elucidate the relationship between ARHGAP22 expression and EPC levels in type 2 diabetes (T2D) patients with DR...
April 3, 2018: Oncotarget
https://www.readbyqxmd.com/read/29706627/the-rho-gtpase-rnd1-inhibits-epithelial-mesenchymal-transition-in-hepatocellular-carcinoma-and-is-a-favorable-anti-metastasis-target
#17
Cheng-Dong Qin, De-Ning Ma, Shi-Zhe Zhang, Ning Zhang, Zheng-Gang Ren, Xiao-Dong Zhu, Qing-An Jia, Zong-Tao Chai, Cheng-Hao Wang, Hui-Chuan Sun, Zhao-You Tang
Rnd1, a member of Rho GTPases, was found to be downregulated in human malignancies and downregulation of Rnd1 promotes tumor invasion via various mechanisms. However, the role of Rnd1 in hepatocellular carcinoma (HCC) progression remains unclear. In this study, our results demonstrated that Rnd1 was downregulated in HCC cells and in human HCC tissues. Low expression of Rnd1 was associated with aggressive clinic-pathologic characteristics, such as vascular invasion, and poor prognosis in patients who underwent curative surgery for HCC...
April 30, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29704149/the-small-gtpase-arf-1-2-is-a-regulator-of-unicellular-tube-formation-in-caenorhabditis-elegans
#18
Eriko Kage-Nakadai, Simo Sun, Satoru Iwata, Sawako Yoshina, Yoshikazu Nishikawa, Shohei Mitani
The membrane trafficking events that regulate unicellular tube formation and maintenance are not well understood. Here, using an RNAi screen, we identified the small GTPase ARF1 homolog ARF-1.2 as a regulator of excretory tube formation in Caenorhabditis elegans. RNAi-mediated knockdown and knockout of the arf-1.2 gene resulted in the formation of large intracellular vacuoles at the growth sites (varicosities) of the excretory canals. arf-1.2 mutant animals were sensitive to hyperosmotic conditions. arf-1.2 RNAi affected the localization of the anion transporter SULP-8, which is expressed in the basal plasma membrane of the excretory canals, but did not affect the expression of SULP-4, which is expressed in the apical membrane...
April 27, 2018: Journal of Physiological Sciences: JPS
https://www.readbyqxmd.com/read/29702701/glycolysis-regulates-pollen-tube-polarity-via-rho-gtpase-signaling
#19
Wei Chen, Pingping Gong, Jingzhe Guo, Hui Li, Ruizi Li, Weiman Xing, Zhenbiao Yang, Yuefeng Guan
As a universal energy generation pathway utilizing carbon metabolism, glycolysis plays an important housekeeping role in all organisms. Pollen tubes expand rapidly via a mechanism of polarized growth, known as tip growth, to deliver sperm for fertilization. Here, we report a novel and surprising role of glycolysis in the regulation of growth polarity in Arabidopsis pollen tubes via impingement of Rho GTPase-dependent signaling. We identified a cytosolic phosphoglycerate kinase (pgkc-1) mutant with accelerated pollen germination and compromised pollen tube growth polarity...
April 27, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29702193/mir-19a-mediated-downregulation-of-rhob-inhibits-the-dephosphorylation-of-akt1-and-induces-osteosarcoma-cell-metastasis
#20
Qingping Zou, Xin Xiao, Ying Liang, Lina Peng, Zheng Guo, Wei Li, Wenqiang Yu
Osteosarcoma is a primary malignancy that develops in bone, along with serious recurrence and metastasis. As an isoform of Rho family GTPases, RhoB could suppress cell proliferation, invasion, and anti-angiogenesis. But it is not clear how RhoB involves in tumor metastasis. Here we found that expression of RhoB was decreased in osteosarcoma primary samples and cell lines. Ectopic expression of RhoB restrains the migration of osteosarcoma cells in vitro and in vivo, and induces osteosarcoma cell apopotsis. Further study showed that RhoB could interact with B55, increase the proportion of B55 in PP2A complex, and then enhance the dephosphorylation of AKT1...
April 24, 2018: Cancer Letters
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