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https://www.readbyqxmd.com/read/29337666/tuning-of-in-vivo-cognate-b-t-cell-interactions-by-intersectin-2-is-required-for-effective-anti-viral-b-cell-immunity
#1
Marianne Burbage, Francesca Gasparrini, Shweta Aggarwal, Mauro Gaya, Johan Arnold, Usha Nair, Michael Way, Andreas Bruckbauer, Facundo D Batista
Wiskott-Aldrich syndrome (WAS) is an immune pathology associated with mutations in WAS protein (WASp) or in WASp interacting protein (WIP). Together with the small GTPase Cdc42 and other effectors, these proteins participate in the remodelling of the actin network downstream of BCR engagement. Here we show that mice lacking the adaptor protein ITSN2, a G-nucleotide exchange factor (GEF) for Cdc42 that also interacts with WASp and WIP, exhibited increased mortality during primary infection, incomplete protection after Flu vaccination, reduced germinal centre formation and impaired antibody responses to vaccination...
January 16, 2018: ELife
https://www.readbyqxmd.com/read/29321004/rcc2-over-expression-in-tumor-cells-alters-apoptosis-and-drug-sensitivity-by-regulating-rac1-activation
#2
Nan Wu, Dong Ren, Su Li, Wenli Ma, Shaoyan Hu, Yan Jin, Sheng Xiao
BACKGROUND: Small GTP binding protein Rac1 is a component of NADPH oxidases and is essential for superoxide-induced cell death. Rac1 is activated by guanine nucleotide exchange factors (GEFs), and this activation can be blocked by regulator of chromosome condensation 2 (RCC2), which binds the switch regions of Rac1 to prevent access from GEFs. METHODS: Three cancer cell lines with up- or down-regulation of RCC2 were used to evaluate cell proliferation, apoptosis, Rac1 signaling and sensitivity to a group of nine chemotherapeutic drugs...
January 10, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29318657/crystal-structure-of-tetrameric-human-rabin8-gef-domain
#3
Melanie Vetter, Niels Boegholm, Anni Christensen, Sagar Bhogaraju, Marie B Andersen, Anna Lorentzen, Esben Lorentzen
Rab GTPases and their effectors, activators and guanine nucleotide exchange factors (GEFs) are essential for vesicular transport. Rab8 and its GEF Rabin8 function in formation of the cilium organelle important for developmental signaling and sensory reception. Here we show by size exclusion chromatography and analytical ultracentrifugation that Rabin8 exists in equilibrium between dimers and tetramers. The crystal structure of tetrameric Rabin8 GEF domain reveals an occluded Rab8 binding site suggesting that this oligomer is enzymatically inactive, a notion we verify experimentally using Rabin8/Rab8 GEF assays...
January 10, 2018: Proteins
https://www.readbyqxmd.com/read/29314704/use-of-a-novel-embolic-filter-in-carotid-artery-stenting-30-day-results-from-the-embolden-clinical-study
#4
William A Gray, Manish Mehta, Firas Alani, Karthikeshwar Kasirajan, Richard J Begg, J Michael Bacharach, Peter A Soukas
OBJECTIVES: The EMBOLDEN study was conducted to test the safety and efficacy of a novel emboli protection filter design for use in carotid artery stenting (CAS) in patients with severe carotid stenosis who were at high risk of operative complications from carotid endarterectomy (CEA). BACKGROUND: General considerations for filter design usually involve trade-offs between trackability/profile and wall apposition/capture efficiency. The GORE® Embolic Filter (GEF) is intended to address these design goals via a hybrid construction...
January 3, 2018: Catheterization and Cardiovascular Interventions
https://www.readbyqxmd.com/read/29313423/rho-guanosine-nucleotide-exchange-factors-are-not-such-bad-guys-after-all-in-cancera
#5
Javier Robles-Valero, L Francisco Lorenzo-Martín, Isabel Fernández-Pisonero, Xosé R Bustelo
Rho GDP/GTP exchange factors (GEFs), the enzymes that trigger the stimulation of Rho GTPases during cell signaling, are widely deemed as potential therapeutic targets owing to their protumorigenic functions. However, the sparse use of animal models has precluded a full understanding of their pathophysiological roles at the organismal level. In a recent article in Cancer Cell, we have reported that the Vav1 GEF unexpectedly acts as a tumor suppressor by mediating the noncatalytic nucleation of cytoplasmic complexes between the E3 ubiquitin ligase Cbl-b and the active Notch1 intracellular domain (ICN1)...
January 9, 2018: Small GTPases
https://www.readbyqxmd.com/read/29276036/structural-dynamics-control-allosteric-activation-of-cytohesin-family-arf-gtpase-exchange-factors
#6
Andrew W Malaby, Sanchaita Das, Srinivas Chakravarthy, Thomas C Irving, Osman Bilsel, David G Lambright
Membrane dynamic processes including vesicle biogenesis depend on Arf guanosine triphosphatase (GTPase) activation by guanine nucleotide exchange factors (GEFs) containing a catalytic Sec7 domain and a membrane-targeting module such as a pleckstrin homology (PH) domain. The catalytic output of cytohesin family Arf GEFs is controlled by autoinhibitory interactions that impede accessibility of the exchange site in the Sec7 domain. These restraints can be relieved through activator Arf-GTP binding to an allosteric site comprising the PH domain and proximal autoinhibitory elements (Sec7-PH linker and C-terminal helix)...
December 16, 2017: Structure
https://www.readbyqxmd.com/read/29273580/the-two-trapp-complexes-of-metazoans-have-distinct-roles-and-act-on-different-rab-gtpases
#7
Falko Riedel, Antonio Galindo, Nadine Muschalik, Sean Munro
Originally identified in yeast, transport protein particle (TRAPP) complexes are Rab GTPase exchange factors that share a core set of subunits. TRAPPs were initially found to act on Ypt1, the yeast orthologue of Rab1, but recent studies have found that yeast TRAPPII can also activate the Rab11 orthologues Ypt31/32. Mammals have two TRAPP complexes, but their role is less clear, and they contain subunits that are not found in the yeast complexes but are essential for cell growth. To investigate TRAPP function in metazoans, we show that Drosophila melanogaster have two TRAPP complexes similar to those in mammals and that both activate Rab1, whereas one, TRAPPII, also activates Rab11...
December 22, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29246943/tight-junctions-negatively-regulate-mechanical-forces-applied-to-adherens-junctions-in-vertebrate-epithelial-tissue
#8
Guillaume Hatte, Claude Prigent, Jean-Pierre Tassan
Epithelia are layers of polarised cells tightly bound to each other by adhesive contacts. Epithelia act as barriers between an organism and its external environment. Understanding how epithelia maintain their essential integrity while remaining sufficiently plastic to allow events such as cytokinesis to take place is a key biological problem. In vertebrates, the remodelling and reinforcement of adherens junctions maintains epithelial integrity during cytokinesis. The involvement of tight junctions in cell division, however, has remained unexplored...
December 15, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/29242061/phosphorylation-of-ser-525-in-%C3%AE-pix-impairs-nox1-activating-ability-in-caco-2%C3%A2-cells
#9
Yuuki Kaito, Ryosuke Kataoka, Tatsuya Mihara, Kento Takechi, Akira Takahira, Shuhei Watanabe, Fei Han, Minoru Tamura
βPix activates Nox1, an O2--generating NADPH oxidase, through Rac activation. In this study, we found that S525E mutation of βPix eliminated its Nox1-activating ability in transfected Caco-2 cells. Unexpectedly, affinity for Rac was not diminished but rather enhanced by S525E mutation, and guanine nucleotide exchange factor (GEF) activity was not altered. The N-terminal fragment (amino acids 1-400) showed similar Rac-binding and GEF activity to wild-type βPix. In contrast, the C-terminal fragment (amino acids 408-646) had higher Rac-binding activity, particularly for Rac-GTP, than wild-type βPix, and showed no GEF activity...
December 11, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/29233866/rho-gtpase-signaling-complexes-in-cell-migration-and-invasion
#10
REVIEW
Campbell D Lawson, Anne J Ridley
Cell migration is dependent on the dynamic formation and disassembly of actin filament-based structures, including lamellipodia, filopodia, invadopodia, and membrane blebs, as well as on cell-cell and cell-extracellular matrix adhesions. These processes all involve Rho family small guanosine triphosphatases (GTPases), which are regulated by the opposing actions of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Rho GTPase activity needs to be precisely tuned at distinct cellular locations to enable cells to move in response to different environments and stimuli...
December 12, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29208526/larg-gef-and-arhgap18-orchestrate-rhoa-activity-to-control-mesenchymal-stem-cell-lineage
#11
William R Thompson, Sherwin S Yen, Gunes Uzer, Zhihui Xie, Buer Sen, Maya Styner, Keith Burridge, Janet Rubin
The quantity and quality of bone depends on osteoblastic differentiation of mesenchymal stem cells (MSCs), where adipogenic commitment depletes the available pool for osteogenesis. Cell architecture influences lineage decisions, where interfering with cytoskeletal structure promotes adipogenesis. Mechanical strain suppresses MSC adipogenesis partially through RhoA driven enhancement of cytoskeletal structure. To understand the basis of force-driven RhoA activation, we considered critical GEFs (activators) and GAPs (inactivators) on bone marrow MSC lineage fate...
December 2, 2017: Bone
https://www.readbyqxmd.com/read/29208460/ralgps2-is-involved-in-tunneling-nanotubes-formation-in-5637-bladder-cancer-cells
#12
A D'Aloia, G Berruti, B Costa, C Schiller, R Ambrosini, V Pastori, E Martegani, M Ceriani
RalGPS2 is a Ras-independent Guanine Nucleotide Exchange Factor (GEF) for RalA containing a PH domain and an SH3-bindind region and it is involved in several cellular processes, such as cytokinesis, control of cell cycle progression, differentiation, cytoskeleton organization and rearrangement. Up to now, few data have been published regarding RalGPS2 role in cancer cells, and its involvement in bladder cancer is yet to be established. In this paper we demonstrated that RalGPS2 is expressed in urothelial carcinoma-derived 5637 cancer cells and is essential for cellular growth...
December 2, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/29199510/regulation-of-rhoa-gtpase-and-novel-target-proteins-for-rock
#13
Eun-Kyoung Choi, Jae-Gyu Kim, Hee-Jun Kim, Jung-Yoon Cho, Hwalrim Jeong, Yohan Park, Rokibul Islam, Cuong Kim Cap, Jae-Bong Park
Rho GTPases play significant roles in cellular function and their activity is regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), providing activation and inactivation of these GTPases, respectively. Active GTP-bound form of RhoA activates its effector proteins while the inactive GDP-bound form of RhoA exists in a RhoA-RhoGDI (guanine nucleotide dissociation inhibitor) complex in the cytosol. In particular, IκB kinase γ IKKγ/NF-κB essential modulator (NEMO) plays a role as a GDI displacement factor (GDF) for RhoA activation through binding to RhoA-RhoGDI complex...
December 3, 2017: Small GTPases
https://www.readbyqxmd.com/read/29189096/regulation-and-functions-of-rhou-and-rhov
#14
Richard G Hodge, Anne J Ridley
Rho GTPases play central roles in a wide variety of cellular processes, including cytoskeletal dynamics, cell adhesion and cell polarity. RhoU and RhoV are Rho GTPases that have some atypical properties compared with classical Rho family members, such as the presence of N- and C-terminal extension regions, unusual GDP/GTP cycling and post-translational modification by palmitoylation but not prenylation. Their activity and localization is regulated by the N-terminal and C-terminal regions, and so far no GEFs or GAPs have been identified for them...
November 30, 2017: Small GTPases
https://www.readbyqxmd.com/read/29188751/go-with-the-flow-gef-h1-mediated-shear-stress-mechanotransduction-in-neutrophils
#15
Noah Fine, Ioannis D Dimitriou, Robert Rottapel
Neutrophils in circulation experience significant shear forces due to blood flow when they tether to the vascular endothelium. Biochemical and biophysical responses of neutrophils to the physical force of flowing blood modulate their behavior and promote tissue recruitment under pro-inflammatory conditions. Neutrophil mechanotransduction responses occur through mechanisms that are not yet fully understood. In our recent work, we showed that GEF-H1, a RhoA specific guanine nucleotide exchange factor (GEF), is required to maintain neutrophil motility and migration in response to shear stress...
November 30, 2017: Small GTPases
https://www.readbyqxmd.com/read/29184140/induced-cortical-tension-restores-functional-junctions-in-adhesion-defective-carcinoma-cells
#16
Shoko Ito, Satoru Okuda, Masako Abe, Mari Fujimoto, Tetsuo Onuki, Tamako Nishimura, Masatoshi Takeichi
Normal epithelial cells are stably connected to each other via the apical junctional complex (AJC). AJCs, however, tend to be disrupted during tumor progression, and this process is implicated in cancer dissemination. Here, using colon carcinoma cells that fail to form AJCs, we investigated molecular defects behind this failure through a search for chemical compounds that could restore AJCs, and found that microtubule-polymerization inhibitors (MTIs) were effective. MTIs activated GEF-H1/RhoA signaling, causing actomyosin contraction at the apical cortex...
November 28, 2017: Nature Communications
https://www.readbyqxmd.com/read/29184002/a-guanine-nucleotide-exchange-factor-gef-limits-rab-gtpase-driven-membrane-fusion
#17
Lars Langemeyer, Angela Perz, Daniel Kuemmel, Christian Ungermann
The identity of organelles in the endomembrane system of any eukaryotic cell critically depends on the correctly localized Rab GTPase, which binds effectors and thus promotes membrane remodeling or fusion. However, it is still unresolved which factors are required and therefore define the localization of the correct fusion machinery. Using SNARE-decorated proteoliposomes that cannot fuse on their own, we now demonstrate that full fusion activity can be achieved by just four soluble factors: a soluble SNARE (V am7), a guanine nucleotide exchange factor (GEF, Mon1-Ccz1), a Rab- GDP dissociation inhibitor (GDI) complex (prenylated Ypt7:GDI), and a Rab effector complex (HOPS)...
November 28, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29173011/genetic-deletion-of-the-rho-gef-net1-impairs-mouse-macrophage-motility-and-actin-cytoskeletal-organization
#18
Yan Zuo, John d'Aigle, Anjali Chauhan, Jeffrey A Frost
Macrophages are innate immune cells that constantly patrol an organism to fulfill protective and homeostatic roles. Previous studies have shown that Rho GTPase activity is required for macrophage mobility, yet the roles of upstream regulatory proteins controlling Rho GTPase function in these cells are not well defined. Previously we have shown that the RhoA GEF Net1 is required for human breast cancer cell motility and extracellular matrix invasion. To assess the role of Net1 in macrophage motility, we isolated bone marrow macrophage (BMM) precursors from wild type and Net1 knockout mice...
November 26, 2017: Small GTPases
https://www.readbyqxmd.com/read/29172991/characterisation-of-hras-local-signal-transduction-networks-using-engineered-site-specific-exchange-factors
#19
Ana Herrero, Mariana Reis-Cardoso, Iñaki Jiménez-Gómez, Carolanne Doherty, Lorena Agudo-Ibañez, Adán Pinto, Fernando Calvo, Walter Kolch, Piero Crespo, David Matallanas
Ras GTPases convey signals from different types of membranes. At these locations, different Ras isoforms, interactors and regulators generate different biochemical signals and biological outputs. The study of Ras localisation-specific signal transduction networks has been hampered by our inability to specifically activate each of these Ras pools. Here, we describe a new set of site-specific tethered exchange factors, engineered by fusing the RasGRF1 CDC25 domain to sub-localisation-defining cues, whereby Ras pools at specific locations can be precisely activated...
November 26, 2017: Small GTPases
https://www.readbyqxmd.com/read/29168172/extracellular-adenosine-induced-rac1-activation-in-pulmonary-endothelium-molecular-mechanisms-and-barrier-protective-role
#20
Anita Kovacs-Kasa, Kyung Mi Kim, Mary Cherian-Shaw, Stephen M Black, David J Fulton, Alexander D Verin
We have previously shown that Gs-coupled adenosine receptors (A2a) are primarily involved in adenosine-induced human pulmonary artery endothelial cell (HPAEC) barrier enhancement. However, the downstream events that mediate the strengthening of the endothelial cell (EC) barrier via adenosine signaling are largely unknown. In the current study we tested the overall hypothesis that adenosine-induced Rac1 activation and EC barrier enhancement is mediated by Gs-dependent stimulation of cAMP-dependent Epac1-mediated signaling cascades...
November 23, 2017: Journal of Cellular Physiology
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