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Ying Ying Sun, Yong-Feng Yang, Kate E Keller
Purpose: The actin cytoskeleton plays a key role in outflow regulation through the trabecular meshwork (TM). Although actin stress fibers are a target of glaucoma therapies, the role of other actin cellular structures is unclear. Myosin-X (Myo10) is an actin-binding protein that is involved in tunneling nanotube (TNT) and filopodia formation. Here, we inhibited Myo10 pharmacologically or by gene silencing to investigate the role of filopodia/TNTs in the TM. Methods: Short hairpin RNA interference (RNAi) silencing lentivirus targeting myosin-X (shMyo10) was generated...
February 1, 2019: Investigative Ophthalmology & Visual Science
Heather E Miller, Charles L Larson, Robert A Heinzen
Coxiella burnetii is an intracellular bacterium that replicates within an expansive phagolysosome-like vacuole. Fusion between the Coxiella-containing vacuole (CCV) and late endosomes/multivesicular bodies requires Rab7, the HOPS tethering complex, and SNARE proteins, with actin also speculated to play a role. Here, we investigated the importance of actin in CCV fusion. Filamentous actin patches formed around the CCV membrane that were preferred sites of vesicular fusion. Accordingly, the mediators of endolysosomal fusion Rab7, VAMP7, and syntaxin 8 were concentrated in CCV actin patches...
April 2018: PLoS Pathogens
Yuka Yamagishi, Kazumasa Oya, Akira Matsuura, Hiroshi Abe
Two types of Arp2/3 complex inhibitors, CK-666/636 and CK-548/869, are commonly used to study Arp2/3 complex-dependent actin assembly both in vitro and in vivo. However, we found that CK-548 and CK-869 directly suppress microtubule (MT) assembly independent of the actin cytoskeleton. Treatment of cultured mammalian cells with 50 μM CK-869 dramatically decreased MT networks and, instead, accumulated tubulin at the cell periphery, as did nocodazole that inhibits MT assembly. An in vitro MT-sedimentation assay revealed that CK-548 and CK-869 significantly suppressed MT polymerization...
February 12, 2018: Biochemical and Biophysical Research Communications
Patrick Belvitch, Mary E Brown, Brittany N Brinley, Eleftheria Letsiou, Alicia N Rizzo, Joe G N Garcia, Steven M Dudek
Pulmonary endothelial cell (EC) barrier dysfunction and recovery is critical to the pathophysiology of acute respiratory distress syndrome. Cytoskeletal and subsequent cell membrane dynamics play a key mechanistic role in determination of EC barrier integrity. Here, we characterizAQe the actin related protein 2/3 (Arp 2/3) complex, a regulator of peripheral branched actin polymerization, in human pulmonary EC barrier function through studies of transendothelial electrical resistance (TER), intercellular gap formation, peripheral cytoskeletal structures and lamellipodia...
March 2017: Pulmonary Circulation
Sreetama Basu, Irina Kustanovich, Raphael Lamprecht
The actin cytoskeleton is involved in key neuronal functions such as synaptic transmission and morphogenesis. However, the roles and regulation of actin cytoskeleton in memory formation remain to be clarified. In this study, we unveil the mechanism whereby actin cytoskeleton is regulated to form memory by exploring the roles of the major actin-regulatory proteins Arp2/3, VASP, and formins in long-term memory formation. Inhibition of Arp2/3, involved in actin filament branching and neuronal morphogenesis, in lateral amygdala (LA) with the specific inhibitor CK-666 during fear conditioning impaired long-term, but not short-term, fear memory...
November 2016: ENeuro
Tao Zhou, Chen-Han Wang, Hua Yan, Rui Zhang, Jin-Bing Zhao, Chun-Fa Qian, Hong Xiao, Hong-Yi Liu
The Ras-related C3 botulinum toxin substrate 1 (Rac1)-WASP-family verprolin-homologous protein-2 (WAVE2)-actin-related protein 2/3 (Arp2/3) signaling pathway has been identified to be involved in cell migration and invasion in various types of cancer cell. Cofilin‑1 (CFL‑1), which is regulated by the Rac1‑WAVE2‑Arp2/3 signaling pathway, may promote radioresistance in glioma. Therefore, the present study aimed to investigate the potential role of the Rac1‑WAVE2‑Arp2/3 signaling pathway in radioresistance in U251 human glioma cells and elucidate its affect on CFL‑1 expression...
May 2016: Molecular Medicine Reports
Elizabeth M Haynes, Sreeja B Asokan, Samantha J King, Heath E Johnson, Jason M Haugh, James E Bear
The lamellipodium is an important structure for cell migration containing branched actin nucleated via the Arp2/3 complex. The formation of branched actin is relatively well studied, but less is known about its disassembly and how this influences migration. GMF is implicated in both Arp2/3 debranching and inhibition of Arp2/3 activation. Modulation of GMFβ, a ubiquitous GMF isoform, by depletion or overexpression resulted in changes in lamellipodial dynamics, branched actin content, and migration. Acute pharmacological inhibition of Arp2/3 by CK-666, coupled to quantitative live-cell imaging of the complex, showed that depletion of GMFβ decreased the rate of branched actin disassembly...
June 22, 2015: Journal of Cell Biology
Yu M Efremov, A A Dokrunova, A V Efremenko, M P Kirpichnikov, K V Shaitan, O S Sokolova
The actin cytoskeleton is substantially modified in cancer cells because of changes in actin-binding protein abundance and functional activity. As a consequence, cancer cells have distinctive motility and mechanical properties, which are important for many processes, including invasion and metastasis. Here, we studied the effects of actin cytoskeleton alterations induced by specific nucleation inhibitors (SMIFH2, CK-666), cytochalasin D, Y-27632 and detachment from the surface by trypsinization on the mechanical properties of normal Vero and prostate cancer cell line DU145...
November 2015: Biochimica et Biophysica Acta
Abdallah Abu Taha, Muna Taha, Jochen Seebach, Hans-J Schnittler
Maintenance and remodeling of endothelial cell junctions critically depend on the VE-cadherin/catenin complex and its interaction with the actin filament cytoskeleton. Here we demonstrate that local lack of vascular endothelial (VE)-cadherin at established cell junctions causes actin-driven and actin-related protein 2/3 complex (ARP2/3)-controlled lamellipodia to appear intermittently at those sites. Lamellipodia overlap the VE-cadherin-free adjacent plasma membranes and facilitate formation of new VE-cadherin adhesion sites, which quickly move into the junctions, driving VE-cadherin dynamics and remodeling...
January 2014: Molecular Biology of the Cell
Minseon Park, Hyun-Jung Kim, Brian Lim, Adam Wylegala, Michal Toborek
Methamphetamine (METH) is a drug of abuse with neurotoxic and neuroinflammatory effects, which include disruption of the blood-brain barrier (BBB) and alterations of tight junction protein expression. This study focused on the actin cytoskeletal rearrangement as a modulator of METH-induced redistribution of tight junction protein occludin in brain endothelial cells. Exposure to METH resulted in a shift of occludin localization from plasma membranes to endosomes. These changes were accompanied by activation of the actin-related protein 2/3 (Arp2/3) complex, which stimulates actin polymerization by promoting actin nucleation...
November 15, 2013: Journal of Biological Chemistry
Daria V Ilatovskaya, Vladislav Chubinskiy-Nadezhdin, Tengis S Pavlov, Leonid S Shuyskiy, Viktor Tomilin, Oleg Palygin, Alexander Staruschenko, Yuri A Negulyaev
Dynamic remodeling of the actin cytoskeleton plays an essential role in cell migration and various signaling processes in living cells. One of the critical factors that controls the nucleation of new actin filaments in eukaryotic cells is the actin-related protein 2/3 (Arp2/3) complex. Recently, two novel classes of small molecules that bind to different sites on the Arp2/3 complex and inhibit its ability to nucleate F-actin have been discovered and described. The current study aims at investigating the effects of CK-0944666 (CK-666) and its analogs (CK-869 and inactive CK-689) on the reorganization of the actin microfilaments in the cortical collecting duct cell line, M-1...
December 2013: Cell and Tissue Research
Byron Hetrick, Min Suk Han, Luke A Helgeson, Brad J Nolen
Actin-related protein 2/3 (Arp2/3) complex is a seven-subunit assembly that nucleates branched actin filaments. Small molecule inhibitors CK-666 and CK-869 bind to Arp2/3 complex and inhibit nucleation, but their modes of action are unknown. Here, we use biochemical and structural methods to determine the mechanism of each inhibitor. Our data indicate that CK-666 stabilizes the inactive state of the complex, blocking movement of the Arp2 and Arp3 subunits into the activated filament-like (short pitch) conformation, while CK-869 binds to a serendipitous pocket on Arp3 and allosterically destabilizes the short pitch Arp3-Arp2 interface...
May 23, 2013: Chemistry & Biology
Andrew W Baggett, Zoe Cournia, Min Suk Han, George Patargias, Adam C Glass, Shih-Yuan Liu, Brad J Nolen
CK-666 (1) is a recently discovered small-molecule inhibitor of the actin-related protein 2/3 (Arp2/3) complex, a key actin cytoskeleton regulator with roles in bacterial pathogenesis and cancer cell motility. Although 1 is commercially available, the crystal structure of Arp2/3 complex with 1 bound has not been reported, making its mechanism of action uncertain. Furthermore, its relatively low potency increases its potential for off-target effects in vivo, complicating interpretation of its influence in cell biological studies and precluding its clinical use...
July 2012: ChemMedChem
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