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Hiroaki Mizuno, Kotaro Tanaka, Sawako Yamashiro, Akihiro Narita, Naoki Watanabe
The complex interplay between actin regulatory proteins facilitates the formation of diverse cellular actin structures. Formin homology proteins (formins) play an essential role in the formation of actin stress fibers and yeast actin cables, to which the major actin depolymerizing factor cofilin barely associates. In vitro, F-actin decorated with cofilin exhibits a marked increase in the filament twist. On the other hand, a mammalian formin mDia1 rotates along the long-pitch actin helix during processive actin elongation (helical rotation)...
May 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
Ting Yan, Ailiang Zhang, Fangfang Shi, Fei Chang, Jie Mei, Yongjian Liu, Yichao Zhu
The formin protein dishevelled-associated activator of morphogenesis 1 (DAAM1) polymerizes straight actin filaments and mediates migration of cancer cells. However, how DAAM1 governs cell haptotaxis in response to collagen remains unexplored in breast cancer cells. We hypothesized that DAAM1 mediates invadopodia extension and cell haptotaxis in response to type IV collagen in association with integrin receptors. Using Boyden chamber membranes coated with type IV collagen, we show here that type IV collagen activates both DAAM1 and  Ras homolog family member A (RHOA)  and promotes haptotaxis of MDA-MB-231 and MDA-MB-453 breast cancer cells, a process abolished by treatment with the integrin αvβ3 inhibitor cyclo(-RGDfK)...
May 11, 2018: Journal of Biological Chemistry
Shanna K Williams, Zachary P Weiner, Robert D Gilmore
Borrelia burgdorferi, the agent of Lyme borreliosis, can elude hosts' innate and adaptive immunity as part of the course of infection. The ability of B. burgdorferi to invade or be internalized by host cells in vitro has been proposed as a mechanism for the pathogen to evade immune responses or antimicrobials. We have previously shown that B. burgdorferi can be internalized by human neuroglial cells. In this study we demonstrate that these cells take up B. burgdorferi via coiling phagocytosis mediated by the formin, Daam1, a process similarly described for human macrophages...
2018: PloS One
Sarah J Copeland, Andrea McRae, Giulia Guarguaglini, Laura Trinkle-Mulcahy, John W Copeland
A primary cilium is found on most mammalian cells where it acts as a cellular antenna for the reception of both mechanical and chemical signals. A variety of diseases are associated with defective ciliogenesis reflecting the ubiquity of their function and the number of proteins required for cilia assembly. Proper cilia length is necessary for cilia signaling and is regulated through a poorly understood balance of assembly and disassembly rates. FHDC1 is a unique member of the formin family of cytoskeletal regulatory proteins...
May 9, 2018: Molecular Biology of the Cell
Elena Kudryashova, David B Heisler, Blake Williams, Alyssa J Harker, Kyle Shafer, Margot E Quinlan, David R Kovar, Dimitrios Vavylonis, Dmitri S Kudryashov
Delivery of bacterial toxins to host cells is hindered by host protective barriers. This obstruction dictates a remarkable efficiency of toxins, a single copy of which may kill a host cell. Efficiency of actin-targeting toxins is further hampered by an overwhelming abundance of their target. The actin cross-linking domain (ACD) toxins of Vibrio species and related bacterial genera catalyze the formation of covalently cross-linked actin oligomers. Recently, we reported that the ACD toxicity can be amplified via a multivalent inhibitory association of actin oligomers with actin assembly factors formins, suggesting that the oligomers may act as secondary toxins...
April 21, 2018: Current Biology: CB
Yasuhiro Matsunaga, Yuji Sugita
Single-molecule experiments and molecular dynamics (MD) simulations are indispensable tools for investigating protein conformational dynamics. The former provide time-series data, such as donor-acceptor distances, whereas the latter give atomistic information, although this information is often biased by model parameters. Here, we devise a machine-learning method to combine the complementary information from the two approaches and construct a consistent model of conformational dynamics. It is applied to the folding dynamics of the formin-binding protein WW domain...
May 3, 2018: ELife
Osama Refai, Ryan B Smit, SarahBeth Votra, David Pruyne, Paul E Mains
The cytoskeleton is the basic machinery that drives many morphogenetic events. Elongation of the C. elegans embryo from a spheroid into a long, thin larva initially results from actomyosin contractility, mainly in the lateral epidermal seam cells, while the corresponding dorsal and ventral epidermal cells play a more passive role. This is followed by a later elongation phase involving muscle contraction. Early elongation is mediated by parallel genetic pathways involving LET-502/Rho kinase and MEL-11/MYPT myosin phosphatase in one pathway and FEM-2/PP2c phosphatase and PAK-1/p21 activated kinase in another...
May 2, 2018: G3: Genes—Genomes—Genetics
Hunter LeCorgne, Andrew M Tudosie, Kari Lavik, Robin Su, Kathryn N Becker, Sara Moore, Yashna Walia, Alexander Wisner, Daniel Koehler, Arthur S Alberts, Frederick E Williams, Kathryn M Eisenmann
The mammalian Diaphanous-related (mDia) formins are cytoskeletal regulators that assemble and, in some cases, bundle filamentous actin (F-actin), as well as stabilize microtubules. The development of small molecule antagonists and agonists that interrogate mDia formin function has allowed us to investigate the roles of formins in disease states. A small molecule inhibitor of FH2 domain (SMIFH2) inhibits mDia-dependent actin dynamics and abrogates tumor cell migration and cell division in vitro and ex vivo tissue explants...
2018: Frontiers in Pharmacology
Sho Matsuyama, Yohko Kage, Noriko Fujimoto, Tomoki Ushijima, Toshihiro Tsuruda, Kazuo Kitamura, Akira Shiose, Yujiro Asada, Hideki Sumimoto, Ryu Takeya
Mutations in cardiac myosin-binding protein C (cMyBP-C) are a major cause of familial hypertrophic cardiomyopathy. Although cMyBP-C has been considered to regulate the cardiac function via cross-bridge arrangement at the C-zone of the myosin-containing A-band, the mechanism by which cMyBP-C functions remains unclear. We identified formin Fhod3, an actin organizer essential for the formation and maintenance of cardiac sarcomeres, as a cMyBP-C-binding protein. The cardiac-specific N-terminal Ig-like domain of cMyBP-C directly interacts with the cardiac-specific N-terminal region of Fhod3...
April 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
Claudia Hinze, Emmanuel Boucrot
Extracellular macromolecules, pathogens and cell surface proteins rely on endocytosis to enter cells. Key steps of endocytic carrier formation are cargo molecule selection, plasma membrane folding and detachment from the cell surface. While dedicated proteins mediate each step, the actin cytoskeleton contributes to all. However, its role can be indirect to the actual molecular events driving endocytosis. Here, we review our understanding of the molecular steps mediating local actin polymerization during the formation of endocytic carriers...
April 20, 2018: Biochemical Society Transactions
Olga Ossipova, Ryan Kerney, Jean-Pierre Saint-Jeannet, Sergei Y Sokol
The neural crest (NC) multipotent progenitor cells form at the neural plate border and migrate to diverse locations in the embryo to differentiate into many cell types. NC is specified by several embryonic pathways, however the role of noncanonical Wnt signaling in this process remains poorly defined. Daam1 is a formin family protein that is present in embryonic ectoderm at the time of NC formation and can mediate noncanonical Wnt signaling. Our interference experiments indicated that Daam1 is required for NC gene activation...
April 19, 2018: Genesis: the Journal of Genetics and Development
Manish K Rana, Francesca M Aloisio, Changhoon Choi, Diane L Barber
The role of distinct actin filaments architectures in epithelial plasticity remains incompletely understood. We, therefore, determined roles for formins and the Arp2/3 complex, which are actin nucleators generating unbranched and branched actin filaments, respectively, in the process of epithelial to mesenchymal transition (EMT). In clonal lung, mammary and renal epithelial cells, the formin activity inhibitor SMIFH2 but not the Arp2/3 complex activity inhibitor CK666 blocked EMT induced by TGF-β. SMIFH2 prevented the proximal signal of increased Smad2 phosphorylation, and hence also blocked downstream EMT markers, including actin filament remodeling, decreased expression of the adherens junction protein E-cadherin and increased expression of the matrix protein fibronectin and the transcription factor Snail...
April 18, 2018: Molecular Biology of the Cell
Gewei Lian, Anjen Chenn, Victor Ekuta, Sneha Kanaujia, Volney Sheen
Although neural progenitor proliferation along the ventricular zone is regulated by β-catenin through Wnt signaling, the cytoskeletal mechanisms that regulate expression and localization of these proteins are not well understood. Our prior studies have shown that loss of the actin-binding Filamin A (FlnA) and actin-nucleating protein Formin 2 (Fmn2) impairs endocytosis of low-density-lipoprotein-receptor-related protein 6 (Lrp6), thereby disrupting β-catenin activation, resulting in decreased brain size. Here, we report that activated RhoA-GTPase disengages Fmn2 N- to C-terminal binding to promote Fmn2 activation and redistribution into lysosomal vesicles...
April 5, 2018: Cerebral Cortex
Prabhat Suman, Sarthak Mishra, Harish Chander
Metastatic spread of the cancer is usually the consequence of the activation of signaling pathways that generate cell motility and tissue invasion. Metastasis involves the reorganization of cytoskeleton and cell shape for the swift movement of the cells through extracellular matrix. Previously, we have described the invasive and metastatic role played by one of the members (Toca-1) of CIP4 subfamily of F-BAR proteins. In the present study, we address the role of another member (FBP17) of same family in the invasion breast cancer cells...
April 12, 2018: Medical Oncology
Lin Li, Huabao Liu, Xiaoyu Hu, Yi Huang, Yanan Wang, Yansha He, Qingsong Lei
Due to economic development and lifestyle changes, the incidence of non‑alcoholic fatty liver disease (NAFLD) has gradually increased in recent years. However, the pathogenesis of NAFLD is not yet fully understood. To identify candidate genes that contribute to the development and progression of NAFLD, two microarray datasets were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified and functional enrichment analyses were performed. A protein‑protein interaction network was constructed and modules were extracted using the Search Tool for the Retrieval of Interacting Genes and Cytoscape...
April 5, 2018: Molecular Medicine Reports
Kaitlyn M Dvorak, Krista M Pettee, Kaitlin Rubinic-Minotti, Robin Su, Andrea Nestor-Kalinoski, Kathryn M Eisenmann
The tumor microenvironment (TME) promotes tumor cell invasion and metastasis. An important step in the shift to a pro-cancerous microenvironment is the transformation of normal stromal fibroblasts to carcinoma-associated fibroblasts (CAFs). CAFs are present in a majority of solid tumors and can directly promote tumor cell motility via cytokine, chemokine and growth factor secretion into the TME. The exact effects that the TME has upon cytoskeletal regulation in motile tumor cells remain enigmatic. The conserved formin family of cytoskeleton regulating proteins plays an essential role in the assembly and/or bundling of unbranched actin filaments...
2018: PloS One
Adrian Drazic, Henriette Aksnes, Michaël Marie, Malgorzata Boczkowska, Sylvia Varland, Evy Timmerman, Håvard Foyn, Nina Glomnes, Grzegorz Rebowski, Francis Impens, Kris Gevaert, Roberto Dominguez, Thomas Arnesen
Actin, one of the most abundant proteins in nature, participates in countless cellular functions ranging from organelle trafficking and pathogen motility to cell migration and regulation of gene transcription. Actin's cellular activities depend on the dynamic transition between its monomeric and filamentous forms, a process exquisitely regulated in cells by a large number of actin-binding and signaling proteins. Additionally, several posttranslational modifications control the cellular functions of actin, including most notably N-terminal (Nt)-acetylation, a prevalent modification throughout the animal kingdom...
March 26, 2018: Proceedings of the National Academy of Sciences of the United States of America
Gang Li, Xiujuan Yang, Xiaoqing Zhang, Yu Song, Wanqi Liang, Dabing Zhang
For successful fertilization in angiosperms, rapid tip growth in pollen tubes delivers the male gamete into the ovules. The actin-binding protein (ABP)-mediated organization of the actin cytoskeleton within the pollen tube plays a crucial role in this polarized process. However, the mechanism underlying the polarity of the actin filament (F-actin) array and behaviors in pollen tube growth remain largely unknown. Here, we demonstrate that an actin-organizing protein, Rice Morphology Determinant (RMD), a type II formin from rice (Oryza sativa), controls pollen tube growth by modulating the polarity and distribution of the F-actin array...
March 26, 2018: Plant Physiology
Hanna Grobe, Andrea Wüstenhagen, Christian Baarlink, Robert Grosse, Katharina Grikscheit
De novo formation of epithelial cell-cell contacts relies on actin-based protrusions as well as tightly controlled turnover of junctional actin once cells encounter each other and adhesion complexes assemble. The specific contributions of individual actin regulators on either protrusion formation or junctional actin turnover remain largely unexplored. Based on our previous findings of Formin-like 2 (FMNL2)-mediated control of junctional actin dynamics, we investigated its potential role in membrane protrusions and impact on newly forming epithelial contacts...
2018: PloS One
Massimo Venditti, Chiara Fasano, Alessandra Santillo, Francesco Aniello, Sergio Minucci
Dishevelled-associated activator of morphogenesis 1 (DAAM1) is a protein belonging to the formin family, which regulates, together with the small GTPase RhoA, the nucleation and the assembly of actin fibres through Wnt-Dishevelled PCP pathway. Its role has been investigated in essential biological processes, such as cell polarity, movement and adhesion during morphogenesis and organogenesis. In this work, we studied the expression of DAAM1 mRNA and protein by PCR and Western blot analyses and its co-localization with actin in adult mouse seminal vesicles by immunofluorescence...
March 20, 2018: Comptes Rendus Biologies
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