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Claudin-2: Roles Beyond Permeability Functions
International Journal of Molecular Sciences Review Claudin-2: Roles beyond Permeability Functions Shruthi Venugopal, Shaista Anwer and Katalin Szászi * Keenan Research Centre for Biomedical Science of the St. Michael’s Hospital and Department of Surgery, University of Toronto, Toronto, ON M5B 1W8, Canada; [email protected] (S.V.); [email protected] (S.A.) * Correspondence: [email protected]; Tel.: +1-416-8471752 Received: 13 October 2019; Accepted: 9 November 2019; Published: 12 November 2019 Abstract: Claudin-2 is expressed in the tight junctions of leaky epithelia, where it forms cation-selective and water permeable paracellular channels. Its abundance is under fine control by a complex signaling network that affects both its synthesis and turnover in response to various environmental inputs. Claudin-2 expression is dysregulated in many pathologies including cancer, inflammation, and fibrosis. Claudin-2 has a key role in energy-efficient ion and water transport in the proximal tubules of the kidneys and in the gut. Importantly, strong evidence now also supports a role for this protein as a modulator of vital cellular events relevant to diseases. Signaling pathways that are overactivated in diseases can alter claudin-2 expression, and a good correlation exists between disease stage and claudin-2 abundance. Further, loss- and gain-of-function studies showed that primary changes in claudin-2 expression impact vital cellular processes such as proliferation, migration, and cell fate determination. These effects appear to be mediated by alterations in key signaling pathways. The specific mechanisms linking claudin-2 to these changes remain poorly understood, but adapters binding to the intracellular portion of claudin-2 may play a key role. -
4 Mechanics of the Cytoskeleton
4 Mechanics of the cytoskeleton 4.1 Motivation In the previous section, we have seen how biopolymers dynamically assemble and dis- assemble during polymerization. We have discussed the individual mechanical prop- erties such as Young’s modulus E, the axial stiffness EA, the bending stiffness EI, and the persistence length A for individual filaments. In particular, have talked about actin filaments, intermediate filaments, and microtubules. Now, assuming we know the me- chanical properties of the individual filaments, what does that actually tell us about the assembly of filaments that we find in the cell? Or, to put it differently, if we knew elements of the cytoskeleton microtubules intermediate filaments actin filaments Figure 4.1: The cytoskeleton provides structural stability and is responsible for forces during cell loco- motion. Microtubules are thick hollow cylinders reaching out from the nucleus to the membrane, inter- mediate filaments can be found anywhere in the cytosol, and actin filaments are usually concentrated close to the cell membrane. the structural arrangement of filaments, could we then predict the stiffness of the over- all assembly? How does the filament microstructure affect cytoskeletal properties? Or, more precisely, how can we calculate the macroscopic network properties from the in- dividual microscopic filament properties? In mechanics, the derivation of macroscopic parameters based on microscopic considerations is referred to as homogenization. In this chapter, we illustrate the homogenization by means of three different examples, the fiber bundle model for filopodia, the network model for red blood cell membranes, and the tensegrity model for generic cell structures. 4.2 Fiber bundle model for filopodia Filopodia are thin dynamic cytoplasmic projections composed of tight bundles of long actin filaments extending from the leading edge of migrating cells. -
Computational Modeling of Claudin Structure and Function
International Journal of Molecular Sciences Review Computational Modeling of Claudin Structure and Function Shadi Fuladi 1, Ridaka-Wal Jannat 1 , Le Shen 2,3 , Christopher R. Weber 2,* and Fatemeh Khalili-Araghi 1,* 1 Department of Physics, University of Illinois at Chicago, Chicago, IL 60607, USA; [email protected] (S.F.); [email protected] (R.-W.J.) 2 Department of Pathology, University of Chicago, Chicago, IL 60637, USA; [email protected] 3 Department of Surgery, University of Chicago, Chicago, IL 60637, USA * Correspondence: [email protected] (C.R.W.); [email protected] (F.K.-A.) Received: 15 December 2019; Accepted: 16 January 2020; Published: 23 January 2020 Abstract: Tight junctions form a barrier to control passive transport of ions and small molecules across epithelia and endothelia. In addition to forming a barrier, some of claudins control transport properties of tight junctions by forming charge- and size-selective ion channels. It has been suggested claudin monomers can form or incorporate into tight junction strands to form channels. Resolving the crystallographic structure of several claudins in recent years has provided an opportunity to examine structural basis of claudins in tight junctions. Computational and theoretical modeling relying on atomic description of the pore have contributed significantly to our understanding of claudin pores and paracellular transport. In this paper, we review recent computational and mathematical modeling of claudin barrier function. We focus on dynamic modeling of global epithelial barrier function as a function of claudin pores and molecular dynamics studies of claudins leading to a functional model of claudin channels. Keywords: claudin; molecular dynamics; tight junction; ion transport; ion channel 1. -
Defenders and Challengers of Endothelial Barrier Function
REVIEW published: 18 December 2017 doi: 10.3389/fimmu.2017.01847 Defenders and Challengers of Endothelial Barrier Function Nader Rahimi* Department of Pathology, Boston University School of Medicine, Boston, MA, United States Regulated vascular permeability is an essential feature of normal physiology and its dysfunction is associated with major human diseases ranging from cancer to inflam- mation and ischemic heart diseases. Integrity of endothelial cells also play a prominent role in the outcome of surgical procedures and organ transplant. Endothelial barrier function and integrity are regulated by a plethora of highly specialized transmembrane receptors, including claudin family proteins, occludin, junctional adhesion molecules (JAMs), vascular endothelial (VE)-cadherin, and the newly identified immunoglobulin (Ig) and proline-rich receptor-1 (IGPR-1) through various distinct mechanisms and signaling. On the other hand, vascular endothelial growth factor (VEGF) and its tyrosine kinase receptor, VEGF receptor-2, play a central role in the destabilization of endothelial barrier function. While claudins and occludin regulate cell–cell junction via recruitment of zonula occludens (ZO), cadherins via catenin proteins, and JAMs via ZO and afadin, IGPR-1 recruits bullous pemphigoid antigen 1 [also called dystonin (DST) and SH3 protein inter- Edited by: acting with Nck90/WISH (SH3 protein interacting with Nck)]. Endothelial barrier function Thomas Luft, is moderated by the function of transmembrane receptors and signaling events that act University Hospital Heidelberg, Germany to defend or destabilize it. Here, I highlight recent advances that have provided new Reviewed by: insights into endothelial barrier function and mechanisms involved. Further investigation Luiza Guilherme, of these mechanisms could lead to the discovery of novel therapeutic targets for human University of São Paulo, Brazil diseases associated with endothelial dysfunction. -
Of Polarity Ups and Downs of Guided Vessel Sprouting
Ups and Downs of Guided Vessel Sprouting: The Role of Polarity Christina Y. Lee and Victoria L. Bautch Physiology 26:326-333, 2011. doi:10.1152/physiol.00018.2011 You might find this additional info useful... This article cites 82 articles, 38 of which can be accessed free at: /content/26/5/326.full.html#ref-list-1 This article has been cited by 2 other HighWire hosted articles Rasip1 regulates vertebrate vascular endothelial junction stability through Epac1-Rap1 signaling Christopher W. Wilson, Leon H. Parker, Christopher J. Hall, Tanya Smyczek, Judy Mak, Ailey Crow, George Posthuma, Ann De Mazière, Meredith Sagolla, Cecile Chalouni, Philip Vitorino, Merone Roose-Girma, Søren Warming, Judith Klumperman, Philip S. Crosier and Weilan Ye Blood, November 21, 2013; 122 (22): 3678-3690. [Abstract] [Full Text] [PDF] Cas and NEDD9 Contribute to Tumor Progression through Dynamic Regulation of the Cytoskeleton Michael S. Guerrero, J. Thomas Parsons and Amy H. Bouton Genes & Cancer, May , 2012; 3 (5-6): 371-381. [Abstract] [Full Text] [PDF] Downloaded from Updated information and services including high resolution figures, can be found at: /content/26/5/326.full.html Additional material and information about Physiology can be found at: http://www.the-aps.org/publications/physiol on August 25, 2014 This information is current as of August 25, 2014. Physiology (formerly published as News in Physiological Science) publishes brief review articles on major physiological developments. It is published bimonthly in February, April, June, August, October, and December by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright © 2011 by the American Physiological Society. -
Adherens Junctions, Desmosomes and Tight Junctions in Epidermal Barrier Function Johanna M
14 The Open Dermatology Journal, 2010, 4, 14-20 Open Access Adherens Junctions, Desmosomes and Tight Junctions in Epidermal Barrier Function Johanna M. Brandner1,§, Marek Haftek*,2,§ and Carien M. Niessen3,§ 1Department of Dermatology and Venerology, University Hospital Hamburg-Eppendorf, Hamburg, Germany 2University of Lyon, EA4169 Normal and Pathological Functions of Skin Barrier, E. Herriot Hospital, Lyon, France 3Department of Dermatology, Center for Molecular Medicine, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany Abstract: The skin is an indispensable barrier which protects the body from the uncontrolled loss of water and solutes as well as from chemical and physical assaults and the invasion of pathogens. In recent years several studies have suggested an important role of intercellular junctions for the barrier function of the epidermis. In this review we summarize our knowledge of the impact of adherens junctions, (corneo)-desmosomes and tight junctions on barrier function of the skin. Keywords: Cadherins, catenins, claudins, cell polarity, stratum corneum, skin diseases. INTRODUCTION ADHERENS JUNCTIONS The stratifying epidermis of the skin physically separates Adherens junctions are intercellular structures that couple the organism from its environment and serves as its first line intercellular adhesion to the cytoskeleton thereby creating a of structural and functional defense against dehydration, transcellular network that coordinate the behavior of a chemical substances, physical insults and micro-organisms. population of cells. Adherens junctions are dynamic entities The living cell layers of the epidermis are crucial in the and also function as signal platforms that regulate formation and maintenance of the barrier on two different cytoskeletal dynamics and cell polarity. -
Myth4-FERM Myosin Based Filopodia Initiation
MyTH4-FERM Myosin based filopodia initiation A DISSERTATION SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL OF THE UNIVERSITY OF MINNESOTA BY Ashley L. Arthur IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY Margaret A. Titus, PhD ADVISOR July 2020 © Ashley L Arthur 2020 ACKNOWLEDGEMENTS I would first and foremost like to advisor my mentor, Dr. Margaret Titus, for her unassailable commitment to training, enthusiasm for science and her sup- port of my career. Meg has been superb advisor, has made me a better scientist and communicator and I genuinely enjoyed working for her. I am grateful for the long list of positive experiences and opportunities I gained while working in the Titus lab. I would like to thank all of my past and present lab mates. Thank you to Hilary Bauer, Sinzi Cornea and Zoe Henrot for welcoming me into the lab when I started and especially to Karl Petersen who share his imaging and analysis ex- pertise. I am so grateful for the help and from my PLA project teammate Livia Songster, you brought such great energy to the project and to the lab. Thanks Casey Eddington, Annika Schroeder for their support, encouragement and help reading and discussing many aspect of this work. Thanks to the University of MN undergraduate students who joined my on research projects over the years espe- cially to Himanshu Jain. I would like to thank Jordan Beach at Loyola, Guillermo Marques, Mark Sanders, for their help with imaging. I thank Ashim Rai for his as- sistance with motor purification and motility assays. -
Tight Junction-Based Epithelial Microenvironment and Cell Proliferation
Oncogene (2008) 27, 6930–6938 & 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $32.00 www.nature.com/onc REVIEW Tight junction-based epithelial microenvironment and cell proliferation S Tsukita1, Y Yamazaki, T Katsuno, A Tamura and S Tsukita2 Laboratory of Biological Science, Graduate School of Frontier Biosciences/Graduate School of Medicine, Osaka University, Suita, Osaka, Japan Belt-like tight junctions (TJs), referred to as zonula bodies of multicellular organisms. The sheet-like divi- occludens, have long been regarded as a specialized sions allow diffusion barrier formation and selective differentiation of epithelial cell membranes. They are permeation of substances and ions (permselectivity), required for cell adhesion and paracellular barrier func- both excluding unnecessary or toxic molecules and tions, and are now thought to be partly involved in fence including necessary components to maintain home- functions and in cell polarization. Recently, the molecular ostasis. The combination of the belt-like adherens bases of TJs have gradually been unveiled. TJs are junctions (AJs) and tight junctions (TJs) have important constructed by TJ strands, whose basic frameworks are functions in the formation of epithelial cell sheets and composed of integral membrane proteins with four also in the formation of paracellular permselective transmembrane domains, designated claudins. The claudin barriers through their functions as septa (Mitic and family is supposedly composed of at least 24 members in Anderson, 1998; Tsukita and Furuse, 1999; Hartsock mice and humans. Other types of integral membrane and Nelson, 2008). Paracellular barrier functions with proteins with four transmembrane domains, namely occlu- permselectivity are unique to the epithelial cell system din and tricellulin, as well as the single transmembrane and regulate the internal homeostasis of ions and solutes proteins, JAMs (junctional adhesion molecules)and CAR in the body. -
Dynamics of Thin Filopodia During Sea Urchin Gastrulation
Development 121, 2501-2511 (1995) 2501 Printed in Great Britain © The Company of Biologists Limited 1995 Dynamics of thin filopodia during sea urchin gastrulation Jeffrey Miller1, Scott E. Fraser2 and David McClay1,* 1Developmental, Cell and Molecular Biology, Duke University, SRC, Box 91000, Durham, NC 27708, USA 2Division of Biology, Beckman Institute (139-74), California Institute of Technology, Pasadena CA 91125, USA *Author for correspondence: e-mail [email protected] SUMMARY At gastrulation in the sea urchin embryo, a dramatic involvement in cell-cell interactions associated with rearrangement of cells establishes the three germ layers of signaling and patterning at gastrulation. Nickel-treatment, the organism. Experiments have revealed a number of cell which is known to create a patterning defect in skeleto- interactions at this stage that transfer patterning informa- genesis due to alterations in the ectoderm, alters the normal tion from cell to cell. Of particular significance, primary position-dependent differences in the thin filopodia. The mesenchyme cells, which are responsible for production of effect is present in recombinant embryos in which the the embryonic skeleton, have been shown to obtain ectoderm alone was treated with nickel, and is absent in extensive positional information from the embryonic recombinant embryos in which only the primary mes- ectoderm. In the present study, high resolution Nomarski enchyme cells were treated, suggesting that the filopodial imaging reveals the presence of very thin filopodia (0.2-0.4 length is substratum dependent rather than being primary µm in diameter) extending from primary mesenchyme cells mesenchyme cell autonomous. The thin filopodia provide a as well as from ectodermal and secondary mesenchyme means by which cells can contact others several cell cells. -
002 Sempozyum1 5 SON.Qxd
Abstracts www.anatomy.org.tr doi:10.2399/ana.11.001s Abstracts for the Joint Meeting of Anatomical Societies, 19-22 May 2011, Bursa, Turkey Anatomy 2011; 5 Suppl: S1-S171, © 2011 TSACA Opening Lecture New genoarchitectonic viewpoints on the developing hypothalamus Puelles L effects suggests that, rather than being a diencephalic floor ele- ment, the hypothalamus is best understood as a transverse region Department of Human Anatomy, Faculty of lying ventral to the telencephalon and rostral to the dien- Medicine, University of Murcia, Murcia, Spain cephalon; the latter separates it from the midbrain. A number of gene expression patterns observed in the developing forebrain, part of the emergent genoarchitectonic neuroanatomy, have The anatomic concept of the hypothalamus changed consider- revealed the true topologic position of the hypothalamus, as well ably since its earliest definition. Tridimensional reconstructions, as the nature of its fundamental subdivisions. There are interest- experiments and many staining methods have expanded consid- ing parallelisms with genoarchitectonic patterns in the dien- erably the number of anatomical details recognized in this terri- cephalon and midbrain. In all these cases continuous longitudi- tory, probably one of the most complex in the brain. For a long nal domains can be distinguished, as well as a number of antero- time the predominant anatomic view has interpreted the hypo- posterior (transverse) neuromeric units of the neural wall. The thalamus as a longitudinal column at the floor of the dien- hypothalamus has been newly recognized to have two antero- cephalon, connected rostrally with the telencephalon and cau- posterior neuromeric subdivisions, named terminal and pedun- dally with the midbrain. -
An EMT-Primary Cilium-GLIS2 Signaling Axis Regulates Mammogenesis and Claudin-Low Breast Tumorigenesis
bioRxiv preprint doi: https://doi.org/10.1101/2020.12.29.424695; this version posted December 29, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 An EMT-primary cilium-GLIS2 signaling axis regulates mammogenesis 2 and claudin-low breast tumorigenesis 3 4 5 6 7 Molly M. Wilson1, Céline Callens2, Matthieu Le Gallo3,4, Svetlana Mironov2, Qiong Ding5, 8 Amandine Salamagnon2, Tony E. Chavarria1, Abena D. Peasah6, Arjun Bhutkar1, Sophie 9 Martin3,4, Florence Godey3,4, Patrick Tas3,4, Anton M. Jetten8, Jane E. Visvader7, Robert A. 10 Weinberg9, Massimo Attanasio5, Claude Prigent2, Jacqueline A. Lees1, Vincent J Guen2* 11 12 13 14 1Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts 15 Institute of Technology, Cambridge, MA, USA. 16 2Institut de Génétique et Développement de Rennes - Centre National de la Recherche 17 Scientifique, Rennes, France. 18 3INSERM U1242, Rennes 1 University, Rennes, France. 19 4Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France. 20 5Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, 21 USA. 22 6Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 23 USA. 24 7Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research and 25 Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia. 26 8Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health 27 Sciences, National Institutes of Health, Research Triangle Park, NC, USA. 28 9MIT Department of Biology and the Whitehead Institute, Cambridge, MA, USA. -
Functional Integrity of the Contractile Actin Cortex Is Safeguarded by Multiple Diaphanous-Related Formins
Functional integrity of the contractile actin cortex is safeguarded by multiple Diaphanous-related formins Christof Litschkoa,1, Stefan Brühmanna,1, Agnes Csiszárb, Till Stephana, Vanessa Dimchevc,d, Julia Damiano-Guercioa, Alexander Junemanna, Sarah Körbera, Moritz Winterhoffa, Benjamin Nordholza,2, Nagendran Ramalingame, Michelle Peckhamf, Klemens Rottnerc,d, Rudolf Merkelb, and Jan Faixa,3 aInstitute for Biophysical Chemistry, Hannover Medical School, 30625 Hannover, Germany; bInstitute of Complex Systems, ICS-7: Biomechanics, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany; cDivision of Molecular Cell Biology, Zoological Institute, Technische Universität Braunschweig, 38106 Braunschweig, Germany; dMolecular Cell Biology Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; eAnn Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; and fAstbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom Edited by Bruce L. Goode, Brandeis University, Waltham, MA, and accepted by Editorial Board Member Yale E. Goldman January 4, 2019 (received for review December 21, 2018) The contractile actin cortex is a thin layer of filamentous actin, This cortex contains actin, myosin, and associated factors assem- myosin motors, and regulatory proteins beneath the plasma bling into a multicomponent layer (9, 10), which is intimately linked to membrane crucial to cytokinesis, morphogenesis, and cell migra- the membrane in a phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]- tion. However, the factors regulating actin assembly in this dependent manner by the ezrin, radixin, and moesin (ERM) compartment are not well understood. Using the Dictyostelium family of proteins in animal cells (11, 12) and cortexillin (Ctx) in model system, we show that the three Diaphanous-related for- Dictyostelium (13–15).