DOCSLIB.ORG

Understanding Tight Junction Clinical Physiology at the Molecular Level

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Understanding Tight Junction Clinical Physiology at the Molecular Level Understanding tight junction clinical physiology at the molecular level Bruce R. Stevenson J Clin Invest. 1999;104(1):3-4. https://doi.org/10.1172/JCI7599. Commentary A century of investigation has led to a reasonable understanding of the role the tight junction (zonula occludens) plays in epithelial physiology (1, 2). This intercellular junction forms a regulated, semipermeable barrier in the spaces between epithelial and endothelial cells (the paracellular space). It also acts as a fence, delimiting the compositionally distinct apical and basolateral plasma membrane domains characteristic of these cell types. Both the barrier and fence functions, in conjunction with transcellular vectorial transport processes, permit the establishment of unique environments in opposing compartments separated by epithelial cell sheets. Interaction and exchange between these environments is critical to normal organ biology. Moreover, integrity of compartmental boundaries is key to protecting an organism from noxious agents present in the outside world. Our knowledge of the molecules that make up the tight junction is less developed, dating back slightly over a decade. While we are aware of 9 peripheral and 3 integral membrane proteins (Table 1), we have only just started to obtain isolated and limited information on the possible functions of individual molecules (3, 4). However, in this issue of the JCI, Wan et al. (5) establish the first direct link between a clinically relevant issue — the access of asthma-inducing dust mite allergen to the immune system — and a specific molecular event at the tight junction. This […] Find the latest version: https://jci.me/7599/pdf Understanding tight junction clinical physiology Commentary at the molecular level See related article this issue, pages 123–133. Bruce R. Stevenson Department of Cell Biology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada Address correspondence to: Bruce R. Stevenson, Department of Cell Biology, Edmonton, Alberta T6G 2H7, Canada. Phone: (780) 492-1841; Fax: (780) 492-0450; E-mail: [email protected]. A century of investigation has led to a supramolecular complexes at specific leads to increased paracellular move- reasonable understanding of the role areas of the cell surface (3). These pro- ment of the Der p 1 allergen across the tight junction (zonula occludens) teins are capable of interacting direct- the epithelial boundary. Such plays in epithelial physiology (1, 2). ly with the cytoplasmic domain of transepithelial transit in a respira- This intercellular junction forms a occludin, a 4-passage transmem- tory system in vivo would increase regulated, semipermeable barrier in brane protein present at the tight exposure of the host immune system the spaces between epithelial and junction (6). Most recently, a family of to this allergen, potentially explain- endothelial cells (the paracellular transmembrane elements, the clau- ing allergic sensitization and subse- space). It also acts as a fence, delimit- dins, have been identified (7). Mem- quent asthma development. Most ing the compositionally distinct api- bers of the claudin family, now total- importantly, the authors provide evi- cal and basolateral plasma membrane ing 16 individual proteins, are present dence indicating that Der p 1 acts domains characteristic of these cell in varying amounts in different tis- to increase paracellular permeability types. Both the barrier and fence func- sues, suggesting that expression of by direct proteolytic cleavage of tions, in conjunction with transcellu- various claudins relates to the distinct occludin and possibly claudin. This lar vectorial transport processes, per- paracellular permeability properties proteolysis is assumed to then cause mit the establishment of unique observed in different epithelia or the breakdown of the tight junction environments in opposing compart- endothelia (4). protein complex. ments separated by epithelial cell Although we know that permeability This information raises questions sheets. Interaction and exchange through the tight junction is regulated and avenues for further investigations between these environments is critical in a physiologically relevant manner of both the dust mite allergen system to normal organ biology. Moreover, (2), the molecular mechanisms under- and the molecular mechanisms operat- integrity of compartmental bound- lying this regulation are unresolved. It ing at tight junctions. The data indi- aries is key to protecting an organism is widely assumed that actin filaments cate that both occludin and claudin from noxious agents present in the found at the tight junction participate are proteolyzed by Der p 1, although it outside world. in junctional regulation (2), and actin will be important to demonstrate that Our knowledge of the molecules may be linked to occludin through the claudin is acted on directly. Must both that make up the tight junction is less ZO proteins (8–10). While there is evi- proteins be cleaved to open the junc- developed, dating back slightly over a dence that occludin acts in the regula- tion, or is degradation of one or the decade. While we are aware of 9 tion of the junctional barrier (11), it is other sufficient? How does Der p 1 peripheral and 3 integral membrane likely that formation and regulation of gain access to the extracellular portion proteins (Table 1), we have only just the paracellular barrier and intramem- of either protein, given the close prox- started to obtain isolated and limited brane fence require claudins and imity of cell-cell interactions presumed information on the possible func- occludin acting in concert. It is also at junctional contact sites? And does tions of individual molecules (3, 4). clear that the tight junction can be reg- Der p 1 act on JAM, a third transmem- However, in this issue of the JCI, Wan ulated from within the cell (2), as well brane protein found at the tight junc- et al. (5) establish the first direct link as by externally applied factors both tion (14)? Since JAM participates in between a clinically relevant issue — artificial (e.g., synthetic peptides; the access of asthma-inducing dust ref. 12) and natural (e.g., cholera toxin; Table 1 mite allergen to the immune system — ref. 13). However, prior to the results Tight junction proteins and a specific molecular event at the presented here, there have been no tight junction. This paper is a land- data directly linking the effects of a Peripheral Integral mark in the molecular understanding natural external agent and a tight ZO-1 occludin of the tight junction and the clinical junction molecule. cingulin JAM physiology of epithelia. Dust mite allergen and the tight junc- ZO-2 claudins Tight junction molecules and regulation tion: Where are we? Where are we going? 7H6 of paracellular permeability. The pro- Wan et al. (5) demonstrate that treat- Rab3B teins peripherally associated with the ment of epithelial cell lines with symplekin tight junction membrane include either dust mite fecal pellets or Der p AF-6 ZO-1, ZO-2, and ZO-3, members of a 1, a protease purified from these pel- ZO-3 larger protein family known to be lets, reversibly disrupts tight junc- ASIP involved in the organization of tions. Moreover, this disruption The Journal of Clinical Investigation | July 1999 | Volume 104 | Number 1 3 monocyte transmigration across targeted to the extracellular segments 7. Morita, K., Furuse, M., Fujimoto, K., and Tsuki- ta, S. 1999. Claudin multigene family encoding endothelial monolayers, the results of occludin, claudins, or JAM be effec- four-transmembrane domain protein compo- provided (5) suggest a mechanism by tive in reversibly opening tight junc- nents of tight junction strands. Proc. Natl. Acad. which cells migrating across endothe- tions at sites where increased drug Sci. USA. 96:511–516. 8. Itoh, M., Nagafuchi, A., Moroi, S., and Tsukita, S. lia might utilize cell surface proteases delivery would be advantageous, such 1997. Involvement of ZO-1 in cadherin-based cell to “chew” their way through tight as the intestine or blood-brain barrier? adhesion through its direct binding to a catenin junctions. How does cleavage of a Like all good science, the results pre- and actin filaments. J. Cell Biol. 138:181–192. 9. Itoh, M., Morita, K., and Tsukita, S. 1999. Char- transmembrane element signal the dis- sented by Wan et al. (5) generate as acterization of ZO-2 as a MAGUK family mem- solution of the cytoplasmic complex of many questions as they answer. The ber associated with tight as well as adherens junctional proteins? Again, are both fun lies in the ongoing pursuit of junctions with a binding affinity to occludin and alpha catenin. J. Biol. Chem. 274:5981–5986. occludin and claudins involved in such these questions. 10. Wittchen, E.S., and Stevenson, B.R. 1998. Novel signaling? Although some informa- binding interactions among tight junction pro- tion is available on the cytoplasmic 1. Balda, M.S., and Matter, K. 1998. Tight junc- teins. Mol. Biol. Cell. 9:82a. (Abstr.) tions. J. Cell Sci. 111:541–547. 11. Matter, K., and Balda, M.S. 1999. Occludin and binding partners of occludin (3), no 2. Madara, J.L. 1998. Regulation of the movement the function of tight junctions. Int. Rev. Cytol. information on molecular interactions of solutes across tight junctions. Annu. Rev. Phys- 186:117–146. involving the claudins is currently iol. 60:143–159. 12. Wong, V., and Gumbiner, B.M. 1997. A synthetic 3. Stevenson, B.R., and Keon, B.H. 1998. The tight peptide corresponding to the extracellular available. Finally, the results of Wan et junction: morphology to molecules. Annu. Rev. domain of occludin perturbs the tight junction al. (5) engender the exciting possibility Cell Dev. Biol. 14:89–109. permeability barrier. J. Cell Biol. 136:399–409. that tight junction permeability can be 4. Goodenough, D.A. 1999. Plugging the leaks. 13. Fasano, A., et al. 1991. Vibrio cholerae produces a Proc. Natl. Acad. Sci. USA. 96:319–321. second enterotoxin, which affects intestinal tight modulated for clinical means.
Load more

Recommended publications
  • Vocabulario De Morfoloxía, Anatomía E Citoloxía Veterinaria
    Vocabulario de Morfoloxía, anatomía e citoloxía veterinaria (galego-español-inglés) Servizo de Normalización Lingüística Universidade de Santiago de Compostela COLECCIÓN VOCABULARIOS TEMÁTICOS N.º 4 SERVIZO DE NORMALIZACIÓN LINGÜÍSTICA Vocabulario de Morfoloxía, anatomía e citoloxía veterinaria (galego-español-inglés) 2008 UNIVERSIDADE DE SANTIAGO DE COMPOSTELA VOCABULARIO de morfoloxía, anatomía e citoloxía veterinaria : (galego-español- inglés) / coordinador Xusto A. Rodríguez Río, Servizo de Normalización Lingüística ; autores Matilde Lombardero Fernández ... [et al.]. – Santiago de Compostela : Universidade de Santiago de Compostela, Servizo de Publicacións e Intercambio Científico, 2008. – 369 p. ; 21 cm. – (Vocabularios temáticos ; 4). - D.L. C 2458-2008. – ISBN 978-84-9887-018-3 1.Medicina �������������������������������������������������������������������������veterinaria-Diccionarios�������������������������������������������������. 2.Galego (Lingua)-Glosarios, vocabularios, etc. políglotas. I.Lombardero Fernández, Matilde. II.Rodríguez Rio, Xusto A. coord. III. Universidade de Santiago de Compostela. Servizo de Normalización Lingüística, coord. IV.Universidade de Santiago de Compostela. Servizo de Publicacións e Intercambio Científico, ed. V.Serie. 591.4(038)=699=60=20 Coordinador Xusto A. Rodríguez Río (Área de Terminoloxía. Servizo de Normalización Lingüística. Universidade de Santiago de Compostela) Autoras/res Matilde Lombardero Fernández (doutora en Veterinaria e profesora do Departamento de Anatomía e Produción Animal.
    [Show full text]
  • Molecular Dynamics Simulations of Tight Junction Proteins
    Molecular Dynamics Simulations of Tight Junction Proteins Eleni Fitsiou This dissertation is submitted for the degree of Doctor of Philosophy August 2020 Department of Chemistry I would like to dedicate this dissertation to my husband Antonios and sons Dimitrios and Ioannis. ii “Wisdom begins in wonder” Socrates iii Declaration I, Eleni Fitsiou, declare that this thesis titled ‘Molecular Dynamics Simulations of Tight Junction Proteins’ has not been submitted in support of an application for another degree at this or any other university. It is the result of my own work and includes nothing that is the outcome of work done in collaboration except where specifically indicated. Where I have quoted from the work of others, the source is always given. Lancaster University, UK iv Abstract Tight junctions (TJs) are specialised cell-cell structures that serve primarily as a barrier to molecular transport through the intercellular space between the cells. The claudin family of proteins are the main structural and functional components of the TJ strands that circumscribe the cells. The detailed molecular organisation at the TJs is not entirely resolved, being relatively inaccessible by current experimental methods. Here, we have employed molecular dynamics simulations using both atomistic and coarse-grained models to investigate the TJ structure formed by claudin-1 using self-assembly coupled with free energy calculations and enhanced sampling techniques. A feature of the studies is that the self-assembly simulations have been carried out using atomistic detail (a first) by simulating only the extracellular domains of claudin-1 in an implied membrane. The results show that the cis-interaction can occur in the absence of trans-interacting partners and that a claudin dimer is the smallest stable unit.
    [Show full text]
  • Claudins in the Renal Collecting Duct
    International Journal of Molecular Sciences Review Claudins in the Renal Collecting Duct Janna Leiz 1,2 and Kai M. Schmidt-Ott 1,2,3,* 1 Department of Nephrology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, 12203 Berlin, Germany; [email protected] 2 Molecular and Translational Kidney Research, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany 3 Berlin Institute of Health (BIH), 10178 Berlin, Germany * Correspondence: [email protected]; Tel.: +49-(0)30-450614671 Received: 22 October 2019; Accepted: 20 December 2019; Published: 28 December 2019 Abstract: The renal collecting duct fine-tunes urinary composition, and thereby, coordinates key physiological processes, such as volume/blood pressure regulation, electrolyte-free water reabsorption, and acid-base homeostasis. The collecting duct epithelium is comprised of a tight epithelial barrier resulting in a strict separation of intraluminal urine and the interstitium. Tight junctions are key players in enforcing this barrier and in regulating paracellular transport of solutes across the epithelium. The features of tight junctions across different epithelia are strongly determined by their molecular composition. Claudins are particularly important structural components of tight junctions because they confer barrier and transport properties. In the collecting duct, a specific set of claudins (Cldn-3, Cldn-4, Cldn-7, Cldn-8) is expressed, and each of these claudins has been implicated in mediating aspects of the specific properties of its tight junction. The functional disruption of individual claudins or of the overall barrier function results in defects of blood pressure and water homeostasis. In this concise review, we provide an overview of the current knowledge on the role of the collecting duct epithelial barrier and of claudins in collecting duct function and pathophysiology.
    [Show full text]
  • Tight Junction Structure and Function Revisited
    Trends in Cell Biology Review Tight Junction Structure and Function Revisited Tetsuhisa Otani 1,2,3,*,@ and Mikio Furuse1,2,3 Tight junctions (TJs) are intercellular junctions critical for building the epithelial Highlights barrier and maintaining epithelial polarity. The claudin family of membrane pro- Tight junction strand formation and teins play central roles in TJ structure and function. However, recent findings membrane apposition formation are have uncovered claudin-independent aspects of TJ structure and function, and differentially regulated. additional players including junctional adhesion molecules (JAMs), membrane Claudins form charge-selective small lipids, phase separation of the zonula occludens (ZO) family of scaffolding pores, while junctional adhesion mole- proteins, and mechanical force have been shown to play important roles in TJ cules regulate the formation of size- structure and function. In this review, we discuss how these new findings have selective large pores. the potential to transform our understanding of TJ structure and function, and Tight junction proteins regulate epithelial how the intricate network of TJ proteins and membrane lipids dynamically polarity, although how tight junctions interact to drive TJ assembly. form a membrane fence remains unclear. Tight Junctions Regulate Epithelial Barrier and Polarity Tight junction associated membrane proteins regulate tight junction assembly – Tight junctions (TJs) are epithelial intercellular junctions located at the most apical region of cell in conjunction with zonula occludens cell contacts. TJs are structurally defined by electron microscopy. On ultrathin sections, TJs protein phase separation, membrane appear as a region with close apposition of adjacent plasma membranes where adjacent plasma lipids, mechanical force, and polarity signaling proteins.
    [Show full text]
  • 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.
    [Show full text]
  • Tight Junctions: from Simple Barriers to Multifunctional Molecular Gates
    Tight Junctions: From simple barriers to multifunctional molecular gates Ceniz Zihni1, Clare Mills1, Karl Matter1# and Maria S Balda1# Department of Cell Biology UCL Institute of Ophthalmology University College London London EC1V 9EL, UK # Address for correspondence UCL Institute of Ophthalmology University College London Bath Street London EC1V 9EL United Kingdom Tel – 44 20 7608 4014/6861 Fax – 44 20 7608 4034 E-mail: [email protected]/[email protected] Main body of text: 5983 words 1 Epithelia and endothelia separate different tissue compartments and protect multicellular organisms form the outside world. This requires the formation of tight junctions, selective gates that control paracellular diffusion of ions and solutes. Tight junctions also form the border between the apical and basolateral plasma membrane domains and are linked to the machinery that controls apicobasal polarization. Additionally, signalling networks that guide diverse cell behaviours and functions are connected to tight junctions, transmitting information to and from the cytoskeleton, nucleus and different cell adhesion complexes. Here, we discuss recent advances in our understanding of the molecular architecture and cellular functions of tight junctions. Microscopists in the 19th century described the paracellular space between neighbouring cells within an epithelial sheet to be sealed by a “terminal bar”, a structure later resolved by electron microscopy into a composite of distinct cell-cell junctions that is now called the epithelial junctional complex and is formed by tight junctions, adherens junctions and desmosomes1,2. As the former two junctions are more tightly associated and often reside at the apical end of the lateral membrane, they are often referred to as the apical junctional complex (however, in endothelia, tight junctions and adherens junctions can be intercalated) (Fig.
    [Show full text]
  • Cx43 and the Actin Cytoskeleton: Novel Roles and Implications for Cell-Cell Junction-Based Barrier Function Regulation
    biomolecules Review Cx43 and the Actin Cytoskeleton: Novel Roles and Implications for Cell-Cell Junction-Based Barrier Function Regulation Randy E. Strauss 1,* and Robert G. Gourdie 2,3,4,* 1 Virginia Tech, Translational Biology Medicine and Health (TBMH) Program, Roanoke, VA 24016, USA 2 Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, VA 24016, USA 3 Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA 4 Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA * Correspondence: [email protected] (R.E.S.); [email protected] (R.G.G.) Received: 29 October 2020; Accepted: 7 December 2020; Published: 10 December 2020 Abstract: Barrier function is a vital homeostatic mechanism employed by epithelial and endothelial tissue. Diseases across a wide range of tissue types involve dynamic changes in transcellular junctional complexes and the actin cytoskeleton in the regulation of substance exchange across tissue compartments. In this review, we focus on the contribution of the gap junction protein, Cx43, to the biophysical and biochemical regulation of barrier function. First, we introduce the structure and canonical channel-dependent functions of Cx43. Second, we define barrier function and examine the key molecular structures fundamental to its regulation. Third, we survey the literature on the channel-dependent roles of connexins in barrier function, with an emphasis on the role of Cx43 and the actin cytoskeleton. Lastly, we discuss findings on the channel-independent roles of Cx43 in its associations with the actin cytoskeleton and focal adhesion structures highlighted by PI3K signaling, in the potential modulation of cellular barriers.
    [Show full text]
  • 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.
    [Show full text]
  • ILDR1 Is Important for Paracellular Water Transport and Urine Concentration Mechanism
    ILDR1 is important for paracellular water transport and urine concentration mechanism Yongfeng Gonga,1, Nina Himmerkusb,1, Abby Sunqa, Susanne Milatzb, Cosima Merkelb, Markus Bleichb,2, and Jianghui Houa,2 aDepartment of Internal Medicine, Washington University in St. Louis, St. Louis, MO 63110; and bDepartment of Physiology, University of Kiel, 24118 Kiel, Germany Edited by David W. Russell, University of Texas Southwestern Medical Center, Dallas, TX, and approved April 6, 2017 (received for review January 18, 2017) Whether the tight junction is permeable to water remains highly chromosome 12, and the sites of mutations were found to be controversial. Here, we provide evidence that the tricellular tight functionally important in making the water permeation pore (12) junction is important for paracellular water permeation and that Ig- or facilitating proper intracellular trafficking (13). Whether there like domain containing receptor 1 (ILDR1) regulates its permeability. may exist any previously unknown gene important for renal water In the mouse kidney, ILDR1 is localized to tricellular tight junctions reabsorption is a tantalizing question. Here, we have revealed Ildr1 of the distal tubules. Genetic knockout of in the mouse kidney that homozygous deletion of the ILDR1 gene, which encodes a causes polyuria and polydipsia due to renal concentrating defects. TJ protein controlling the putative paracellular water pathway, Microperfusion of live renal distal tubules reveals that they are im- can cause NDI-like phenotypes in the mouse kidney. permeable to water in normal animals but become highly perme- able to water in Ildr1 knockout animals whereas paracellular ionic Results permeabilities in the Ildr1 knockout mouse renal tubules are not The Gene Expression of ILDR1 in the Kidney.
    [Show full text]
  • Actin-Related Protein2/3 Complex Regulates Tight Junctions and Terminal Differentiation to Promote Epidermal Barrier Formation
    Actin-related protein2/3 complex regulates tight junctions and terminal differentiation to promote epidermal barrier formation Kang Zhoua,1, Andrew Muroyamaa,1, Julie Underwooda, Rebecca Leyleka, Samriddha Raya, Scott H. Soderlinga,b, and Terry Lechlera,c,2 Departments of aCell Biology, bNeurobiology, and cDermatology, Duke University Medical Center, Durham, NC 27710 Edited by Joan S. Brugge, Harvard Medical School, Boston, MA, and approved August 19, 2013 (received for review May 3, 2013) The epidermis provides an essential seal from the external gastrulation in Caenorhabditis elegans embryos(11,12).In environment and retains fluids within the body. To form an Drosophila, the Arp2/3 complex plays roles in myoblast fusion, effective barrier, cells in the epidermis must form tight junctions ring canal expansion, adherens junction formation, Notch sig- and terminally differentiate into cornified envelopes. Here, we naling, and bristle development (6, 13, 14). demonstrate that the branched actin nucleator, the actin-related The functions of the Arp2/3 complex in intact tissues during protein (Arp)2/3 complex, is unexpectedly required for both these mammalian development and homeostasis have only begun to be activities. Loss of the ArpC3 subunit of the Arp2/3 complex addressed. Loss of the Arp2/3 complex globally results in early resulted in minimal changes in the morphogenesis and architec- lethality at the blastocyst stage in mice (15). In the mouse oocyte, ture of this stratified squamous epithelium, but resulted in the Arp2/3 complex is required for asymmetric cell division profound defects in its physiology. Mutant embryos did not through positioning of the mitotic spindle (16).
    [Show full text]
  • Restoration of Desmosomal Junction Protein Expression and Inhibition Of
    MOLECULAR AND CLINICAL ONCOLOGY 3: 171-178, 2015 Restoration of desmosomal junction protein expression and inhibition of H3K9‑specifichistone demethylase activity by cytostatic proline‑rich polypeptide‑1 leads to suppression of tumorigenic potential in human chondrosarcoma cells KARINA GALOIAN1, AMIR QURESHI1, GINA WIDEROFF1 and H.T. TEMPLE2 1Department of Orthopaedic Surgery; 2University of Miami Tissue Bank Division, Miller School of Medicine, University of Miami, Miami, FL 33136, USA Received September 18, 2014; Accepted October 8, 2014 DOI: 10.3892/mco.2014.445 Abstract. Disruption of cell-cell junctions and the concomi- and inhibits H3K9 demethylase activity, contributing to the tant loss of polarity, downregulation of tumor-suppressive suppression of tumorigenic potential in chondrosarcoma cells. adherens junctions and desmosomes represent hallmark phenotypes for several different cancer cells. Moreover, a Introduction variety of evidence supports the argument that these two common phenotypes of cancer cells directly contribute to Chondrosarcoma is a highly aggressive bone cancer of tumorigenesis. In this study, we aimed to determine the status mesenchymal origin, which is resistant to chemo- and radia- of intercellular junction proteins expression in JJ012 human tion therapies, leaving surgical resection as the only option. malignant chondrosarcoma cells and investigate the effect Metastatic spread of malignant cells eventually develops of the antitumorigenic cytokine, proline-rich polypeptide-1 following surgical resection. The malignant progression to (PRP-1) on their expression. The cell junction pathway array chondrosarcoma has been suggested to involve a degree of data indicated downregulation of desmosomal proteins, mesenchymal-to-epithelial transition (MET) and it has been such as desmoglein (1,428-fold), desmoplakin (620-fold) and demonstrated in an in vitro model that chondrosarcoma cells plakoglobin (442-fold).
    [Show full text]
  • The Density of Small Tight Junction Pores Varies Among Cell Types and Is Increased by Expression of Claudin-2
    298298 Research Article The density of small tight junction pores varies among cell types and is increased by expression of claudin-2 Christina M. Van Itallie1,*, Jennifer Holmes2, Arlene Bridges3, Jody L. Gookin4, Maria R. Coccaro4, William Proctor3, Oscar R. Colegio5 and James M. Anderson2 1Department of Medicine, 2Cell and Molecular Physiology and 3School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA 4Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC 27695, USA 5Department of Dermatology, Yale University School of Medicine, New Haven, CT 06510, USA *Author for correspondence (e-mail: [email protected]) Accepted 4 November 2007 Journal of Cell Science 121, 298-305 Published by The Company of Biologists 2008 doi:10.1242/jcs.021485 Summary Epithelial tight junctions contain size- and charge-selective cell types and is not necessarily related to electrical resistance. pores that control the paracellular movement of charged and Expression of claudin-2 results in a selective increase in pore noncharged solutes. Claudins influence the charge selectivity number but not size and has no effect on the permeability of and electrical resistance of junctions, but there is no direct PEGs that are larger than the pores; however, neither evidence describing pore composition or whether pore size or knockdown of claudin-2 nor overexpression of several other density differs among cell types. To characterize paracellular claudins altered either the number of small pores or their size. pores independent of influences from charge selectivity, we We speculate that permeability of all small solutes is profiled the ‘apparent permeabilities’ (Papp) of a continuous proportional to pore number but that small electrolytes are series of noncharged polyethylene glycols (PEGs) across subject to further selectivity by the profile of claudins monolayers of five different epithelial cell lines and porcine expressed, explaining the dissociation between the Papp for ileum.
    [Show full text]