DOCSLIB.ORG

Alterations in the Establishment and Maintenance of Epithelial Cell Polarity As a Basis for Disease Processes

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Alterations in the Establishment and Maintenance of Epithelial Cell Polarity As a Basis for Disease Processes Alterations in the establishment and maintenance of epithelial cell polarity as a basis for disease processes. B A Molitoris, W J Nelson J Clin Invest. 1990;85(1):3-9. https://doi.org/10.1172/JCI114427. Research Article Find the latest version: https://jci.me/114427/pdf Perspectives Alterations in the Establishment and Maintenance of Epithelial Cell Polarity as a Basis for Disease Processes Bruce A. Molitons* and W. James Nelsont *Department ofMedicine, Veterans Administration Medical Center, University ofColorado School ofMedicine, Denver, Colorado 80220; and tInstitutefor Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 Polarized epithelial cells play fundamental roles in the vecto- internal milieu and has a compliment of intrinsic and extrinsic rial movement of ions, water, and macromolecules between membrane proteins found over the entire surface membrane biological compartments. These vectorial processes include of nonpolarized cells. These basolateral membrane proteins absorption (enterocytes and renal proximal tubule cells), se- maintain the normal physiologic state of the cell and also par- cretion (hepatocytes, endocrine and exocrine cells), and ex- ticipate in signal recognition and transduction. The lipid com- change (alveolar cells and capillary endothelium). The ability position of apical and basolateral membranes also differs to conduct these vectorial processes is dependent on the struc- markedly (Table I; for review, see reference 3). This difference tural and functional organization of epithelial cells into: (a) is responsible for large physiochemical differences between the structurally, biochemically, and physiologically distinct apical two membrane domains (4) and influences the function of and basolateral plasma membrane domains that contain dif- numerous membrane proteins. The establishment and main- ferent ion channels, transport proteins, enzymes, and lipids; tenance of these specific apical and basolateral membrane and (b) cell-cell junctional complexes that integrate cells into a protein and lipid differences is essential for the efficient func- monolayer forming a cellular barrier between biological com- tioning of polarized epithelial cells. For example, sodium partments. reabsorption by renal proximal tubular cells is dependent on The establishment and maintenance of this specialized cel- the polarized localization of specific carrier proteins such as lular organization is a multistage process involving the forma- the Na+/H' antiporter and glucose, amino acid- and phos- tion of cell-cell and cell-substratum contacts, and the estab- phate Na'-dependent cotransporters to the apical membrane, lishment and maintenance of the polarized distributions of and the polarized distribution of Na',K+-ATPase to the baso- plasma membrane and cytoplasmic components. Aberrations lateral membrane. in any stage of this process could result in the development of Junctional complex. The lateral membrane domain pos- cell- and tissue-specific abnormalities, and ultimately a patho- sesses a specialized intercellular junctional complex composed logic state. of zonula occludens (tight junction), zonula adherens (inter- In this review we describe recent findings regarding basic mediate junction), desmosomes, gap junctions, and cell adhe- cellular mechanisms involved in the organization of polarized sion proteins (Fig. 1). The components of the junctional com- epithelial cells. These fundamental cellular concepts are then plex have four important functions: (a) regulating initial cell- used as a foundation for discussing potential alterations in- cell recognition and adhesion (cell adhesion proteins); (b) volved in disease processes in epithelial cells. maintaining the cohesive structural integrity of the epithelial monolayer (intermediate junctions and desmosomes); (c) al- Characteristics ofpolarized epithelial cells lowing for intercellular communication (gap junctions); and Distinct surface membrane domains. Polarized epithelial cells (d) (the tight junction) regulating the permeability of the para- have a characteristic cellular organization that includes a sur- cellular pathway ("gate" function) and maintaining the pro- face plasma membrane organized into distinct apical and ba- tein and lipid differences between apical and basolateral solateral domains. Within these surface membrane domains membrane domains ("fence" function) (5, 6). enzymes, transport proteins, hormone receptors, and lipids are The basal membrane contains specialized proteins that reg- localized in a polarized fashion (Table I; for review, see refer- ulate cell-substratum interactions. Cell attachment to the sub- ences 1 and 2). Apical membranes face the external compart- stratum occurs via specific receptors to type IV collagen, pro- ment and are composed of membrane proteins with special- teoglycan, and laminin (7, 8), is tissue specific, and is impor- ized properties related to the cell's primary function (e.g., ab- tant for epithelial morphogenesis, maintenance of the sorption). The basolateral membrane domain faces the differentiated state, and tissue-specific gene expression (7, 8). Cytoskeletal organization. The structural organization of epithelial cells is dependent on the polarized nature of the Address correspondence to Dr. Bruce A. Molitoris, Department of cytoskeleton and its interaction with the surface membrane Medicine (I 1 IC), V.A. Medical Center, 1055 Clermont St., Denver, (Fig. 1; 9-1 1). Actin microfilaments and their associated pro- CO 80220. teins interact with surface membrane proteins via direct or Received for publication 11 October 1989 and in revised form 16 October 1989. indirect linkages to fodrin (termed spectrin in erythrocytes), ankyrin, protein 4.1, vinculin, the ll0-kD protein (brush J. Clin. Invest. border myosin I) of the microvillus, and talin (1 1). For exam- © The American Society for Clinical Investigation, Inc. ple, ankyrin binds with high affinity to Na+,K+-ATPase (12), 0021-9738/90/01/0003/07 $2.00 and a complex containing Na+,K+-ATPase, ankyrin, and fo- Volume 85, January 1990, 3-9 drin has been detected in extracts of Madin-Darby canine kid- Epithelial Cell Polarity and Disease Processes 3 Table . Asymmetry of the Surface Membrane ofPolarized Subsequently, cells develop biochemically and physiologically Epithelial Cells distinct apical and basolateral membrane domains, and cyto- plasmic and cytoskeletal organization (2). In the mammalian Basolateral Characteristic Apical membrane membrane embryo, formation of a polarized epithelium (trophectoderm) occurs at the 8 cell stage (morula) during induction of exten- Proteins sive cell-cell contact (compaction) (17). Cell-cell and cell- Enzymes Leucine aminopeptidase Adenylate cyclase substratum contact also induces development of cell polarity Maltase in freshly isolated hepatocytes and MDCK cells previously GPI-linked proteins grown under suspension conditions. Before this cellular reor- (alkaline phosphatase) ganization, surface membrane proteins and lipids are ran- domly distributed over the entire surface membrane (18). Po- Receptors Insulin larization of the apical membrane follows either cell substra- Parathyroid tum attachment or cell-cell contact, but basolateral hormone membrane polarization requires extensive cell-substratum Epidermal and cell-cell contact ( 19). growth factor Cell-cell contact and the establishment of polarity. Cell- Laminin cell recognition and contact between individual cells is initi- ATPases H+-ATPase Na',K+-ATPase ated by cell adhesion molecules (CAMs). CAMs are cell sur- Mg2+-ATPase Ca2+-ATPase face membrane glycoproteins that are highly conserved, bind to each other in a homophilic manner and mediate calcium- Carriers Amiloride-sensitive Na' C1-/HCO3 dependent aggregation of epithelial cells (20-22). Cell-cell channel exchanger contact results in the rapid assembly of other components of Na'-dependent Na'-independent the junctional complex (e.g., tight junctions and desmosomes) cotransporters glucose carrier and the subsequent demarcation of apical and basolateral Na+/K+/Cl membrane domains. After cell-cell contact there is a redistri- cotransporter bution of surface membrane and cytoskeletal proteins to the Na+/H+ antiporter basolateral membrane. For example, after cell-cell and cell- Lipids substratum contact, Na',K+-ATPase, ankyrin, and fodrin, Cholesterol High Low which are distributed randomly over the entire surface mem- Sphingomyelin High Low brane, undergo a spatial reorganization resulting in the forma- Phosphatidylcholine Low High tion of metabolically stable, nonextractable cytoskeletal- Phosphatidylinositol Low High membrane protein complexes localized to the basolateral membrane (23, 24). Physical properties This process of recruitment and stabilization of surface Electrical resistance High Low membrane proteins may be initiated by cytoskeletal-CAM in- Membrane fluidity Low High teractions. As noted earlier, Na+,K+-ATPase forms a metaboli- cally stable detergent-insoluble complex with actin, fodrin, and ankyrin (12, 13; Fig. 1, inset). Uvomorulin (E-cadherin) may also form complexes with ankyrin and fodrin (25). Inter- ney (MDCK)' epithelial cells (13), demonstrating a direct link- estingly, deletion of part of the cytoplasmic domain of uvo- age of cytoskeletal proteins to a specific integral membrane morulin inhibits cell-cell binding in transfected fibroblasts protein. Cytokeratin intermediate filaments, composed of (26), perhaps because of loss of linkage to cytoplasmic proteins
Load more

Recommended publications
  • Epithelia and Gastrointestinal Function
    CHAPTER 18 Epithelia and gastrointestinal function Jerrold R. Turner University of Chicago, Chicago, IL, USA Chapter menu Organization of the gut wall, 317 Epithelial barrier and disease , 326 Organization of epithelial cells and sheets, 318 Integration of mucosal function, 329 Mucosal barriers, 322 Further reading, 329 All cavities within the alimentary tract, from the small ducts An underlying layer of fibroconnective tissue called the sub- and acini of the pancreas to the gastric lumen, are lined by mucosa, which contains nerves, vessels, and lymphatics, sup- sheets of polarized epithelial cells. Common to all of these epi- ports the mucosa. The submucosa rests on the muscularis thelia is the ability to create selective barriers that separate propria, which is composed of two or three layers of smooth luminal and tissue spaces. Most epithelia are also able to direct muscle and is home to the myenteric plexus (see Chapters 1, 15, vectorial transport of solutes and solvents. These essential func- and 16). In most instances, gastrointestinal organs are encased tions are based on the structural polarity of individual cells, the by an outermost delicate layer of fibrofatty tissue, the serosa, complex organization of membranes, cell–cell and cell–substrate encircled by a continuous layer of mesothelial cells. In areas interactions, and interactions with other cell types. This chapter where no serosa exists, as in portions of the esophagus and the reviews intestinal wall structure and examines how mucosal distal colorectum, fibrofatty tissues interface with the external functions are supported by the organization of the gut and the portion of the muscularis propria.
    [Show full text]
  • EGF Shifts Human Airway Basal Cell Fate Toward a Smoking-Associated Airway Epithelial Phenotype
    EGF shifts human airway basal cell fate toward a smoking-associated airway epithelial phenotype Renat Shaykhiev1, Wu-Lin Zuo1, IonWa Chao, Tomoya Fukui, Bradley Witover, Angelika Brekman, and Ronald G. Crystal2 Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065 Edited* by Michael J. Welsh, Howard Hughes Medical Institute, Iowa City, IA, and approved May 29, 2013 (received for review February 19, 2013) The airway epithelium of smokers acquires pathological phenotypes, phosphorylation, indicative of EGFR receptor activation, has including basal cell (BC) and/or goblet cell hyperplasia, squamous been observed in airway epithelial cells exposed to cigarette metaplasia, structural and functional abnormalities of ciliated cells, smoke in vitro (26, 27). decreased number of secretoglobin (SCGB1A1)-expressing secretory Based on this knowledge, we hypothesized that smoking- cells, and a disordered junctional barrier. In this study, we hypoth- induced changes in the EGFR pathway are relevant to the EGFR- fi esized that smoking alters airway epithelial structure through dependent modi cation of BCs toward the abnormal differentia- modification of BC function via an EGF receptor (EGFR)-mediated tion phenotypes present in the airway epithelium of smokers. mechanism. Analysis of the airway epithelium revealed that EGFR is In this study, we provide evidence that although EGFR is ex- pressed predominantly in BCs, smoking induces expression of enriched in airway BCs, whereas its ligand EGF is induced by smoking EGF in ciliated
    [Show full text]
  • A Novel PLEKHA7 Interactor at Adherens Junctions
    Thesis PDZD11: a novel PLEKHA7 interactor at adherens junctions GUERRERA, Diego Abstract PLEKHA7 is a recently identified protein of the AJ that has been involved by genetic and genomic studies in the regulation of miRNA signaling and cardiac contractility, hypertension and glaucoma. However, the molecular mechanisms behind PLEKHA7 involvement in tissue physiology and pathology remain unknown. In my thesis I report novel results which uncover PLEKHA7 functions in epithelial and endothelial cells, through the identification of a novel molecular interactor of PLEKHA7, PDZD11, by yeast two-hybrid screening, mass spectrometry, co-immunoprecipitation and pulldown assays. I dissected the structural basis of their interaction, showing that the WW domain of PLEKHA7 binds to the N-terminal region of PDZD11; this interaction mediates the junctional recruitment of PDZD11, identifying PDZD11 as a novel AJ protein. I provided evidence that PDZD11 forms a complex with nectins at AJ, its PDZ domain binds to the PDZ-binding motif of nectins. PDZD11 stabilizes nectins promoting the early steps of junction assembly. Reference GUERRERA, Diego. PDZD11: a novel PLEKHA7 interactor at adherens junctions. Thèse de doctorat : Univ. Genève, 2016, no. Sc. 4962 URN : urn:nbn:ch:unige-877543 DOI : 10.13097/archive-ouverte/unige:87754 Available at: http://archive-ouverte.unige.ch/unige:87754 Disclaimer: layout of this document may differ from the published version. 1 / 1 UNIVERSITE DE GENÈVE FACULTE DES SCIENCES Section de Biologie Prof. Sandra Citi Département de Biologie Cellulaire PDZD11: a novel PLEKHA7 interactor at adherens junctions THÈSE Présentée à la Faculté des sciences de l’Université de Genève Pour obtenir le grade de Doctor ès science, mention Biologie par DIEGO GUERRERA de Benevento (Italie) Thèse N° 4962 GENÈVE Atelier d'impression Repromail 2016 1 Table of contents RÉSUMÉ ..................................................................................................................
    [Show full text]
  • Cell and Tissue Polarity As a Non-Canonical Tumor Suppressor
    Commentary 1141 Cell polarity and cancer – cell and tissue polarity as a non-canonical tumor suppressor Minhui Lee1,2 and Valeri Vasioukhin1,3,* 1Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N., C3-168, Seattle, WA 98109, USA 2Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98109, USA 3Department of Pathology and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA *Author for correspondence (e-mail: [email protected]) Accepted 19 February 2008 Journal of Cell Science 121, 1141-1150 Published by The Company of Biologists 2008 doi:10.1242/jcs.016634 Summary Correct establishment and maintenance of cell polarity is and differentiation of cancer stem cells. Data from in vivo and required for the development and homeostasis of all three-dimensional (3D) cell-culture models demonstrate that metazoans. Cell-polarity mechanisms are responsible not only tissue organization attenuates the phenotypic outcome of for the diversification of cell shapes but also for regulation of oncogenic signaling. We suggest that polarized 3D tissue the asymmetric cell divisions of stem cells that are crucial for organization uses cell-cell and cell-substratum adhesion their correct self-renewal and differentiation. Disruption of cell structures to reinforce and maintain the cell polarity of pre- polarity is a hallmark of cancer. Furthermore, recent evidence cancerous cells. In this model, polarized 3D tissue organization indicates that loss of cell polarity is intimately involved in functions as a non-canonical tumor suppressor that prevents cancer: several crucial cell-polarity proteins are known proto- the manifestation of neoplastic features in mutant cells and, oncogenes or tumor suppressors, basic mechanisms of cell ultimately, suppresses tumor development and progression.
    [Show full text]
  • 2003 Cell Bio Gibson.Pdf
    747 Apicobasal polarization: epithelial form and function Matthew C Gibson and Norbert Perrimonà The structure and function of epithelial sheets generally depend (Figure 1a). Contrasting with Drosophila, vertebrate on apicobasal polarization, which is achieved and maintained by epithelial cells lack SJs and instead exhibit tight junctions linking asymmetrically distributed intercellular junctions to the (TJs), cell–cell adhesive structures that lie apical to the cytoskeleton of individual cells. Recent studies in both vertebrate ZA in a position analogous to the Drosophila Drosophila and vertebrate epithelia have yielded new insights SAR [2] (Figure 1b). The apical TJ complexes between into the conserved mechanisms by which apicobasal polarity is vertebrate epithelial cells serve an organizing role in established and maintained during development. In mature epithelial polarization and establish a paracellular diffu- polarized epithelia, apicobasal polarity is important for the sion barrier that restricts the movement of solutes across establishment of adhesive junctions and the formation of a the cell layer [4,5]. This barrier effectively segregates the paracellular diffusion barrier that prevents the movement of epithelium and surrounding media into immiscible apical solutes across the epithelium. Recent findings show that and basolateral compartments. In Drosophila, SJs appear segregation of ligand and receptor with one on each side of this to fulfill a similar paracellular barrier role to the vertebrate barrier can be a crucial regulator of cell–cell signaling events. TJs [6,7], albeit with the functional barrier lying basal to the ZA. Addresses Department of Genetics, Harvard Medical School, 200 Longwood Despite differences in the distribution of cell–cell junc- Avenue, Boston MA, 02115, USA tions, conserved sets of polarity proteins govern api- Ãe-mail: [email protected] cobasal polarization in both Drosophila and vertebrate epithelia.
    [Show full text]
  • Deciphering the Mechanoresponsive Role of Β-Catenin in Keratoconus
    bioRxiv preprint doi: https://doi.org/10.1101/603738; this version posted April 9, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Deciphering the mechanoresponsive role of β-catenin in Keratoconus 2 epithelium 3 4 Chatterjee Amit 1,2, Prema Padmanabhan3, Janakiraman Narayanan#1 5 1 Department of Nanobiotechnology, Vision Research Foundation,Sankara Nethralaya campus, 6 Chennai, Tamil Nadu, India 7 2 School of Chemical and Biotechnology, SASTRA University, Tanjore, Tamil Nadu, India 8 3 Department of Cornea, Medical Research Foundation, Sankara Nethralaya campus, Chennai, 9 Tamil Nadu ,India 10 Running Title: β-catenin mechanotransduction in kerataconus 11 Correspondence: #Dr. Janakiraman Narayanan, Department of Nanobiotechnology, KNBIRVO 12 Block, Vision Research Foundation, Sankara Nethralaya campus 18/41, College road 13 Nungambakkam, Chennai, Tamil Nadu, India 600006, Tel-+91-44-28271616, (Ext) 1358, Fax- 14 +91-44-28254180, Email: [email protected] 15 16 17 18 19 20 21 22 23 1 bioRxiv preprint doi: https://doi.org/10.1101/603738; this version posted April 9, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 24 25 Abstract 26 Keratoconus (KC) a disease with established biomechanical instability of the corneal stroma, is an 27 ideal platform to identify key proteins involved in mechanosensing.
    [Show full text]
  • A Fence Function for Adherens Junctions in Epithelial Cell Polarity
    bioRxiv preprint doi: https://doi.org/10.1101/605808; this version posted April 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. A fence function for adherens junctions in epithelial cell polarity Mario Aguilar-Aragon, Alex Tournier & Barry J Thompson* The Francis Crick Institute, 1 Brill Place, St Pancras, NW1 1BF, London, United Kingdom. * [email protected]; @thompsonlab Word count: 3,500 Figures: 4 1 bioRxiv preprint doi: https://doi.org/10.1101/605808; this version posted April 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Abstract Adherens junctions are a defining feature of all epithelial cells, providing cell- cell adhesion and being essential for cell and tissue morphology. In Drosophila, adherens junctions are concentrated between the apical and basolateral plasma membrane domains, but whether they contribute to apical- basal polarisation itself has been unclear. Here we show that, in the absence of adherens junctions, apical-basal polarity determinants can still segregate into complementary domains, but control of apical versus basolateral domain size is lost. Manipulation of the level of apical or basal polarity determinants in experiments and in computer simulations suggests that junctions provide a moveable diffusion barrier, or fence, that restricts the diffusion of polarity determinants to enable precise domain size control.
    [Show full text]
  • HHS Public Access Author Manuscript
    HHS Public Access Author manuscript Author Manuscript Author ManuscriptFertil Steril Author Manuscript. Author manuscript; Author Manuscript available in PMC 2017 February 01. Published in final edited form as: Fertil Steril. 2016 February ; 105(2): 501–510.e1. doi:10.1016/j.fertnstert.2015.10.011. Cryopreservation and Recovery of Human Endometrial Epithelial Cells with High Viability, Purity, and Functional Fidelity Joseph C. Chen, PhD, MSa, Jacquelyn R. Hoffman, BAa, Ripla Arora, PhD, MSa, Lila A. Perronea, Christian J Gonzalez-Gomeza, Kim Chi Vo, BSa, Diana J. Laird, PhDa, Juan C. Irwin, MD, PhDa, and Linda C. Giudice, MD, PhDa aCenter for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco Abstract Objective—To develop a protocol for cryopreservation and recovery of human endometrial epithelial cells (eEC) retaining molecular and functional characteristics of endometrial epithelium in vivo. Design—This is an in vitro study using human endometrial cells. Setting—University research laboratory. Patients—Endometrial biopsies were obtained from premenopausal women undergoing benign gynecological procedures. Interventions—Primary eEC were cryopreserved in 1% fetal bovine serum (FBS)/10% dimethyl sulfoxide (DMSO) in Defined Keratinocyte Serum Free Medium (KSFM). Recovered cells were observed for endometrial stromal fibroblast (eSF) contamination and subsequently evaluated for morphology, gene expression, and functional characteristics of freshly cultured eECs and in vivo endometrial epithelium. Main Outcome Measures—Analysis of eEC morphology and the absence of eSF contamination; evaluation of epithelial-specific gene and protein expression; assessment of epithelial polarity. Results—eEC recovered after cryopreservation (n=5) displayed epithelial morphology and expressed E-cadherin (CDH1), occludin (OCLN), claudin1 (CLDN1), and keratin18 (KRT18).
    [Show full text]
  • A Common Framework for EMT and Collective Cell Migration Kyra Campbell1,2,* and Jordi Casanova1,2,*
    © 2016. Published by The Company of Biologists Ltd | Development (2016) 143, 4291-4300 doi:10.1242/dev.139071 HYPOTHESIS A common framework for EMT and collective cell migration Kyra Campbell1,2,* and Jordi Casanova1,2,* ABSTRACT occur during animal development tend to escape from the simplicity During development, cells often switch between static and migratory of these definitions. First, not only do many intermediate situations behaviours. Such transitions are fundamental events in development exist, with migrating cells possessing a combination of epithelial and are linked to harmful consequences in pathology. It has long and mesenchymal features, but it is evident that these are far more been considered that epithelial cells either migrate collectively as commonly seen in vivo than previously thought (Nakaya and Sheng, epithelial cells, or undergo an epithelial-to-mesenchymal transition 2008; Shook and Keller, 2003). Second, it is now clear that and migrate as individual mesenchymal cells. Here, we assess what mesenchymal cells often migrate exhibiting the coordination and is currently known about in vivo cell migratory phenomena and cooperation ascribed to collectively migrating cells (Scarpa and hypothesise that such migratory behaviours do not fit into alternative Mayor, 2016; Theveneau and Mayor, 2011). To cope with these and mutually exclusive categories. Rather, we propose that these observations, distinctions between individual and collective cell categories can be viewed as the most extreme cases of a general migration have evolved from very strict to more inclusive or loose continuum of morphological variety, with cells harbouring different definitions (Rørth, 2012; Theveneau and Mayor, 2011). degrees or combinations of epithelial and mesenchymal features and Accordingly, any attempts to classify migratory events and thus displaying an array of migratory behaviours.
    [Show full text]
  • The Crumbs3 Polarity Protein
    Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press The Crumbs3 Polarity Protein Ben Margolis Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-5680 Correspondence: [email protected] The Crumbs proteins are evolutionarily conserved apical transmembrane proteins. Drosophila Crumbs was discovered via its crucial role in epithelial polarity during fly em- bryogenesis. Crumbs proteins have variable extracellular domains but a highly conserved intracellular domain that can bind FERM and PDZ domain proteins. Mammals have three Crumbs genes and this review focuses on Crumbs3, the major Crumbs isoform expressed in mammalian epithelial cells. Although initial work has highlighted the role of Crumbs3 in polarity, more recent studies have found it has an important role in tissue morphogenesis functioning as a linker between the apical membrane and the actin cytoskeleton. In addi- tion, recent publications have linked Crumbs3 to growth control via regulation of the Hippo/ Yap pathway. pithelia polarize into apical and basolateral by mutual antagonism of apical and basolateral Emembranes with unique protein composi- protein complexes. In lower organisms, such as tions. This polarization is crucial for proper Drosophila, polarity is maintained solely by an- epithelial functions such as ion transport and tagonistic polarity complexes. In mammalian barrier protection. In mammalian epithelia, a cells, this biochemical polarization is further seal known as the tight junction separates the enforced by the tight junction seal (Shin et al. apical and basolateral membranes (Shin et al. 2006). There are two main evolutionarily con- 2006; Nelson 2009). The tight junction is com- served apical polarity complexes: the Crumbs posed of transmembrane proteins, primarily complex and the partitioning defective (Par) claudins that are organized by scaffold proteins complex (Pieczynski and Margolis 2011).
    [Show full text]
  • Functional Restoration of Irradiated Salivary Glands Through Modulation of Apkcζ and Nuclear Yap in Salivary Progenitors
    Functional Restoration of Irradiated Salivary Glands Through Modulation of aPKCζ and Nuclear Yap in Salivary Progenitors Item Type text; Electronic Dissertation Authors Martinez Chibly, Agustin Alejandro Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 11/10/2021 05:49:05 Link to Item http://hdl.handle.net/10150/621771 FUNCTIONAL RESTORATION OF IRRADIATED SALIVARY GLANDS THROUGH MODULATION OF APKC AND NUCLEAR YAP IN SALIVARY PROGENITORS by Agustin Alejandro Martinez Chibly ___________________________________________ Copyright © Agustin Alejandro Martinez Chibly 2016 A Dissertation Submitted to the Faculty of the THE GRADUATE INTERDISCIPLINARY PROGRAM IN CANCER BIOLOGY In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 2016 2 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Dissertation Committee, we certify that we have read the dissertation prepared by Agustin Alejandro Martinez Chibly entitled “Functional Restoration of Irradiated Salivary Glands Through Modulation of aPKC and nuclear Yap in Salivary Progenitors” and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy _______________________________________________________________________
    [Show full text]
  • Case Studies in Cholera: Lessons in Medical History and Science
    YALE JOURNAL OF BIOLOGY AND MEDICINE 72 (1999), pp. 393-408. Copyright C) 2000. All rights reserved. MEDICAL REVIEW Case Studies in Cholera: Lessons in Medical History and Science Stephen M. Kavica, Eric J. Frehmb, and Alan S. Segalc aDepartment of Surgery, Yale University School of Medicine, New Haven, Connecticut; bDepartment of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania; and CDepartments of Medicine, Molecular Physiology and Biophysics, and Pharmacology, University of Vermont, Burlington, Vermont Cholera, a prototypical secretory diarrheal disease, is an ancient scourge that has both wrought great suffering and taught many valuable lessons, from basic sanitation to molecular signal trans- duction. Victims experience the voluminous loss of bicarbonate-rich isotonic saline at a rate that may lead to hypovolemic shock, metabolic acidosis, and death within afew hours. Intravenous solu- tion therapy as we know it wasfirst developed in an attempt to provide life-saving volume replace- mentfor cholera patients. Breakthroughs in epithelial membrane transport physiology, such as the discovery ofsugar and salt cotransport, have paved the wayfor oral replacement therapy in areas of the world where intravenous replacement is not readily available. In addition, the discovery of the cholera toxin has yielded vital information about toxigenic infectious diseases, providing a framework in which to study fundamental elements of intracellular signal transduction pathways, such as G-proteins. Cholera may even shed light on the evolution and pathophysiology of cystic fibrosis, the most commonly inherited disease among Caucasians. The goal of this paper is to review, using case studies, some of the lessons learned from cholera throughout the ages, acknowledging those pioneers whose seminal work led to our understanding ofmany basic concepts in medical epidemiology, microbiology, physiology, and therapeuticsf INTRODUCTION a short, curved, bacterium that produces an enterotoxin (choleragen).
    [Show full text]