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Advanced Drug Delivery Reviews (v.57, #6)
Tight junctions, from tight intercellular seals to sophisticated protein complexes involved in drug delivery, pathogens interaction and cell proliferation
by Lorenza Gonzalez-Mariscal; Porfirio Nava (pp. 811-814).
Tight junctions (TJ) are intercellular seals that regulate the passage of ions and molecules through the paracellular pathway. This property allows epithelial and endothelial sheets to function as barriers between different body compartments. Although TJ were identified by electron microscopy since the 1950's, the analysis in recent years of their molecular composition, has depicted TJ as signaling complexes involved in a wide spectrum of physiological and pathological processes, such as cell growth and differentiation, cancer and metastasis, and pathogen interaction. This new knowledge has in turn given rise to novel strategies for enhancing the paracellular flux of poorly absorbed therapeutics.
Keywords: tight junctions; drug delivery; paracellular flux; epithelia
Molecular perspective on tight-junction assembly and epithelial polarity
by Jun Miyoshi; Yoshimi Takai (pp. 815-855).
Apical–basal polarity and a highly organized actin cytoskeleton are main characteristics of epithelial cells that support exchange of ions and nutrients from one body compartment to another. The junctional complexes, localized to the apical end of the basolateral domain of the plasma membrane, are not simply epithelial barriers in paracellular transport or fences preventing diffusion of integral proteins in the plasma membrane, but also contain proteins involved in the maintenance of the physiologic epithelial cell state and signal transduction. Claudin-based tight junctions and E-cadherin-based adherens junctions have been extensively studied. Nectins, along with a unique scaffolding protein, afadin, form homophilic and heterophilic trans-dimers and play a key role in identifying cell partners in the primordial cell–cell adhesion. Nectin-based cell–cell adhesion participates in the epithelial morphogenesis, both independently and cooperatively with claudin-based tight junctions and cadherin-based adherens junctions. This review discusses how these adhesion systems interact with each other to form apical junctional complexes, and how they reorganize the actin cytoskeleton in a multistage process of cell adhesion, migration, and polarization.
Keywords: Actin cytoskeleton; Adherens junctions; Cadherin; Claudin; Nectin; PDZ-domain protein; Small G protein
The JAM family of proteins
by Kenneth J. Mandell; Charles A. Parkos (pp. 857-867).
Junctional adhesion molecules (JAMs) are immunoglobulin superfamily (IgSF) proteins expressed at cell junctions in epithelial and endothelial cells as well as on the surface of leukocytes, platelets, and erythrocytes. Evidence suggests JAM proteins are important for a variety of cellular processes, including tight junction assembly, leukocyte transmigration, platelet activation, angiogenesis and virus binding. This review will highlight what is currently known about the structure, function, and mechanism of action of JAM proteins as well as comment on potential directions for future JAM-related research.
Keywords: Abbreviations; A33; glycoprotein A33; AF6; ALL1 fused gene from chromosome 6; aPKC; atypical PKC; bFGF; basic fibroblast growth factor; CAR; coxsackie virus and adenovirus receptor; CASK; calcium/calmodulin-dependent serine protein kinase; CD; cluster of differentiation; CDC42; cell division cycle 42; CLMP; CAR-like membrane protein; CTX; cortical thymocyte marker in Xenopus; ERK; extracellular signal-regulated kinase; ESAM; endothelial cell-selective adhesion molecule; Ig; immunoglobulin; IgSF; immunoglobulin superfamily; JAM; junctional adhesion molecule; JAML; junctional adhesion molecule-like; LFA-1; leukocyte function-associated antigen-1; MAGI; membrane-associated guanylate kinase inverted; MUPP1; multiple PDZ domain protein; PAR; partitioning-defective; PDZ; PSD-95/Discs-Large/ZO-1; PKC; protein kinase C; TJ; tight junction; ZO1; zonula occludens-1Junctional adhesion molecule; Tight junctions; Cell adhesion; Homophilic interactions; Leukocyte migration; Barrier function
CAR: A virus receptor within the tight junction
by Carolyn B. Coyne; Jeffrey M. Bergelson (pp. 869-882).
The coxsackievirus and adenovirus receptor (CAR) mediates cell attachment and infection by coxsackie B viruses and by a number of adenoviruses. CAR also mediates homotypic intercellular interactions. In polarized epithelial cells, CAR is closely associated with the tight junction, where it contributes to the barrier to paracellular flow of solutes and macromolecules. CAR's biological roles are not well defined, but emerging evidence suggests that it may function during embryonic development and in regulating cell proliferation.
Keywords: Coxsackievirus adenovirus receptor (CAR); Tight junction; Junctional adhesion molecule (JAM); Coxsackie virus B (CVB); Adenovirus (Ad)
Occludin: Structure, function and regulation
by Gemma J. Feldman; James M. Mullin; Michael P. Ryan (pp. 883-917).
Epithelial and/or endothelial barriers play a critical role in animal, including human, life forms. The tight junction (TJ) is an essential component of these barriers. Occludin is a major component of the TJ. The structure of occludin, including its gene splice variants and protein essential components have been elucidated.Phosphorylation/dephosphorylation plays a major role in regulation of occludin and TJ. Disruption of occludin regulation is an important aspect of a number of diseases. Strategies to prevent and/or reverse occludin downregulation may be an important therapeutic target.
Keywords: Abbreviations; TJ; tight junction; ZO; zonula occludens; mAb; monoclonal antibody; BRB; blood–retinal barrier; TER; transepithelial/endothelial electrical resistance; IPTG; isopropyl-β-; d; -thiogalactoside; RT-PCR; reverse transcription-polymerase chain reaction; bp; base pair; TM4; fourth transmembrane domain; MAGUK; membrane-associated guanylate kinase; CTX; cortical thymocyte marker in; Xenopus; CLMP; coxsackie- and adenovirus receptor-like membrane protein; LC; low calcium; NC; normal calcium; MW; molecular weight; LMW; low molecular weight; HMW; high molecular weight; CBDL; common bile duct ligation; BBB; blood–brain barrier; CNS; central nervous system; IFN; interferon; PKC; protein kinase C; PMA; phorbol-12-myristate-13-acetate; Ca; 2+; calcium; MAPK; mitogen-activated protein kinase; PP2A; protein phosphatase 2A; BBB; blood–brain barrier; PLC; phospholipase C; MMP; matrix metalloproteinase; PAO; phenylarsine oxide; PV; pervanadate; PI; phosphatidylinositol; EPEC; enteropathogenic; Escherichia coli; CK; casein kinase; PKA; protein kinase A; HDM; house dust mite; TGF; transforming growth factor; IL; interleukin; HGF; hepatocyte growth factor; EMT; epithelial–mesenchymal transitionOccludin; Tight junction; ZO-1; Claudin; Phosphorylation; GTPases; Proteases; Cytokines; Cancer; Inflammatory diseases
Role of claudins in tumorigenesis
by Karen Swisshelm; Robert Macek; Manfred Kubbies (pp. 919-928).
The family of more than 20 claudin (CLDN) proteins comprises one of the major structural elements within the apical tight junction apparatus, a dynamic cellular nexus for maintenance of a luminal barrier, paracellular transport, and signal transduction. Loss of normal tight junction functions constitutes a hallmark of human carcinomas. CLDN1 may support tumor suppressive functions in tissues such as the brain, where dramatic loss of expression has been demonstrated in glioblastoma multiforme. The role(s) for CLDNs 3 and 4 in tumorigenesis is less clear. CLDN4 appears to be over-expressed in ovarian and pancreatic carcinomas, and this raises the possibility that a unique, potentially non-toxic cancer cell target may be developed through the design of enterotoxin analogues. Future goals include understanding the biochemical and physiological mechanisms that are perturbed as a consequence of CLDN alterations in the progression of solid tumors.
Keywords: Neoplasia; Tight junctions; Signaling pathways; Tumor suppression; Enterotoxin
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