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Cell Junctions (cell + junction)
Selected AbstractsSignal Transduction Pathways in Enhanced Microvascular PermeabilityMICROCIRCULATION, Issue 6 2000SARAH Y. YUAN ABSTRACT We have been investigating the molecular mechanisms underlying pathophysiological regulation of microvascular permeability on isolated venules and cultured venular endothelial monolayers. Physiological approaches have been employed in combination with molecular analyses to probe the signal transduction pathways leading to enhanced microvascular permeability. A newly developed technique of protein transfection into cells and intact microvessels enables the correlation of functional reactions and signaling events at the molecular level in a direct and specific fashion. The results indicate that inflammatory mediators increase microvascular permeability via intracellular signaling pathways involving the activation of phospholipase C, cytosolic calcium, protein kinase C, nitric oxide synthase, guanylate cyclase, and protein kinase G. In response to the signaling stimulation, complex biochemical and conformational reactions occur at the endothelial structural proteins. Specifically, myosin light-chain activation-mediated myosin light-chain phosphorylation can result in cell contraction. VE-cadherin and ,-catenin phosphorylation may induce dissociation of the junctional proteins and their connection to the cytoskeleton, leading to a loose or opened intercellular junction. Focal adhesion phosphorylation and redistribution further provide an anchorage support for the conformational changes in the cells and at the cell junction. The three processes may act in concert to facilitate the flux of fluid and macromolecules across the microvascular endothelium. [source] Fine structure of neuronal and glial processes in neuropathologyNEUROPATHOLOGY, Issue 1 2006Asao Hirano The cells of the nervous system are characterized by their well-formed cell processes and by cell-to-cell relationships that they form. The neuron reveals essentially cylindrical processes, which form synaptic junctions. On the other hand, the peripheral parts of the glial cells are mainly sheet-like in nature. Thus, the oligodendroglial cell elaborates many sheet-like processes, each of which forms a segment of the myelin sheath. Unique cell junction, transverse bands are present at the interface of oligodendroglial processes and the axon. Finally, the astrocytes also form elaborate sheet-like processes, which separate most of the CNS from the mesodermal tissue as well as surrounding certain neuronal surfaces, including synapses. Punctate adhesions, gap junctions and other adhesive devices are present between astrocytic processes. Defects or anomalies in the neuronal and glial cell processes characterize numerous pathological conditions. [source] ,-Catenin dysregulation in cancer: interactions with E-cadherin and beyond,THE JOURNAL OF PATHOLOGY, Issue 2 2010Qun Lu Abstract Stable E-cadherin-based adherens junctions are pivotal in maintaining epithelial tissue integrity and are the major barrier for epithelial cancer metastasis. Proteins of the p120ctn subfamily have emerged recently as critical players for supporting this stability. The identification of the unique juxtamembrane domain (JMD) in E-cadherin that binds directly to ,-catenin/NPRAP/neurojungin (CTNND2) and p120ctn (CTNND1) provides a common motif for their interactions. Recently, crystallographic resolution of the JMD of p120ctn further highlighted possibilities of intervening between interactions of p120ctn subfamily proteins and E-cadherin for designing anti-cancer therapeutics. For most epithelial cancers, studies have demonstrated a reduction of p120ctn expression or alteration of its subcellular distribution. On the other hand, ,-catenin, a primarily neural-enriched protein in the brain of healthy individuals, is up-regulated in all cancer types that have been studied to date. Two research articles in the September 2010 issue of The Journal of Pathology increase our understanding of the involvement of these proteins in lung cancer. One reports the identification of rare p120ctn (CTNND1) gene amplification in lung cancer. One mechanism by which ,-catenin and p120ctn may play a role in carcinogenesis is their competitive binding to E-cadherin through the JMD. The other presents the first vigorous characterization of ,-catenin overexpression in lung cancer. Unexpectedly, the authors observed that ,-catenin promotes malignant phenotypes of non-small cell lung cancer by non-competitive binding to E-cadherin with p120ctn in the cytoplasm. Looking towards the future, the understanding of ,-catenin and p120ctn with and beyond their localization at the cell,cell junction should provide further insight into their roles in cancer pathogenesis. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Invited Commentary for Castillo et al. Gene amplification of the transcription factor DP1 and CTNND1 in human lung cancer, Journal of Pathology, 2010; 222: 89,98. And for Zhang et al. ,-Catenin promotes malignant phenotype of non-small cell lung cancer by non-competative binding to E-cadherin with p120ctn in cytoplasm. Journal of Pathology, 2010; 222: 76,88. [source] Cryopreservable neutrophil surrogates: Granule-poor, motile cytoplasts from polymorphonuclear leukocytes home to inflammatory lesions in vivoCYTOSKELETON, Issue 5 2006Stephen E. Malawista Abstract Cytokineplasts (CKP) are anucleate, motile, granule-poor fragments induced from polymorphonuclear leukocytes on surfaces by the brief application of heat. Derived from the peripheral cytoplasm and membranes of PMN, they retain the sensing, transducing, and effector mechanisms necessary for chemotaxis and phagocytosis, and appear to represent a functional, self-purification of the motile apparatus. Unlike their parent PMN, CKP are cryopreservable. We have shown that they can adhere to endothelial cell monolayers, open interendothelial cell junctions, and migrate to the abluminal side when stimulated by a chemoattractant. Employing an animal model, we now show that, given intravenously, they can home to an inflammatory target lesion in vivo. Cell Motil. Cytoskeleton 2006. © 2006 Wiley-Liss, Inc. [source] Erythropoietin protects the in vitro blood,brain barrier against VEGF-induced permeabilityEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2003Ofelia María Martínez-Estrada Abstract The blood,brain barrier (BBB) ensures the homeostasis of the brain microenvironment, mostly through complex tight junctions between brain endothelial cells that prevent the passage of hydrophilic molecules from blood to brain and vice versa. A recent study has shown in vivo that systemic administration of erythropoietin (Epo) protects against brain injury. Using an in vitro model of the bovine BBB, we observed that the expression of the Epo receptor is modulated by its ligand and hypoxic stimuli such as vascular endothelial growth factor (VEGF) treatment. In addition, Epo protects against the VEGF-induced permeability of the BBB, decreases the levels of endothelial nitric oxide synthase and restores junction proteins. The kinetic transport experiments revealed the capacity of Epo to cross the in vitro BBB in a saturable and specific way. Our results suggest a new mechanism for Epo-induced neuroprotection, in which circulating Epo controls and maintains the BBB through an Epo receptor signalling pathway and the re-establishment of cell junctions. [source] Scaffolding proteins organize multimolecular protein complexes for sensory signal transductionEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2001Armin Huber Abstract Scaffolding proteins composed of protein,protein interaction domains have emerged as organizers of multiprotein complexes in diverse cellular compartments, including neuronal synapses, cell,cell junctions of epithelial cells, and the stimulus perceiving structures of sensory neurons. This review focuses on the INAD-assembled signalling complex of Drosophila photoreceptors, which organizes key components of the phototransduction cascade into a multiprotein signal transduction unit. The structure, the physiological consequences, and the assembly and targeting of the members of the INAD signalling complex will be described. In addition, the existence of signalling complexes in vertebrate photoreceptors, olfactory neurons and mechanosensitive hair cells will be discussed. [source] Involvement of integrin-induced activation of protein kinase C in the formation of adherens junctionsGENES TO CELLS, Issue 5 2007Misa Ozaki In epithelial cells, tight junctions (TJs) and adherens junctions (AJs) form junctional complexes. At AJs, cadherins and nectins are the major cell-cell adhesion molecules. Nectins first form cell,cell adhesions and then recruit cadherins to the nectin-based cell,cell adhesion sites to form AJs in coordination with the activation of integrin ,v,3, followed by the formation of TJs. We previously demonstrated that when MDCK cells precultured at a low Ca2+ concentration were treated with the protein kinase C (PKC) activator 12- O -tetradecanoyl-phorbol-13-acetate (TPA), incomplete AJs and a TJ-like structure were achieved. However, it remains unknown how PKC is activated and how it regulates the formation of cell,cell junctions. When MDCK cells precultured at a low Ca2+ concentration were treated with TPA, incomplete AJs were formed without the activation of integrin ,v,3. Treatment of cells with TPA also enhanced the phosphorylation of FAK, which transmits the outside-in signal of integrin and plays a role in the nectin-induced formation of AJs. In addition, inhibition of PKC suppressed the formation of AJs. These results indicate that the activation of PKC functions downstream of integrin ,v,3 and upstream of FAK, and is important for the nectin-induced formation of AJs. [source] Campylobacter and IFN, interact to cause a rapid loss of epithelial barrier integrityINFLAMMATORY BOWEL DISEASES, Issue 3 2008Louisa E.N. Rees PhD Abstract Background: The intestinal epithelium is a single layer of polarized cells and is the primary barrier separating foreign antigen and underlying lymphoid tissue. IFN, alters epithelial barrier function during inflammation by disrupting tight cell junctions and facilitating the paracellular transport of luminal antigens. The aim of this work was to determine whether Campylobacter infection of cells exposed to IFN, would lead to greater disruption of cell monolayers and hence increased bacterial translocation. Methods: Monolayers were polarized on Transwell polycarbonate membranes for 14 days and then cultured in the presence or absence of 100 U/mL IFN,. Campylobacter was added to the apical side of the monolayer at an MOI of 30. Transepithelial electrical resistance (TEER) was recorded and bacteria in the basal well counted every 2 hours. Cells were stained for occludin, actin, and nuclear DNA, and cell viability determined by measurement of apoptosis. Results: In the presence of IFN,, TEER dropped significantly after 18 hours, indicating a reduction in barrier function. A further significant decrease was seen in the presence of both IFN, and Campylobacter, indicating a synergistic effect, and cellular morphology and viability were affected. Bacterial translocation across the monolayer was also significantly greater in the presence of IFN,. Conclusions: These combined effects indicate that Campylobacter infection concomitant with intestinal inflammation would result in a rapid and dramatic loss of epithelial barrier integrity, which may be a key event in the pathogenesis of Campylobacter -mediated colitis and the development of bloody diarrhea. (Inflamm Bowel Dis 2007) [source] Lysophosphatidic acid induces ovarian cancer cell dispersal by activating Fyn kinase associated with p120-cateninINTERNATIONAL JOURNAL OF CANCER, Issue 4 2008Ruby Yun-Ju Huang Abstract Lysophosphatidic acid (LPA), known as the "ovarian cancer activating factor," is a natural phospholipid involved in important biological functions, such as cell proliferation, wound healing and neurite retraction. LPA causes colony dispersal in various carcinoma cell lines by inducing morphological changes, including membrane ruffling, lamellipodia formation, cell,cell dissociation and single cell migration. However, its effects on cell,cell dissociation and cell,cell adhesion of ovarian cancer cells have not been studied. In our study, we showed that LPA induced sequential events of intercellular junction dispersal and "half-junction" formation in ovarian cancer SKOV3 cells and that Src-family kinases were involved in both processes, since the effects were abolished by the selective tyrosine kinase inhibitor PP2. LPA induced rapid and transient activation of Src family kinases, which were recruited to cell,cell junctions by increasing the association with the adherens junction protein p120-catenin. We identified the Src family kinase, Fyn, as the key component associated with p120-catenin after LPA stimulation in SKOV3 cells. Our study provides evidence that LPA induces junction dispersal in ovarian cancer SKOV3 cells by activating the Src family kinase Fyn and increasing its association with p120-catenin at the cell,cell junction. © 2008 Wiley-Liss, Inc. [source] Tamoxifen resistance in MCF7 cells promotes EMT-like behaviour and involves modulation of ,-catenin phosphorylationINTERNATIONAL JOURNAL OF CANCER, Issue 2 2006Stephen Hiscox Abstract We have previously demonstrated that, following acquisition of endocrine resistance, breast cancer cells display an altered growth rate together with increased aggressive behaviour in vitro. Since dysfunctional cell,cell adhesive interactions can promote an aggressive phenotype, we investigated the integrity of this protein complex in our breast cancer model of tamoxifen resistance. In culture, tamoxifen-resistant MCF7 (TamR) cells grew as loosely packed colonies with loss of cell,cell junctions and demonstrated altered morphology characteristic of cells undergoing epithelial-to-mesenchymal transition (EMT). Neutralising E-cadherin function promoted the invasion and inhibited the aggregation of endocrine-sensitive MCF7 cells, whilst having little effect on the behaviour of TamR cells. Additionally, TamR cells had increased levels of tyrosine-phosphorylated ,-catenin, whilst serine/threonine-phosphorylated ,-catenin was decreased. These cells also displayed loss of association between ,-catenin and E-cadherin, increased cytoplasmic and nuclear ,-catenin and elevated transcription of ,-catenin target genes known to be involved in tumour progression and EMT. Inhibition of EGFR kinase activity in TamR cells reduced ,-catenin tyrosine phosphorylation, increased ,-catenin,E-cadherin association and promoted cell,cell adhesion. In such treated cells, the association of ,-catenin with Lef-1 and the transcription of c-myc, cyclin-D1, CD44 and COX-2 were also reduced. These results suggest that homotypic adhesion in tamoxifen-resistant breast cancer cells is dysfunctional due to EGFR-driven modulation of the phosphorylation status of ,-catenin and may contribute to an enhanced aggressive phenotype and transition towards a mesenchymal phenotype in vitro. © 2005 Wiley-Liss, Inc. [source] Larval development in the Homoscleromorpha (Porifera, Demospongiae)INVERTEBRATE BIOLOGY, Issue 3 2003Nicole Boury-Esnault Abstract. Embryonic development from coeloblastula to fully developed larva was investigated in 8 Mediterranean homoscleromorph species: Oscarella lobularis, O. tuberculata, O. microlobata, O. imperialis, Plakina trilopha, P. jani, Corticium candelabrum, and Pseudocorticium jarrei. Morphogenesis of the larva is similar in all these species; however, cell proliferation is more active in species of Oscarella than in Plakina and C. candelabrum. The result of cell division is a wrinkled, flagellated larva, called a cinctoblastula. It is composed of a columnar epithelium of polarized, monoflagellated cells among which are scattered a few non-flagellated ovoid cells. The central cavity always contains symbiotic bacteria. Maternal cells are also present in O. lobularis, O. imperialis, and P. jarrei. In the fully developed larva, cell shape and dimensions are constant for each species. The cells of the anterior pole have large vacuoles with heterogeneous material; those of the postero-lateral zone have an intranuclear paracrystalline inclusion; and the flagellated cells of the posterior pole have large osmiophilic inclusions. Intercellular junctions join the apical parts of the cells, beneath which are other specialized cell junctions. A basement membrane underlying the flagellated cells lines the larval cavity. This is the first observation of a basement membrane in a poriferan larva. The basal apparatus of flagellated cells is characterized by an accessory centriole located exactly beneath the basal body. The single basal rootlet is cross striated. The presence of a basement membrane and a true epithelium in the larva of Homoscleromorpha,unique among poriferan clades and shared with Eumetazoa,suggests that Demospongiae could be paraphyletic. [source] A comparative molecular force spectroscopy study of homophilic JAM-A interactions and JAM-A interactions with reovirus attachment protein ,1JOURNAL OF MOLECULAR RECOGNITION, Issue 4 2008Sri Ram Krishna Vedula Abstract JAM-A belongs to a family of immunoglobulin-like proteins called junctional adhesion molecules (JAMs) that localize at epithelial and endothelial intercellular tight junctions. JAM-A is also expressed on dendritic cells, neutrophils, and platelets. Homophilic JAM-A interactions play an important role in regulating paracellular permeability and leukocyte transmigration across epithelial monolayers and endothelial cell junctions, respectively. In addition, JAM-A is a receptor for the reovirus attachment protein, ,1. In this study, we used single molecular force spectroscopy to compare the kinetics of JAM-A interactions with itself and ,1. A chimeric murine JAM-A/Fc fusion protein and the purified ,1 head domain were used to probe murine L929 cells, which express JAM-A and are susceptible to reovirus infection. The bond half-life (t1/2) of homophilic JAM-A interactions was found to be shorter () than that of ,1/JAM-A interactions (). These results are in accordance with the physiological functions of JAM-A and ,1. A short bond lifetime imparts a highly dynamic nature to homophilic JAM-A interactions for regulating tight junction permeability while stable interactions between ,1 and JAM-A likely anchor the virus to the cell surface and facilitate viral entry. Copyright © 2008 John Wiley & Sons, Ltd. [source] Metamorphosis of cinctoblastula larvae (Homoscleromorpha, porifera)JOURNAL OF MORPHOLOGY, Issue 6 2007Alexander V. Ereskovsky Abstract The metamorphosis of the cinctoblastula of Homoscleromorpha is studied in five species belonging to three genera. The different steps of metamorphosis are similar in all species. The metamorphosis occurs by the invagination and involution of either the anterior epithelium or the posterior epithelium of the larva. During metamorphosis, morphogenetic polymorphism was observed, which has an individual character and does not depend on either external or species specific factors. In the rhagon, the development of the aquiferous system occurs only by epithelial morphogenesis and subsequent differentiation of cells. Mesohylar cells derive from flagellated cells after ingression. The formation of pinacoderm and choanoderm occurs by the differentiation of the larval flagellated epithelium. This is possibly due to the conservation of cell junctions in the external surface of the larval flagellated cells and of the basement membrane in their internal surface. The main difference in homoscleromorph metamorphosis compared with Demospongiae is the persistence of the flagellated epithelium throughout this process and even in the adult since exo- and endopinacoderm remain flagellated. The antero-posterior axis of the larva corresponds to the baso-apical axis of the adult in Homoscleromorpha. J. Morphol., 2007. © 2007 Wiley-Liss, Inc. [source] Calcium/calmodulin-dependent serine protein kinase and mental retardation,ANNALS OF NEUROLOGY, Issue 4 2009Yi-Ping Hsueh PhD Calcium/calmodulin-dependent serine protein kinase (CASK) belongs to the membrane-associated guanylate kinase protein family. The members of this protein family function as multiple domain adaptor proteins originally identified at cell junctions and synapses. Insertional mutations or targeted disruption of the CASK gene in mice results in neonatal lethality, indicating an important role for CASK in development. Recently, several reports have also indicated that mutations in the human CASK gene result in X-linked malformations of the brain and mental retardation. At the molecular level, many studies indicate that CASK is critical for synapse formation at both presynaptic and postsynaptic junctions, and in the regulation of gene expression. The known molecular functions of CASK explain, at least partially, mental retardation and brain developmental defects in patients. In this review, recent findings about CASK are summarized and discussed. Ann Neurol 2009;66:438,443 [source] Diabetic macular oedema: physical, physiological and molecular factors contribute to this pathological processACTA OPHTHALMOLOGICA, Issue 3 2010Rita Ehrlich Abstract. Diabetic macular oedema (DMO) is an important cause of vision loss in patients with diabetes mellitus. The underlying mechanisms of DMO, on both macrocellular and microcellular levels, are discussed in this review. The pathophysiology of DMO can be described as a process whereby hyperglycaemia leads to overlapping and inter-related pathways that play a role not only in the initial vascular events, but also in the continued tissue insult that leads to chronic DMO. On a macrocellular level, DMO is believed to be in part caused by alterations in hydrostatic pressure, oxygen tension, oncotic pressure and shear stress. Three key components of the microvascular pathways include angiogenic factor expression, inflammation and oxidative stress. These molecular mediators, acting in conjunction with macrocellular factors, which are all stimulated in part by the hyperglycaemia and hypoxia, can have a direct endothelial effect leading to hyperpermeability, disruption of vascular endothelial cell junctions, and leukostasis. The interactions, signalling events and feedback loops between the various molecules are complicated and are not completely understood. However, by attempting to understand the pathways involved in DMO, we can help guide new treatment options targeted towards specific factors or mediators. [source] | |||||||||||||