Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:B0FTZ7 (catenin)
 18,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tight junction permeability control is important in a variety of physiological and pathological processes. We have investigated the role of tyrosine phosphorylation in the regulation of tight junction permeability. MDCK epithelial cells and brain endothelial cells were grown on filters and tight junction permeability was determined by transcellular electrical resistance (TER). The tyrosine phosphatase inhibitor pervanadate caused a concentration- and time-dependent decrease in TER in both MDCK and brain endothelial cells. However, as expected, pervanadate resulted in the tyrosine phosphorylation of many proteins; hence interpretation of its effects are extremely difficult. Phenylarsine oxide, a more selective tyrosine phosphatase inhibitor, caused the tyrosine phosphorylation of relatively few proteins as analyzed by immunoblotting of whole cell lysates. This inhibitor, like pervanadate, also elicited a decrease in TER in the two cell types. In the MDCK cells, the action of phenylarsine oxide could be reversed by the subsequent addition of the reducing agent 2,3-dimercaptopropanol. Immunocytochemistry revealed that phenylarsine oxide rapidly stimulated the tyrosine phosphorylation of proteins associated with intercellular junctions. Because of the known influence of the adherens junction on tight junctions, we analyzed immunoprecipitates of the E-cadherin/catenin complex from MDCK cells treated with phenylarsine oxide. This revealed an increase in the tyrosine phosphorylation of beta-catenin, but not of alpha-catenin. However, the tight junction associated protein ZO-1 was also tyrosine phosphorylated after PAO treatment. These data indicate that tight junction permeability may be regulated via mechanisms involving tyrosine phosphorylation of adherens junction and tight junction proteins.
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PMID:Evidence that tyrosine phosphorylation may increase tight junction permeability. 776 5

PC9 lung carcinoma cells cannot tightly associate with one another, and therefore grow singly, despite their expression of E-cadherin, because of their lack of alpha-catenin, a cadherin-associated protein. However, when the E-cadherin is activated by transfection with alpha-catenin cDNA, they form spherical aggregates, each consisting of an enclosed monolayer cell sheet. In the present work, we examined whether the alpha-catenin-transfected cell layers expressed epithelial phenotypes, by determining the distribution of various cell adhesion molecules on their surfaces, including E-cadherin, ZO-1, desmoplakin, integrins, and laminin. In untransfected PC9 cells, all these molecules were randomly distributed on their cell surface. In the transfected cells, however, each of them was redistributed into a characteristic polarized pattern without a change in the amount of expression. Electron microscopic study demonstrated that the alpha-catenin-transfected cell layers acquired apical-basal polarity typical of simple epithelia; they formed microvilli only on the outer surface of the aggregates, and a junctional complex composed of tight junction adherens junction, and desmosome arranged in this order. These results indicate that the activation of E-cadherin triggered the formation of the junctional complex and the polarized distribution of cell surface proteins and structures. We also found that, in untransfected PC9 cells, ZO-1 formed condensed clusters and colocalized with E-cadherin, but that other adhesion molecules rarely showed such colocalization with E-cadherin, suggesting that there is some specific interaction between ZO-1 and E-cadherin even in the absence of cell-cell contacts. In addition, we found that the activation of E-cadherin caused a retardation of PC9 cell growth. Thus, we concluded that the E-cadherin-catenin adhesion system is essential not only for structural organization of epithelial cells but also for the control of their growth.
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PMID:Induction of polarized cell-cell association and retardation of growth by activation of the E-cadherin-catenin adhesion system in a dispersed carcinoma line. 792 67

The elevation of tyrosine phosphorylation level is thought to induce the dysfunction of cadherin through the tyrosine phosphorylation of beta catenin. We evaluated this assumption using two cell lines. First, using temperature-sensitive v-src-transfected MDCK cells, we analyzed the modulation of cadherin-based cell adhesion by tyrosine phosphorylation. Cell aggregation and dissociation assays at nonpermissive and permissive temperatures indicated that elevation of the tyrosine phosphorylation does not totally affect the cell adhesion ability of cadherin but shifts it from a strong to a weak state. The tyrosine phosphorylation levels of beta catenin, ZO-1, ERM (ezrin/radixin/moesin), but not alpha catenin, vinculin, and alpha-actinin, were elevated in the weak state. To evaluate the involvement of the tyrosine phosphorylation of beta catenin in this shift of cadherin-based cell adhesion, we introduced v-src kinase into L fibroblasts expressing the cadherin-alpha catenin fusion protein, in which beta catenin is not involved in cell adhesion. The introduction of v-src kinase in these cells shifted their adhesion from a strong to a weak state. These findings indicated that the tyrosine phosphorylation of beta catenin is not required for the strong-to-weak state shift of cadherin-based cell adhesion, but that the tyrosine phosphorylation of other junctional proteins, ERM, ZO-1 or unidentified proteins is involved.
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PMID:V-src kinase shifts the cadherin-based cell adhesion from the strong to the weak state and beta catenin is not required for the shift. 855 50

Embryo implantation necessitates that the apical plasma membrane of uterine epithelial cells acquires adhesiveness. Recent studies have indicated that modulation of a major element of the epithelial phenotype, i.e. apical-basal cell polarity, might be critical in this respect. Here, we analyze polar characteristics of nonadhesive vs. adhesive uterine epithelial cell lines focusing on cytoskeletal-junctional interactions that may play a role in regulating adhesiveness of the apical plasma membrane. HEC-1-A is a human uterine epithelial cell line exhibiting nonadhesive properties of its apical surface for trophoblast, whereas RL95-2 represent another such cell line exhibiting adhesive properties enabling trophoblast attachment. Homotypic intercellular contacts and functionally related proteins, i.e. ZO-1, E-cadherin, alpha-catenin, beta-catenin, plakoglobin, and desmoplakin 1, were examined by transmission electron microscopy, immunocytochemistry, confocal laser scanning microscopy, and immunoprecipitation techniques. In addition, details of actin filament architecture were studied after phalloidin labeling. While nonadhesive HEC-1-A exhibited the well-known pattern of cell-to-cell contacts of polarized epithelial cells, adhesive RL95-2 showed a lack of ZO-1 expression, tracer leakiness of the paracellular pathway, and atypical features in adherens junctions: E-cadherin, alpha-catenin and plakoglobin were colocalized in all plasma membrane domains and beta-catenin was localized in lateral membrane domains. Immunoprecipitations showed in both cell lines the presence of two different E-cadherin-catenin complexes, one composed of E-cadherin, alpha-catenin and beta-catenin, and the other of E-cadherin, alpha-catenin and plakoglobin. Concerning RL95-2 these data indicate that E-cadherin/plakoglobin complexes are randomly distributed, whereas E-cadherin/beta-catenin complexes are laterally localized in these cells. Additionally, the actin-based cytoskeleton of RL95-2 lacked a polar organization. With respect to the intermediate filament-desmosome system, both cell types expressed desmoplakin I, but the vast majority of RL95-2 lacked well-formed desmosomes as demonstrated by electron microscopy. It is concluded that modulation of tight junctions and/or remodelling of adherens junctions, e.g. differential distribution of E-cadherin/plakoglobin complexes and E-cadherin/beta-catenin complexes, are correlated with the development of apical adhesiveness of human uterine epithelial cells. This model system should allow to test experimentally whether this correlation is due to any causal function in the development of epithelial cell polarity.
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PMID:Adhesiveness of the apical surface of uterine epithelial cells: the role of junctional complex integrity. 883 6

The cytokine tumor necrosis factor-alpha (TNF) increases the frequency of apoptosis in confluent renal epithelial LLC-PK1 cells, an effect that can be blocked by an anti-TNFR1 monoclonal antibody. However, there were no visible "holes" in the cell sheet as a result of TNF-induced apoptosis. Instead a striking tissue remodeling occurred in response to the TNF-induced apoptosis. Apoptotic cells became surrounded and engulfed by repositioned neighboring cells distributed in a distinct "rosette" pattern. The cadherin-catenin cell-cell adhesion molecules, the tight junction-associated protein ZO-1, and actin accumulated at the sites of contact between apoptotic and neighboring cells. Pretreatment with cytochalasin B prevented the accumulation of cadherins-catenins and ZO-1 at the sites of apoptosis and resulted in microscopic holes in the TNF-treated cell sheet. Our results indicate that a renal epithelium can accommodate an increased frequency of apoptosis and still maintain its integrity by mechanisms of tissue remodeling involving the cadherin-catenin adhesion molecules, tight junctional proteins, and actin filaments.
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PMID:Tissue remodeling during tumor necrosis factor-induced apoptosis in LLC-PK1 renal epithelial cells. 892 50

Trophectoderm epithelium formation, the first visible differentiation process during mouse embryonic development, is affected in embryos lacking the cell adhesion molecule E-cadherin. Here we analyze the developmental potential of such E-cadherin-negative embryos, focusing on the organization of cell junctions and the cytoskeleton. To do this we used antibodies directed against alpha-, beta-, or gamma-(plakoglobin)-catenin and junctional and cytoskeletal proteins including ZO-1 and occludin (tight junctions), desmoglein1 (desmosomes), connexin43 (gap junctions), and EndoA (cytokeratin intermediate filaments). Membrane localization of alpha- and beta-catenin, and ZO-1, as well as cortical actin filament organization were abnormal in E-cadherin-negative embryos, and the expression levels of alpha- and beta-catenin were dramatically reduced, all suggesting a regulatory role for E-cadherin in forming the cadherin-catenin complex. In contrast, the membrane localization of plakoglobin, occludin, desmoglein1, connexin43, and cytokeratin filaments appeared unaltered. The unusual morphogenesis in E-cadherin-negative embryos apparently reflects defects in the molecular architecture of a supermolecular assembly involving zonulae adherens, tight junctions, and cortical actin filament organization, although the individual structures still appeared normal in electron microscopical analysis.
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PMID:Cell-junctional and cytoskeletal organization in mouse blastocysts lacking E-cadherin. 918 87

ZO-1, a 220-kD peripheral membrane protein consisting of an amino-terminal half discs large (dlg)-like domain and a carboxyl-terminal half domain, is concentrated at the cadherin-based cell adhesion sites in non-epithelial cells. We introduced cDNAs encoding the full-length ZO-1, its amino-terminal half (N-ZO-1), and carboxyl-terminal half (C-ZO-1) into mouse L fibroblasts expressing exogenous E-cadherin (EL cells). The full-length ZO-1 as well as N-ZO-1 were concentrated at cadherin-based cell-cell adhesion sites. In good agreement with these observations, N-ZO-1 was specifically coimmunoprecipitated from EL transfectants expressing N-ZO-1 (NZ-EL cells) with the E-cadherin/alpha, beta catenin complex. In contrast, C-ZO-1 was localized along actin stress fibers. To examine the molecular basis of the behavior of these truncated ZO-1 molecules, N-ZO-1 and C-ZO-1 were produced in insect Sf9 cells by recombinant baculovirus infection, and their direct binding ability to the cadherin/catenin complex and the actin-based cytoskeleton, respectively, were examined in vitro. Recombinant N-ZO-1 bound directly to the glutathione-S-transferase fusion protein with alpha catenin, but not to that with beta catenin or the cytoplasmic domain of E-cadherin. The dissociation constant between N-ZO-1 and alpha catenin was approximately 0.5 nM. On the other hand, recombinant C-ZO-1 was specifically cosedimented with actin filaments in vitro with a dissociation constant of approximately 10 nM. Finally, we compared the cadherin-based cell adhesion activity of NZ-EL cells with that of parent EL cells. Cell aggregation assay revealed no significant differences among these cells, but the cadherin-dependent intercellular motility, i.e., the cell movement in a confluent monolayer, was significantly suppressed in NZ-EL cells. We conclude that in nonepithelial cells, ZO-1 works as a cross-linker between cadherin/catenin complex and the actin-based cytoskeleton through direct interaction with alpha catenin and actin filaments at its amino- and carboxyl-terminal halves, respectively, and that ZO-1 is a functional component in the cadherin-based cell adhesion system.
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PMID:Involvement of ZO-1 in cadherin-based cell adhesion through its direct binding to alpha catenin and actin filaments. 921 91

Cell-to-cell-junctions of endothelial cells are specialized and differentiated areas of the plasma membrane. The main functions include the separation of the intravascular and extravascular compartments, the mechanical connection of the cells, and the maintenance of the cell polarity. Although a wide heterogeneity of endothelial cell-to-cell junctions exists in situ, they should be considered in general as adherens type junctions in which gap and tight junctions are morphologically inserted. Under certain pathological conditions, such as wound healing, angiogenesis and many types of inflammation, the interendothelial junctions have to be dissociated and reorganized in which proteins of the junctions are crucially involved. These important mechanisms predict a sophisticated regulation of junctional proteins. The present paper describes the organization and functional aspects of the occludin/ZO-1 complex typically found in tight junctions, the cadherin/catenin complex of the adherens junctions and the connection of these protein complexes to the dense peripheral band via actin filaments. In addition, special attention has been drawn on the function of junction-associated proteins with respect to their role under fluid shear stress and interendothelial gap formation during inflammation.
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PMID:Structural and functional aspects of intercellular junctions in vascular endothelium. 987 42

ZO-2, a member of the MAGUK family, was thought to be specific for tight junctions (TJs) in contrast to ZO-1, another MAGUK family member, which is localized at TJs and adherens junctions (AJs) in epithelial and nonepithelial cells, respectively. Mouse ZO-2 cDNA was isolated, and a specific polyclonal antibody was generated using corresponding synthetic peptides as antigens. Immunofluorescence microscopy with this polyclonal antibody revealed that, similarly to ZO-1, in addition to TJs in epithelial cells, ZO-2 was also concentrated at AJs in nonepithelial cells such as fibroblasts and cardiac muscle cells lacking TJs. When NH2-terminal dlg-like and COOH-terminal non-dlg-like domains of ZO-2 (N-ZO-2 and C-ZO-2, respectively) were separately introduced into cultured cells, N-ZO-2 was colocalized with endogenous ZO-1/ZO-2, i.e. at TJs in epithelial cells and at AJs in non-epithelial cells, whereas C-ZO-2 was distributed along actin filaments. Consistently, occludin as well as alpha catenin directly bound to N-ZO-2 as well as the NH2-terminal dlg-like portion of ZO-1 (N-ZO-1) in vitro. Furthermore, immunoprecipitation experiments revealed that the second PDZ domain of ZO-2 was directly associated with N-ZO-1. These findings indicated that ZO-2 forms a complex with ZO-1/occludin or ZO-1/alpha catenin to establish TJ or AJ domains, respectively.
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PMID:Characterization of ZO-2 as a MAGUK family member associated with tight as well as adherens junctions with a binding affinity to occludin and alpha catenin. 1002 24

The interaction of cadherin-catenin complex with the actin-based cytoskeleton through alpha-catenin is indispensable for cadherin-based cell adhesion activity. We reported previously that E-cadherin-alpha-catenin fusion molecules showed cell adhesion and cytoskeleton binding activities when expressed in nonepithelial L cells. Here, we constructed deletion mutants of E-cadherin-alpha-catenin fusion molecules lacking various domains of alpha-catenin and introduced them into L cells. Detailed analysis identified three distinct functional domains of alpha-catenin: a vinculin/alpha-actinin-binding domain, a ZO-1-binding domain, and an adhesion-modulation domain. Furthermore, cell dissociation assay revealed that the fusion molecules containing the ZO-1-binding domain in addition to the adhesion-modulation domain conferred the strong state of cell adhesion activity on transfectants, although those lacking the ZO-1-binding domain conferred only the weak state. The disorganization of actin-based cytoskeleton by cytochalasin D treatment shifted the cadherin-based cell adhesion from the strong to the weak state. In the epithelial cells, where alpha-catenin was not precisely colocalized with ZO-1, the ZO-1-binding domain did not completely support the strong state of cell adhesion activity. Our studies showed that the interaction of alpha-catenin with the actin-based cytoskeleton through the ZO-1-binding domain is required for the strong state of E-cadherin-based cell adhesion activity.
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PMID:Functional domains of alpha-catenin required for the strong state of cadherin-based cell adhesion. 1008 72


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