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)

Two cell-cell junctions, the adherens junction and the desmosome, are prominent in epithelial cells. These junctions are composed of transmembrane cadherins which interact with cytoplasmic proteins that serve to link the cadherin to the cytoskeleton. One component of both adherens junctions and desmosomes is plakoglobin. In the adherens junction plakoglobin interacts with both the classical cadherin and with alpha-catenin. Alpha-catenin in turn interacts with microfilaments. The role plakoglobin plays in the desmosome is not well understood. Plakoglobin interacts with the desmosomal cadherins, but how and if this mediates interactions with the intermediate filament cytoskeleton is not known. Here we compare the domains of plakoglobin that allow it to associate with the desmosomal cadherins with those involved in interactions with the classical cadherins. We show that three sites on plakoglobin are involved in associations with the desmosomal cadherins. A domain near the N terminus is unique to the desmosomal cadherins and overlaps with the site that interacts with alpha-catenin, suggesting that there may be competition between alpha-catenin and the desmosomal cadherins for interactions with plakoglobin. In addition, a central domain is shared with regions used by plakoglobin to associate with the classical cadherins. Finally, a domain near the C terminus is shown to strongly modulate the interactions with the desmosomal cadherins. This latter domain also contributes to the association of plakoglobin with the classical cadherins.
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PMID:Plakoglobin domains that define its association with the desmosomal cadherins and the classical cadherins: identification of unique and shared domains. 874 61

Desmosomes are intercellular adhesive junctions that associate with the intermediate filament cytoskeleton. The two major classes of transmembrane desmosomal glycoproteins, desmogleins and desmocollins, are widely considered to function as adhesion molecules. This assumption is based in part on their homology to the cadherin family of calcium-dependent homophilic adhesion molecules. In addition, autoantibodies from pemphigus patients bind directly to desmoglein family members and are thought to cause epidermal blistering by inhibiting the function of these cadherins. To directly test the ability of the desmosomal cadherins to mediate adhesion, desmoglein-1 (Dsg1), desmocollin-2 (Dsc2a) and plakoglobin were expressed in mouse L cell fibroblasts. Similar to catenin:classical cadherin complexes, plakoglobin:Dsc2a complexes exhibited an approximately 1:1 stoichiometry; however, plakoglobin:Dsg1 complexes exhibited a 6:1 stoichiometry. When L cells expressing the desmosomal cadherins were tested for the ability to aggregate in suspension, L cells expressing E-cadherin exhibited extensive aggregation, but L cells expressing Dsg1 or Dsc2a did not aggregate. In addition, L cells co-expressing Dsg1, Dsc2a, and plakoglobin failed to aggregate. The cytoplasmic domain of E-cadherin is thought to play a central role in the adhesive function of E-cadherin by providing a link to the actin cytoskeleton. Therefore, two chimeric cadherins comprising the cytoplasmic domain of E-cadherin and the extracellular domain of either Dsg1 or Dsc2a were expressed in L cells. Both chimeras formed a complex with alpha- and beta-catenin. Nevertheless, neither of these chimeras supported aggregation of L cells when expressed individually or when co-expressed. These data suggest that the extracellular domains of the desmosomal cadherins exhibit functional properties distinct from those of the classical cadherins, such as E-cadherin.
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PMID:Analysis of desmosomal cadherin-adhesive function and stoichiometry of desmosomal cadherin-plakoglobin complexes. 875 59

Regulation of cell adhesion and cell signaling by beta-catenin occurs through a mechanism likely involving the targeted degradation of the protein. Deletional analysis was used to generate a beta-catenin refractory to rapid turnover and to examine its effects on complexes containing either cadherin or the adenomatous polyposis coli (APC) protein. The results show that amino-terminal deletion of beta-catenin results in a protein with increased stability that acts in a dominant fashion with respect to wild-type beta-catenin. Constitutive expression in AtT20 cells of a beta-catenin lacking 89 N-terminal amino acids (deltaN89beta-catenin) resulted in severely reduced levels of the more labile wild-type beta-catenin. The mutant beta-catenin was expressed at endogenous levels but displaced the vast majority of wild-type beta-catenin associated with N-cadherin. The deltaN89beta-catenin accumulated on the APC protein to a level 10-fold over that of wild-type beta-catenin and recruited a kinase into the APC complex. The kinase was highly active toward APC in vitro and promoted a sodium dodecyl sulfate gel band shift that was also evident for endogenous APC from cells expressing the mutant beta-catenin. Unlike wild-type beta-catenin, which partitions solely as part of a high-molecular-weight complex, the deltaN89 mutant protein also fractionated as a stable monomer, indicating that it had escaped the requirement to associate with other proteins. That similar N-terminal mutants of beta-catenin have been implicated in cellular transformation suggests that their abnormal association with APC may, in part, be responsible for this phenotype.
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PMID:Deletion of an amino-terminal sequence beta-catenin in vivo and promotes hyperphosporylation of the adenomatous polyposis coli tumor suppressor protein. 875 7

Endothelial cell (EC) junctions regulate circulating leukocyte extravasation and infiltration at inflammatory sites. Several lines of evidence show that platelet endothelial cell adhesion molecule-1 (PECAM-1), a specific component of EC junctions, is required for leukocyte transmigration through EC monolayers. In this paper, we examined the effects of two inflammatory cytokines, TNF-alpha and IFN-gamma, on PECAM-1 and vascular endothelial-cadherin/catenin organization. We found that the addition of inflammatory cytokines (TNF-alpha plus IFN-gamma in combination, for > or = 24 h) caused PECAM-1 to disappear from EC intercellular contacts. Confocal microscopy indicated that after treatment with the cytokines, PECAM-1 was rapidly internalized. In addition, a strong inhibition of PECAM-1 synthesis and a decrease in PECAM-1 mRNA were observed. This phenomenon was only found when TNF-alpha plus IFN-gamma were used in combination. Adhesion of polymorphonuclear cells to doubly treated EC was increased compared with control cells or cells incubated with TNF-alpha or IFN-gamma separately. This was correlated with an increased expression of intercellular adhesion molecule-1. However, the disappearance of PECAM-1 from cell junctions after treatment with TNF-alpha plus IFN-gamma was accompanied by a marked reduction of leukocyte migration through EC monolayers. The correlation between PECAM-1 level and leukocyte transmigration was supported by transmigration inhibition assays using blocking anti-PECAM-1 mAb. These data indicate that PECAM-1 is a specific target of inflammatory cytokines and suggest that changes in its synthesis and organization might negatively modulate leukocyte recruitment.
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PMID:Inhibition of platelet endothelial cell adhesion molecule-1 synthesis and leukocyte transmigration in endothelial cells by the combined action of TNF-alpha and IFN-gamma. 875 31

Endothelial cell proliferation is inhibited by the establishment of cell to cell contacts. Adhesive molecules at junctions could therefore play a role in transferring negative growth signals. The transmembrane protein VE-cadherin (vascular endothelial cadherin/cadherin-S) is selectively expressed at intercellular clefts in the endothelium. The intracellular domain interacts with cytoplasmic proteins called catenins that transmit the adhesion signal and contribute to the anchorage of the protein to the actin cytoskeleton. Transfection of VE-cadherin in both Chinese hamster ovary (CHO) and L929 cells confers inhibition of cell growth. Truncation of VE-cadherin cytoplasmic region, responsible for linking catenins, does not affect VE-cadherin adhesive properties but abolishes its effect on cell growth. Seeding human umbilical vein endothelial cells or VE-cadherin transfectants on a recombinant VE-cadherin amino-terminal fragment inhibited their proliferation. These data show that VE-cadherin homotypic engagement at junctions participates in density dependent inhibition of cell growth. This effect requires both the extracellular adhesive domain and the intracellular catenin binding region of the molecule.
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PMID:Inhibition of cultured cell growth by vascular endothelial cadherin (cadherin-5/VE-cadherin). 877 Aug 58

In adherens junctions, alpha- and beta-catenin serve to link cadherins to the cortical cytoskeleton. Immunofluorescence and immuno-electron microscopy have been applied to elucidate the nature and localization of cadherin/catenin-mediated cell-cell adhesion sites in adult muscle tissues. Antibodies against alpha- and beta-catenin have been used as indicators of such sites in amphibian and mammalian muscle. Intercalated discs are prominent cell-cell adhesion sites in heart muscle. They contain large amounts of the two catenins, the distributions of which are disclosed. In addition and in contrast to their counterparts in guinea pig, cardiomyocytes of Xenopus are also interconnected laterally by catenin-containing cell-cell junctions. These are doublet structures that approach the intercellular contacts of two adjacent cells from both sides and occur in register with the Z-discs. We interpret these structures as catenin/cadherin-based costameres. Ultrastructural details of these structures are described. In addition to its presence in cell-cell adhesion sites, we have found beta-catenin, but not alpha-catenin, in the Z-discs of heart and skeletal striated muscles. In smooth muscle, actin filaments insert into the dense bodies, which are therefore regarded as functional equivalents of the Z-discs. Accordingly, beta-catenin is also found in these structures, again in the absence of alpha-catenin. These non-peripheral intracellular localizations in the Z-discs of striated muscles and the dense bodies of smooth muscle indicate a hitherto unknown function of beta-catenin in these specialized cells.
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PMID:Fine structural immunocytochemistry of catenins in amphibian and mammalian muscle. 878 Dec 7

Mutations of the human adenomatosis polyposis coli (APC) gene are associated with the development of familial as well as sporadic intestinal neoplasia. To examine the in vivo function of APC, 129/Sv embryonic stem (ES) cells were transfected with DNA encoding the wild-type human protein under the control of a promoter that is active in all four of the small intestine's principal epithelial lineages during their migration-associated differentiation. ES-APC cells were then introduced into C57BL/6-ROSA26 blastocysts. Analyses of adult B6-ROSA26<-->129/Sv-APC chimeric mice revealed that forced expression of APC results in markedly disordered cell migration. When compared with the effects of forced expression of E-cadherin, the data suggest that APC-catenin and E-cadherin-catenin complexes have opposing effects on intestinal epithelial cell movement/adhesiveness; augmentation of E-cadherin-beta-catenin complexes produces a highly ordered, "adhesive" migration, whereas augmentation of APC-beta-catenin complexes produces a disordered, nonadhesive migratory phenotype. We propose that APC mutations may promote tumorigenesis by increasing the relative activity of cadherin-catenin complexes, resulting in enhanced adhesiveness and functional anchorage of initiated cells within the intestinal crypt. Our studies also indicate that chimeric mice generated from B6-ROSA26 blastocysts and genetically manipulated ES cells should be useful for auditing gene function in the gastrointestinal tract and in other tissues.
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PMID:Forced expression of the tumor suppressor adenomatosis polyposis coli protein induces disordered cell migration in the intestinal epithelium. 879 Mar 74

Catenins were first characterized as linking the cytoplasmic domains of cadherin cell-cell adhesion molecules to the cortical actin cytoskeleton. In addition to their essential role in modulating cadherin adhesivity, catenins have more recently been indicated to participate in cell and developmental signaling pathways. beta-Catenin, for example, associates directly with at least two receptor tyrosine kinases and transduces developmental signals within the Wnt pathway. Catenins also complex with the tumor suppressor protein adenomatous polyposis coli (APC), which appears to have a role in regulating cell proliferation. We have used the yeast two-hybrid method to reveal that fascin, a bundler of actin filaments, binds to beta-catenin's central Armadillo repeat domain. Western blotting of immunoprecipitates from cell line and mouse and rat brain extracts indicate that this interaction exists in vivo. Fascin and beta-catenin's association was further substantiated in vitro using purified proteins isolated from recombinant bacterial and baculoviral sources. Immunoprecipitation analysis indicates that fascin additionally binds to plakoglobin, which is highly homologous to beta-catenin but not to p120cas, a newly described catenin which contains a more divergent Armadillo-repeat domain. Immunoprecipitation, in vitro competition, and domain-mapping experiments demonstrate that fascin and E-cadherin utilize a similar binding site within beta-catenin, such that they form mutually exclusive complexes with beta-catenin. Immunofluorescence microscopy reveals that fascin and beta-catenin colocalize at cell-cell borders and dynamic cell leading edges of epithelial and endothelial cells. In addition to cell-cell borders, cadherins were unexpectedly observed to colocalize with fascin and beta-catenin at cell leading edges. It is conceivable that beta-catenin participates in modulating cytoskeletal dynamics in association with the microfilament-bundling protein fascin, perhaps in a coordinate manner with its functions in cadherin and APC complexes.
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PMID:beta-Catenin associates with the actin-bundling protein fascin in a noncadherin complex. 879 67

Loss of E-cadherin-mediated adhesion is an important step in the progression of many carcinomas. In model systems, it has been shown that cadherin function requires not only proper E-cadherin expression but also its linkage to the cytoskeleton through catenins. Hence, defects in catenins may cause defective E-cadherin function, and catenins as well as E-cadherin might constitute prognostic indicators. Here, we extend our previous study on E-cadherin in bladder cancer (Cancer Res., 53: 3241-3245, 1993). We have evaluated the expression of E-cadherin-associated cytoplasmic molecules (alpha-, beta-, and gamma-catenins and p120cas) to clarify whether or not the pattern of their expression could provide additional prognostic information beyond that from E-cadherin alone. Forty-eight frozen bladder tumor specimens and 9 samples of normal urothelium were studied by immunohistochemistry. A discrepancy between the E-cadherin and catenin expression pattern was seen in 20.8% of cases. Abnormal expression of each molecule is significantly correlated with tumor grade (P < 0.01) and stage (P < 0.01). Reduced expression of all of the molecules correlates with poor survival (P < 0.01 for each variable). Proportional hazard regression analysis showed that beta-catenin, E-cadherin, and alpha-catenin have strong predictive value, whereas plakoglobin and p120cas have a somewhat lower predictive value. Within patients with invasive tumors, those with a normal staining for either E-cadherin, alpha-catenin, or beta-catenin show a trend toward better survival. However, the difference in survival is significant only for E-cadherin (P < 0.05). Thus, beta-catenin, E-cadherin, and alpha-catenin have similar prognostic values. Therefore, from a practical point of view, the expression of any of these proteins can be of prognostic value for patients with bladder cancer.
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PMID:Prognostic value of cadherin-associated molecules (alpha-, beta-, and gamma-catenins and p120cas) in bladder tumors. 879 85

Cadherins comprise a family of calcium-dependent glycoproteins that function in mediating cell-cell adhesion in virtually all solid tissues of multicellular organisms. In epithelial cells, E-cadherin represents a key molecule in the establishment and stabilization of cellular junctions. On the cellular level, E-cadherin is concentrated at the adherens junction and interacts homophilically with E-cadherin molecules of adjacent cells. Significant progress has been made in understanding the extra- and intracellular interactions of E-cadherin. Recent success in solving the three-dimensional structure of an extracellular cadherin domain provides a structural basis for understanding the homophilic interaction mechanism and the calcium requirement of cadherins. According to the crystal structure, individual cadherin molecules cooperate to form a linear cell adhesion zipper. The intracellular anchorage of cadherins is regulated by the dynamic association with cytoplasmic proteins, termed catenins. The cytoplasmic domain of E-cadherin is complexed with either beta-catenin or plakoglobin (gamma-catenin). Beta-catenin and plakoglobin bind directly to alpha-catenin, giving rise to two distinct cadherin-catenin complexes (CCC). Alpha-catenin is thought to link both CCC's to actin filaments. The anchorage of cadherins to the cytoskeleton appears to be regulated by tyrosine phosphorylation. Phosphorylation-induced junctional disassembly targets the catenins, indicating that catenins are components of signal transduction pathways. The unexpected association of catenins with the product of the tumor suppressor gene APC has led to the discovery of a second, cadherin-independent catenin complex. Two separate catenin complexes are therefore involved in the cross-talk between cell adhesion and signal transduction. In this review we focus on protein interactions regulating the molecular architecture and function of the CCC. In the light of a fundamental role of the CCC during mammalian development and tissue morphogenesis, we also discuss the phenotypes of embryos lacking E-cadherin or beta-catenin.
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PMID:Cadherin-catenin complex: protein interactions and their implications for cadherin function. 880 74


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