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)

One of the hallmarks of polarized epithelial cells undergoing mitosis is their rounded morphology. This phenotype correlates with a reduced cell-substratum adhesion, apparently caused by a modulation of integrin function. However, it is still unclear whether the cadherin-mediated cell-cell adhesion is affected as well. To address this question, the cadherin complex was analyzed in different cell cycle stages of Madin-Darby canine kidney cells. By immunofluorescence, mitotic Madin-Darby canine kidney cells showed an increased staining of E-cadherin and the catenins (alpha-catenin, beta-catenin, plakoglobin, p120(ctn)) in the cytosol, suggesting a reorganization of the cadherin-catenin complex during mitosis. Biochemical analysis revealed that the overall amount of these components, as well as the proportion of the complex associated with the actin cytoskeleton, remained unchanged in mitotic cells. However, we found evidence for an internalization of E-cadherin during mitosis. In addition, the cadherin-catenin complex was analyzed for mitosis-specific changes in phosphorylation. We report a decrease in the tyrosine phosphorylation of beta-catenin, plakoglobin, and p120(ctn) during mitosis. Moreover, we observed a mitosis-specific Ser/Thr-phosphorylation of p120(ctn), as detected by the MPM-2 antibody. Hence, the cadherin/catenin complex is a target for different posttranslational modifications during mitosis, which may also have a profound impact on cadherin-mediated cell-cell adhesion.
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PMID:Modification of the E-cadherin-catenin complex in mitotic Madin-Darby canine kidney epithelial cells. 977 55

Cadherin-mediated adhesion depends on the association of its cytoplasmic domain with the actin-containing cytoskeleton. This interaction is mediated by a group of cytoplasmic proteins: alpha-and beta- or gamma- catenin. Phosphorylation of beta-catenin on tyrosine residues plays a role in controlling this association and, therefore, cadherin function. Previous work from our laboratory suggested that a nonreceptor protein tyrosine phosphatase, bound to the cytoplasmic domain of N-cadherin, is responsible for removing tyrosine-bound phosphate residues from beta-catenin, thus maintaining the cadherin-actin connection (). Here we report the molecular cloning of the cadherin-associated tyrosine phosphatase and identify it as PTP1B. To definitively establish a causal relationship between the function of cadherin-bound PTP1B and cadherin-mediated adhesion, we tested the effect of expressing a catalytically inactive form of PTP1B in L cells constitutively expressing N-cadherin. We find that expression of the catalytically inactive PTP1B results in reduced cadherin-mediated adhesion. Furthermore, cadherin is uncoupled from its association with actin, and beta-catenin shows increased phosphorylation on tyrosine residues when compared with parental cells or cells transfected with the wild-type PTP1B. Both the transfected wild-type and the mutant PTP1B are found associated with N-cadherin, and recombinant mutant PTP1B binds to N-cadherin in vitro, indicating that the catalytically inactive form acts as a dominant negative, displacing endogenous PTP1B, and rendering cadherin nonfunctional. Our results demonstrate a role for PTP1B in regulating cadherin-mediated cell adhesion.
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PMID:The nonreceptor protein tyrosine phosphatase PTP1B binds to the cytoplasmic domain of N-cadherin and regulates the cadherin-actin linkage. 978 60

The E-cadherin-catenin complex, by mediating intercellular adhesion, regulates the architectural integrity of epithelia. Down-regulation of its expression is thought to contribute to invasion of carcinoma cells. To investigate the involvement of the E-cadherin-catenin adhesion system in the progression of human bronchopulmonary carcinomas, we compared the immunohistochemical distribution of E-cadherin, alpha-catenin, and beta-catenin in four human bronchial cancer cell lines with different invasive abilities and in 44 primary bronchopulmonary tumors. Although invasive bronchial cell lines did not express E-cadherin and alpha-catenin, complete down-regulation of cadherin-catenin complex expression was a rare event in vivo in bronchopulmonary carcinomas. Nevertheless, a spotty and cytoplasmic pattern of E-cadherin and catenins was observed in 32 primary tumors, only in invasive tumor clusters. Immunoprecipitation experiments showed that this redistribution was not related to a disruption of cadherin-catenin interaction but to down-regulated tyrosine phosphorylation of E-cadherin. We conclude that loss of E-cadherin and/or catenins is not a prominent early event in the invasive progression of human bronchopulmonary carcinomas in vivo. The decreased tyrosine phosphorylation of E-cadherin may reflect a loss of functionality of the complex and implicates a major role in tumor invasion.
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PMID:Cytoplasmic redistribution of E-cadherin-catenin adhesion complex is associated with down-regulated tyrosine phosphorylation of E-cadherin in human bronchopulmonary carcinomas. 981 44

This paper is the first in a series aimed at understanding the role of beta-catenin in epithelial-mesenchymal transformation (EMT) and acquisition of mesenchymal invasive motility. Here, we compare the expression of this and related molecules in the two major tissue phenotypes, epithelial and mesenchymal, the latter including normal avian and mammalian fibroblasts and malignant human uveal melanoma cells. Previously, it was proposed that src initiates EMT by tyrosine phosphorylation of the cadherin/catenin complex resulting in a negative effect on epithelial gene expression. On the contrary, we found that although beta-catenin becomes diffuse in the cytoplasm during embryonic EMT, the cytoplasmic beta-catenin of the embryonic and adult mesenchymal cells we examined is not tyrosine phosphorylated. Pervanadate experiments indicate that cytoplasmic PTPases maintain this dephosphorylation. GSK-3beta is present, but little or no APC occurs in normal and neoplastic mesenchymal cells. The function of the nonphosphorylated cytoplasmic beta-catenin in mesenchyme may be related to invasive motility. Indeed, in order to invade extracellular matrix, transitional (Mel 252) melanoma cells transform from an epithelial to a mesenchymal phenotype with increased cytoplasmic beta-catenin. Moreover, antisense beta-catenin and plakoglobin ODNs inhibit Mel 252 and corneal fibroblast invasion of collagen. All fibroblastic, transitional, and spindle melanoma cells contain nuclear as well as cytoplasmic beta-catenin, but they are not significantly more invasive than normal fibroblasts that contain only cytoplasmic beta-catenin.
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PMID:Tissue-specific expression of beta-catenin in normal mesenchyme and uveal melanomas and its effect on invasiveness. 982 3

We presented earlier a 2-dimensional cell-motility assay using a highly metastatic variant (L-10) of human rectal-adenocarcinoma cell line RCM-1 as a motility model of tumor cells of epithelial origin. In this model, L-10 cells moved as coherent cell sheets when stimulated with 12-O-tetradecanoylphorbol-13-acetate (TPA), and we called this type of movement "cohort migration". Electron- and immunoelectron-microscope study of the migrating cell sheets demonstrated localized release from cell-cell adhesion only at the lower portion of the cells with loss of E-cadherin immunoreactivity, and this change was associated with increased tyrosine phosphorylation of the E-cadherin-catenin complex, including beta-catenin. In the present study, to obtain evidence to support the relevance of our model to carcinoma-cell movement in vivo, we sought a naturally occurring motogenic factor(s) able to induce this cohort migration. Among the factors examined, hepatocyte growth factor/scatter factor (HGF/SF) clearly induced cohort migration of L-10 cells. Additionally, not only L-10 but several other human colorectal-carcinoma cell lines showed this type of migration in response to HGF/SF, while yet others showed scattering-type motility. In this HGF/SF-induced migration, localized release from cell-cell adhesion was induced only at the lower portion of the cells, allowing them to extend leading lamellae, whereas close cell-cell contacts remained at the upper portion of the cells, as seen in TPA-induced cohort migration. Scattering-type cell lines tended to express more c-Met (receptor for HGF/SF) mRNA than the cell lines that showed cohort-type migration. LoVo, one of the scattering-type cell lines, expressed more c-Met protein and less E-cadherin than L-10, which showed cohort-type migration. HGF/SF treatment of LoVo reduced the amount of alpha-catenin complexed with E-cadherin more markedly than in L-10, but in both cell lines this reduction was not accompanied by increased tyrosine phosphorylation of beta-catenin, suggesting the presence of a mechanism other than phosphorylation for release from cell-cell adhesion during cell motility.
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PMID:Hepatocyte growth factor/scatter factor induces not only scattering but also cohort migration of human colorectal-adenocarcinoma cells. 983 69

E-cadherin and its associated cytoplasmic proteins alpha-, beta-, and gamma-catenin, play a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture. Perturbation in the expression or function of any of these molecules results in loss of intercellular adhesion, with possible consequent cell transformation and tumour progression. The catenins are connected to many structural and functional proteins, which in turn influence their functions. Among these molecules are type 1 growth factor receptors, which along with other molecules are believed to alter the function of catenins through tyrosine phosphorylation. A recent finding is the association between the catenins and the adenomatous polyposis coli gene product (APC). APC mutation is an early event in colorectal carcinogenesis. It may possibly do so through perturbation of the critical cadherin/catenin complex. Further studies of the cadherin/catenin complex and its connections may give insight into the early molecular interactions critical to the initiation and progression oftumours, which should aid in the development of novel therapeutic strategies for both prevention and treatment.
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PMID:E-cadherin and catenins: molecules with versatile roles in normal and neoplastic epithelial cell biology. 984 Aug

The E-cadherin/catenin complex regulates Ca++-dependent cell-cell adhesion and is localized to the basal-lateral membrane of polarized epithelial cells. Little is known about mechanisms of complex assembly or intracellular trafficking, or how these processes might ultimately regulate adhesion functions of the complex at the cell surface. The cytoplasmic domain of E-cadherin contains two putative basal-lateral sorting motifs, which are homologous to sorting signals in the low density lipoprotein receptor, but an alanine scan across tyrosine residues in these motifs did not affect the fidelity of newly synthesized E-cadherin delivery to the basal-lateral membrane of MDCK cells. Nevertheless, sorting signals are located in the cytoplasmic domain since a chimeric protein (GP2CAD1), comprising the extracellular domain of GP2 (an apical membrane protein) and the transmembrane and cytoplasmic domains of E-cadherin, was efficiently and specifically delivered to the basal-lateral membrane. Systematic deletion and recombination of specific regions of the cytoplasmic domain of GP2CAD1 resulted in delivery of <10% of these newly synthesized proteins to both apical and basal-lateral membrane domains. Significantly, >90% of each mutant protein was retained in the ER. None of these mutants formed a strong interaction with beta-catenin, which normally occurs shortly after E-cadherin synthesis. In addition, a simple deletion mutation of E-cadherin that lacks beta-catenin binding is also localized intracellularly. Thus, beta-catenin binding to the whole cytoplasmic domain of E-cadherin correlates with efficient and targeted delivery of E-cadherin to the lateral plasma membrane. In this capacity, we suggest that beta-catenin acts as a chauffeur, to facilitate transport of E-cadherin out of the ER and the plasma membrane.
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PMID:Coupling assembly of the E-cadherin/beta-catenin complex to efficient endoplasmic reticulum exit and basal-lateral membrane targeting of E-cadherin in polarized MDCK cells. 1003 90

Cell migration requires precise control, which is altered or lost when tumor cells become invasive and metastatic. Although the integrity of cell-cell contacts, such as adherens junctions, is essential for the maintenance of functional epithelia, they need to be rapidly disassembled during migration. The transmembrane cell adhesion protein E-cadherin and the cytoplasmic catenins are molecular elements of these structures. Here we demonstrate that epithelial cell migration is accompanied by tyrosine phosphorylation of beta-catenin and an increase of its free cytoplasmic pool. We show further that the protein-tyrosine phosphatase LAR (leukocyte common antigen related) colocalizes with the cadherin-catenin complex in epithelial cells and associates with beta-catenin and plakoglobin. Interestingly, ectopic expression of protein-tyrosine phosphatase (PTP) LAR inhibits epithelial cell migration by preventing phosphorylation and the increase in the free pool of beta-catenin; moreover, it inhibits tumor formation in nude mice. These data support a function for PTP LAR in the regulation of epithelial cell-cell contacts at adherens junctions as well as in the control of beta-catenin signaling functions. Thus PTP-LAR appears to play an important role in the maintenance of epithelial integrity, and a loss of its regulatory function may contribute to malignant progression and metastasis.
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PMID:Phosphorylation and free pool of beta-catenin are regulated by tyrosine kinases and tyrosine phosphatases during epithelial cell migration. 1018 1

Initial events in the metastatic spread of tumours involve loss of cell-cell adhesion within the primary tumour mass. The integrity and morphology of epithelial tumour cell colonies is maintained primarily by cell-cell adhesions mediated by E-cadherin and its associated intracellular catenin molecules. Hepatocyte growth factor/scatter factor (HGF/SF) is a potent promoter of the metastatic functions of tumour cells, including motility and invasion and also induces the dissociation of tumour cell colonies. In this study we report that HGF/SF promoted the scattering of an epithelial colorectal tumour cell line. Western blotting demonstrated that this was not due to a change in level of either E-cadherin or its associated catenin molecules. Immunoprecipitation studies revealed that HGF/SF elevated the level of tyrosine-phosphorylated beta-catenin within these cells together with reducing the amount of E-cadherin that was observed to co-precipitate with the beta-catenin. These results were confirmed with confocal scanning laser microscopy. We conclude that phosphorylation of beta-catenin by HGF/SF affects its association with E-cadherin at the cell surface and thus regulates E-cadherin function resulting in colony scattering phenomena.
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PMID:Hepatocyte growth factor/scatter factor disrupts epithelial tumour cell-cell adhesion: involvement of beta-catenin. 1022 90

The E-cadherin-catenin complex is pivotal for the regulation of cancer invasion. It not only serves cell-cell adhesion but also transduces signals from the micro-environment to other molecular complexes possibly implicated in invasion. Both functions are disturbed when the extracellular part of E-cadherin is cleaved off. Moreover, upon release into the environment, the E-cadherin fragments may interfere with intact complexes, as indicated by experiments with His-Ala-Val (HAV)-containing peptides that are homologous to parts of the first extracellular domain of E-cadherin. Scatter factor/hepatocyte growth factor (SF/HGF), on binding to its c-met tyrosine kinase receptor, can induce invasion through tyrosine phosphorylation of beta-catenin. SF/HGF-induced invasion is also associated with phosphorylation of pp125FAK, and both invasion and phosphorylation are inhibited by platelet-activating factor (PAF). Activation of the membrane-bound non-receptor tyrosine kinase pp60src can also induce invasion. Signal transduction pathways starting from pp60src include E-cadherin-associated beta-catenin as well as the focal adhesion kinase pp125FAK. Whereas all invasion-inducing pathways implicate phosphoinositide 3-kinase, the PAF pathway seems to be E-cadherin-catenin-independent. We conclude that cancer cell invasion is regulated by paracrine and autocrine factors that are released upon cross-talk with the host cells.
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PMID:Extracellular regulation of cancer invasion: the E-cadherin-catenin and other pathways. 1032 Sep 32


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