E-cadherin binding prevents beta-catenin nuclear localization and beta-catenin/LEF-1-mediated transactivation

Beta-catenin is a multifunctional protein found in three cell compartments: the plasma membrane, the cytoplasm and the nucleus. The cell has developed elaborate ways of regulating the level and localization of beta-catenin to assure its specific function in each compartment. One aspect of this regulation is inherent in the structural organization of beta-catenin itself; most of its protein-interacting motifs overlap so that interaction with one partner can block binding of another at the same time. Using recombinant proteins, we found that E-cadherin and lymphocyte-enhancer factor-1 (LEF-1) form mutually exclusive complexes with beta-catenin; the association of beta-catenin with LEF-1 was competed out by the E-cadherin cytoplasmic domain. Similarly, LEF-1 and adenomatous polyposis coli (APC) formed separate, mutually exclusive complexes with beta-catenin. In Wnt-1-transfected C57MG cells, free beta-catenin accumulated and was able to associate with LEF-1. The absence of E-cadherin in E-cadherin-/- embryonic stem (ES) cells also led to an accumulation of free beta-catenin and its association with LEF-1, thereby mimicking Wnt signaling. beta-catenin/LEF-1-mediated transactivation in these cells was antagonized by transient expression of wild-type E-cadherin, but not of E-cadherin lacking the beta-catenin binding site. The potent ability of E-cadherin to recruit beta-catenin to the cell membrane and prevent its nuclear localization and transactivation was also demonstrated using SW480 colon carcinoma cells.

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Faculty Opinions recommendation of Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1001734.8358 ◽

2001 ◽

Author(s):

Kathleen J Green

Keyword(s):

Vitamin D ◽

Colon Carcinoma ◽

Carcinoma Cells ◽

Beta Catenin ◽

Colon Carcinoma Cells ◽

Vitamin D 3 ◽

E Cadherin

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Human embryonic stem cells

Journal of Cell Science ◽

10.1242/jcs.113.1.5 ◽

2000 ◽

Vol 113 (1) ◽

pp. 5-10 ◽

Cited By ~ 4

Author(s):

M.F. Pera ◽

B. Reubinoff ◽

A. Trounson

Keyword(s):

Stem Cells ◽

Cell Lines ◽

Embryonal Carcinoma ◽

Es Cells ◽

Embryonic Stem ◽

Early Embryo ◽

Carcinoma Cells ◽

Mouse Es Cells ◽

Undifferentiated State ◽

Human Es Cells

Embryonic stem (ES) cells are cells derived from the early embryo that can be propagated indefinitely in the primitive undifferentiated state while remaining pluripotent; they share these properties with embryonic germ (EG) cells. Candidate ES and EG cell lines from the human blastocyst and embryonic gonad can differentiate into multiple types of somatic cell. The phenotype of the blastocyst-derived cell lines is very similar to that of monkey ES cells and pluripotent human embryonal carcinoma cells, but differs from that of mouse ES cells or the human germ-cell-derived stem cells. Although our understanding of the control of growth and differentiation of human ES cells is quite limited, it is clear that the development of these cell lines will have a widespread impact on biomedical research.

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Nuclear localization of E-cadherin but not beta-catenin in human ovarian granulosa cell tumours and normal ovarian follicles and ovarian stroma

Histopathology ◽

10.1111/j.1365-2559.2011.03761.x ◽

2011 ◽

Vol 58 (3) ◽

pp. 423-432 ◽

Cited By ~ 17

Author(s):

Yoshihiro Ohishi ◽

Yoshinao Oda ◽

Shuichi Kurihara ◽

Tsunehisa Kaku ◽

Hiroaki Kobayashi ◽

...

Keyword(s):

Granulosa Cell ◽

Nuclear Localization ◽

Ovarian Follicles ◽

Beta Catenin ◽

Ovarian Stroma ◽

Ovarian Granulosa Cell ◽

Granulosa Cell Tumours ◽

E Cadherin

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p120ctn Acts as an Inhibitory Regulator of Cadherin Function in Colon Carcinoma Cells

The Journal of Cell Biology ◽

10.1083/jcb.145.3.551 ◽

1999 ◽

Vol 145 (3) ◽

pp. 551-562 ◽

Cited By ~ 154

Author(s):

Shinya Aono ◽

Shinichi Nakagawa ◽

Albert B. Reynolds ◽

Masatoshi Takeichi

Keyword(s):

Cell Aggregation ◽

Carcinoma Cells ◽

Mobility Shift ◽

Signaling Mechanism ◽

Colon Carcinoma Cells ◽

Normal Expression ◽

Biochemical State ◽

Induced Aggregation ◽

Ht 29 ◽

E Cadherin

p120ctn binds to the cytoplasmic domain of cadherins but its role is poorly understood. Colo 205 cells grow as dispersed cells despite their normal expression of E-cadherin and catenins. However, in these cells we can induce typical E-cadherin–dependent aggregation by treatment with staurosporine or trypsin. These treatments concomitantly induce an electrophoretic mobility shift of p120ctn to a faster position. To investigate whether p120ctn plays a role in this cadherin reactivation process, we transfected Colo 205 cells with a series of p120ctn deletion constructs. Notably, expression of NH2-terminally deleted p120ctn induced aggregation. Similar effects were observed when these constructs were introduced into HT-29 cells. When a mutant N-cadherin lacking the p120ctn-binding site was introduced into Colo 205 cells, this molecule also induced cell aggregation, indicating that cadherins can function normally if they do not bind to p120ctn. These findings suggest that in Colo 205 cells, a signaling mechanism exists to modify a biochemical state of p120ctn and the modified p120ctn blocks the cadherin system. The NH2 terminus–deleted p120ctn appears to compete with the endogenous p120ctn to abolish the adhesion-blocking action.

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Changes of E-cadherin and beta-catenin levels during induced differentiation of colorectal carcinoma cells.

International Journal of Molecular Medicine ◽

10.3892/ijmm.4.5.541 ◽

1999 ◽

Author(s):

D Kucerová ◽

E Sloncová ◽

Z Tuhácková ◽

M Uhlírová ◽

M Kos ◽

...

Keyword(s):

Colorectal Carcinoma ◽

Carcinoma Cells ◽

Beta Catenin ◽

Induced Differentiation ◽

E Cadherin

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Loss of Function of E-Cadherin in Embryonic Stem Cells and the Relevance to Models of Tumorigenesis

Journal of Oncology ◽

10.1155/2011/352616 ◽

2011 ◽

Vol 2011 ◽

pp. 1-19 ◽

Cited By ~ 28

Author(s):

Lisa Mohamet ◽

Kate Hawkins ◽

Christopher M. Ward

Keyword(s):

Stem Cells ◽

Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Es Cells ◽

Embryonic Stem ◽

Loss Of Function ◽

Mesenchymal Transition ◽

Cell Metastasis ◽

Patient Prognosis ◽

E Cadherin

E-cadherin is the primary cell adhesion molecule within the epithelium, and loss of this protein is associated with a more aggressive tumour phenotype and poorer patient prognosis in many cancers. Loss of E-cadherin is a defining characteristic of epithelial-mesenchymal transition (EMT), a process associated with tumour cell metastasis. We have previously demonstrated an EMT event during embryonic stem (ES) cell differentiation, and that loss of E-cadherin in these cells results in altered growth factor response and changes in cell surface localisation of promigratory molecules. We discuss the implication of loss of E-cadherin in ES cells within the context of cancer stem cells and current models of tumorigenesis. We propose that aberrant E-cadherin expression is a critical contributing factor to neoplasia and the early stages of tumorigenesis in the absence of EMT by altering growth factor response of the cells, resulting in increased proliferation, decreased apoptosis, and acquisition of a stem cell-like phenotype.

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Expression of Eph receptors and ephrins is differentially regulated by E-cadherin

Journal of Cell Science ◽

10.1242/jcs.113.10.1793 ◽

2000 ◽

Vol 113 (10) ◽

pp. 1793-1802 ◽

Cited By ~ 5

Author(s):

S. Orsulic ◽

R. Kemler

Keyword(s):

Epithelial Cells ◽

Expression Pattern ◽

Es Cells ◽

Expression Patterns ◽

Family Members ◽

Embryonic Stem ◽

Eph Receptors ◽

Wild Type ◽

Mesenchymal Transition ◽

E Cadherin

E-cadherin is the main cell adhesion molecule of early embryonic and adult epithelial cells. Downregulation of E-cadherin is associated with epithelial-mesenchymal transition during embryonic mesoderm formation and tumor progression. To identify genes whose expression is affected by the loss of E-cadherin, we compared mRNA expression patterns between wild-type and E-cadherin null mutant embryonic stem (ES) cells. We found that expression of several Eph receptors and ephrins is dependent on E-cadherin. Rescue of E-cadherin null ES cells with E-cadherin cDNA restores the wild-type expression pattern of Eph family members. Rescue of E-cadherin null ES cells with N-cadherin cDNA does not restore the wild-type expression pattern, indicating that the regulation of differential expression of Eph family members is specific to E-cadherin. Constitutive ectopic expression of E-cadherin in non-epithelial NIH3T3 cells results in the production of the EphA2 receptor. In epithelial cells, E-cadherin is required for EphA2 receptor localization at cell-cell contacts; in the absence of functional E-cadherin, EphA2 localizes to the perinuclear region. Our results indicate that E-cadherin may be directly or indirectly required for the membrane localization of Eph receptors and their membrane-bound ligands.

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Expression of E- or P-cadherin is not sufficient to modify the morphology and the tumorigenic behavior of murine spindle carcinoma cells. Possible involvement of plakoglobin

Journal of Cell Science ◽

10.1242/jcs.105.4.923 ◽

1993 ◽

Vol 105 (4) ◽

pp. 923-934 ◽

Cited By ~ 2

Author(s):

P. Navarro ◽

E. Lozano ◽

A. Cano

Keyword(s):

Ectopic Expression ◽

In Vitro Assay ◽

Carcinoma Cells ◽

Beta Catenin ◽

Vitro Assay ◽

Cell Extracts ◽

Spindle Cells ◽

Low Levels ◽

E Cadherin

Transfection of E- and P-cadherin cDNA has been carried out in murine spindle carcinoma cells previously shown to be deficient in both cadherins (Navarro et al., J. Cell Biol. 115, 517–533, 1991). High levels of expression of E- or P-cadherin do not significantly affect the fibroblastic morphology of the parental spindle cells. In addition, the tumorigenic behavior of these highly malignant cells is not influenced by the ectopic expression of either cadherin. Nevertheless, a fraction of the exogenous cadherins is able to associate to detergent-insoluble components of the transfectant cells, and the expression of the exogenous E-cadherin confers Ca(2+)-dependent aggregation on the spindle transfectants in an in vitro assay. Immunoprecipitation analysis of the cadherin-catenin complex of the transfectants revealed that the ectopic E-cadherin associates with the alpha- and beta-catenin proteins. However, the gamma-catenin/plakoglobin component could not be detected in the E-cadherin immunocomplexes of the spindle transfectant cells, in contrast to the epithelial cells where the three catenins appeared to be associated with E-cadherin. The lack of association of gamma-catenin is correlated with very low levels of plakoglobin in whole cell extracts of the parental spindle cells. These results indicate that the association of E-cadherin with the alpha- and beta-catenin components is not sufficient to promote a fibroblastoid-epithelial conversion of highly malignant spindle cells. The presence of plakoglobin could be required for the proper organization of E-cadherin in the transfectant cells in order to acquire an epithelioid phenotype.

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