E-cadherin suppresses cellular transformation by inhibiting beta-catenin signaling in an adhesion-independent manner Journal Article
| Authors: | Gottardi, C. J.; Wong, E.; Gumbiner, B. M. |
| Article Title: | E-cadherin suppresses cellular transformation by inhibiting beta-catenin signaling in an adhesion-independent manner |
| Abstract: | E-cadherin is a tumor suppressor protein with a well-established role in cell-cell adhesion. Adhesion could contribute to tumor suppression either by physically joining cells or by facilitating other juxtacrine signaling events. Alternatively, E-cadherin tumor suppressor activity could result from binding and antagonizing the nuclear signaling function of β-catenin, a known proto-oncogene. To distinguish between an adhesion-versus a β-catenin signaling-dependent mechanism, chimeric cadherin constructs were expressed in the SW480 colorectal tumor cell line. Expression of wild-type E-cadherin significantly inhibits the growth of this cell line. Growth inhibitory activity is retained by all constructs that have the β-catenin binding region of the cytoplasmic domain but not by E-cadherin constructs that exhibit adhesive activity, but lack the β-catenin binding region. This growth suppression correlates with a reduction in β-catenin/T cell factor (TCF) reporter gene activity. Importantly, direct inhibition of β-catenin/TCF signaling inhibits the growth of SW480 cells, and the growth inhibitory activity of E-cadherin is rescued by constitutively activated forms of TCF. Thus, the growth suppressor activity of E-cadherin is adhesion independent and results from an inhibition of the β-catenin/TCF signaling pathway, suggesting that loss of E-cadherin expression can contribute to upregulation of this pathway in human cancers. E-cadherin-mediated growth suppression was not accompanied by overall depletion of β-catenin from the cytosol and nucleus. This appears to be due to the existence of a large pool of cytosolic β-catenin in SW480 cells that is refractory to both cadherin binding and TCF binding. Thus, a small pool of β-catenin that can bind TCF (i.e., the transcriptionally active pool) can be selectively depleted by E-cadherin expression. The existence of functionally distinct pools of cytosolic β-catenin suggests that there are mechanisms to regulate β-catenin signaling in addition to controlling its level of accumulation. |
| Keywords: | signal transduction; controlled study; human cell; dna-binding proteins; sequence deletion; protein localization; cell division; proto oncogene; gene expression; cell growth; protein binding; cancer cell culture; tumor cells, cultured; uvomorulin; transcription factors; cell transformation, neoplastic; cancer inhibition; gene activation; gene expression regulation, neoplastic; correlation analysis; recombinant fusion proteins; cell transformation; cytoplasm; protein structure, tertiary; binding sites; genes, reporter; trans-activators; cell nucleus; tumor suppressor; colon carcinoma; beta catenin; cell adhesion; cadherins; genes, tumor suppressor; e-cadherin; lymphoid enhancer-binding factor 1; gene activity; gene construct; growth inhibition; cytoskeletal proteins; adhesion; β-catenin; humans; human; priority journal; article; t cell factor |
| Journal Title: | Journal of Cell Biology |
| Volume: | 153 |
| Issue: | 5 |
| ISSN: | 0021-9525 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2001-05-28 |
| Start Page: | 1049 |
| End Page: | 1059 |
| Language: | English |
| DOI: | 10.1083/jcb.153.5.1049 |
| PUBMED: | 11381089 |
| PROVIDER: | scopus |
| PMCID: | PMC2174337 |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
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