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Independent interactions of phosphorylated ?-catenin with E-cadherin at cell-cell contacts and APC at cell protrusions.

ABSTRACT: The APC tumour suppressor functions in several cellular processes including the regulation of ?-catenin in Wnt signalling and in cell adhesion and migration.In this study, we establish that in epithelial cells N-terminally phosphorylated ?-catenin specifically localises to several subcellular sites including cell-cell contacts and the ends of cell protrusions. N-terminally phosphorylated ?-catenin associates with E-cadherin at adherens junctions and with APC in cell protrusions. We isolated APC-rich protrusions from stimulated cells and detected ?-catenin, GSK3? and CK1?, but not axin. The APC/phospho-?-catenin complex in cell protrusions appears to be distinct from the APC/axin/?-catenin destruction complex. GSK3? phosphorylates the APC-associated population of ?-catenin, but not the cell junction population. ?-catenin associated with APC is rapidly phosphorylated and dephosphorylated. HGF and wound-induced cell migration promote the localised accumulation of APC and phosphorylated ?-catenin at the leading edge of migrating cells. APC siRNA and analysis of colon cancer cell lines show that functional APC is required for localised phospho-?-catenin accumulation in cell protrusions.We conclude that N-terminal phosphorylation of ?-catenin does not necessarily lead to its degradation but instead marks distinct functions, such as cell migration and/or adhesion processes. Localised regulation of APC-phospho-?-catenin complexes may contribute to the tumour suppressor activity of APC.

SUBMITTER: Faux MC

PROVIDER: S-EPMC2994709 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Independent interactions of phosphorylated β-catenin with E-cadherin at cell-cell contacts and APC at cell protrusions.

Faux Maree C MC Coates Janine L JL Kershaw Nadia J NJ Layton Meredith J MJ Burgess Antony W AW

PloS one 20101130 11

<h4>Background</h4>The APC tumour suppressor functions in several cellular processes including the regulation of β-catenin in Wnt signalling and in cell adhesion and migration.<h4>Findings</h4>In this study, we establish that in epithelial cells N-terminally phosphorylated β-catenin specifically localises to several subcellular sites including cell-cell contacts and the ends of cell protrusions. N-terminally phosphorylated β-catenin associates with E-cadherin at adherens junctions and with APC i ...[more]

PMID: 21152425

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Project description: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 beta-catenin, a known proto-oncogene. To distinguish between an adhesion- versus a beta-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 beta-catenin binding region of the cytoplasmic domain but not by E-cadherin constructs that exhibit adhesive activity, but lack the beta-catenin binding region. This growth suppression correlates with a reduction in beta-catenin/T cell factor (TCF) reporter gene activity. Importantly, direct inhibition of beta-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 beta-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 beta-catenin from the cytosol and nucleus. This appears to be due to the existence of a large pool of cytosolic beta-catenin in SW480 cells that is refractory to both cadherin binding and TCF binding. Thus, a small pool of beta-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 beta-catenin suggests that there are mechanisms to regulate beta-catenin signaling in addition to controlling its level of accumulation.

Dataset Information

Independent interactions of phosphorylated ?-catenin with E-cadherin at cell-cell contacts and APC at cell protrusions.

Publications

Independent interactions of phosphorylated β-catenin with E-cadherin at cell-cell contacts and APC at cell protrusions.

Similar Datasets

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