Abstract
BackgroundEpithelial tissues depend on intercellular homodimerization of E-cadherin and loss of E-cadherin is central to the epithelial to mesenchymal transition seen in multiple human diseases. Signaling pathways regulate E-cadherin function and cellular distribution via phosphorylation of the cytoplasmic region by kinases such as casein kinases but the protein phosphatases involved have not been identified.ResultsThis study shows protein Ser/Thr phosphatase-6 catalytic subunit (PP6c) is expressed in epithelial tissue and its mRNA and protein are robustly up-regulated in epithelial cell lines at high vs. low density. PP6c accumulates at adherens junctions, not tight junctions, co-immunoprecipitates with E-cadherin-catenin complexes without a canonical SAPS subunit, and associates directly with the E-cadherin cytoplasmic tail. Inducible shRNA knockdown of PP6c dispersed E-cadherin from the cell surface and this response was reversed by chemical inhibition of casein kinase-1 and prevented by alanine substitution of Ser846 in murine E-cadherin.ConclusionsPP6c associates with E-cadherin in adherens junctions and is required to oppose casein kinase-1 to maintain cell surface localization of E-cadherin. There is feedback signaling to enhance PP6c transcription and boost protein levels in high density epithelial cells.
Highlights
Epithelial tissues depend on intercellular homodimerization of E-cadherin and loss of E-cadherin is central to the epithelial to mesenchymal transition seen in multiple human diseases
Protein phosphatase-6 in human epithelial cells Protein phosphatase-6 catalytic subunit (PP6c) expression is highest in the gastrointestinal tract and in hematopoietic cells, based on tissue analyses of mRNA and protein in GeneAtlas and ProteinAtlas
There was intense PP6c staining in the epithelial cells, seen as a continuous layer of cells surrounding the large unstained granules of mucosal fluid
Summary
Epithelial tissues depend on intercellular homodimerization of E-cadherin and loss of E-cadherin is central to the epithelial to mesenchymal transition seen in multiple human diseases. The physiological function and physical integrity of epithelial tissues depends on contacts between cells that include adherens junctions and tight junctions (for review [1]). E-cadherin mediated cell-cell junctions play an important role in contact inhibition of cell growth, and loss of E-cadherin expression occurs during tumor progression and metastasis [3,4]. This makes it important to understand the mechanisms that govern E-cadherin expression and distribution to the cell surface. Wnt signaling plays a role in the distinctive switching of gene expression in epithelial cells. The E-cadherin/catenin complex physically associates with the Wnt co-receptor and is necessary for downstream β-catenin activation [6,7]
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