Protein Kinase C ϵ Stabilizes {beta}-Catenin and Regulates Its Subcellular Localization in Podocytes [Signal Transduction]

Kidney disease has been linked to dysregulated signaling via protein kinase C (PKC) in kidney cells such as podocytes. PKCα is a conventional isoform of PKC and a well-known binding partner of β-catenin, which promotes its degradation. β-Catenin is the main effector of the canonical Wnt pathway and is critical in cell adhesion. However, whether other PKC isoforms interact with β-catenin has not been studied systematically. Here we demonstrate that PKCε-deficient mice, which develop proteinuria and glomerulosclerosis, display a lower β-catenin expression compared to PKC wildtype mice, consistent with an altered phenotype of podocytes in culture. Remarkably, β-catenin showed a reversed subcellular localization pattern: while β-catenin exhibited a perinuclear pattern in undifferentiated wild-type cells, it predominantly localized to the nucleus in PKCε-knockout cells. Phorbol 12-myristate 13-acetate stimulation of both cell types revealed that PKCε positively regulates β-catenin expression and stabilization in a glycogen synthase kinase-3β independent manner. Further, β-catenin overexpression in PKCε-deficient podocytes could restore the wildtype phenotype, similar to the rescue with a PKCε construct. This effect was mediated by upregulation of P-cadherin and the β-catenin downstream target fascin1. Zebrafish studies indicated three PKCε-specific phosphorylation sites in β-catenin that are required for full β-catenin function. Co-immunoprecipitation and pulldown assays confirmed PKCε and β-catenin as binding partners and revealed that ablation of the three PKCε phosphorylation sites weakens their interaction. In summary, we identified a novel pathway for regulation of β-catenin levels and define PKCε as an important β-catenin interaction partner and signaling opponent of other PKC isoforms in podocytes.

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