| First Author | Duong M | Year | 2017 |
| Journal | J Biol Chem | Volume | 292 |
| Issue | 29 | Pages | 12100-12110 |
| PubMed ID | 28539358 | Mgi Jnum | J:245895 |
| Mgi Id | MGI:5916751 | Doi | 10.1074/jbc.M117.775700 |
| Citation | Duong M, et al. (2017) Protein kinase C stabilizes beta-catenin and regulates its subcellular localization in podocytes. J Biol Chem 292(29):12100-12110 |
| abstractText | Kidney disease has been linked to dysregulated signaling via PKC in kidney cells such as podocytes. PKCalpha is a conventional isoform of PKC and a well-known binding partner of beta-catenin, which promotes its degradation. beta-Catenin is the main effector of the canonical Wnt pathway and is critical in cell adhesion. However, whether other PKC isoforms interact with beta-catenin has not been studied systematically. Here we demonstrate that PKC-deficient mice, which develop proteinuria and glomerulosclerosis, display lower beta-catenin expression compared with PKC wild-type mice, consistent with an altered phenotype of podocytes in culture. Remarkably, beta-catenin showed a reversed subcellular localization pattern: Although beta-catenin exhibited a perinuclear pattern in undifferentiated wild-type cells, it predominantly localized to the nucleus in PKC knockout cells. Phorbol 12-myristate 13-acetate stimulation of both cell types revealed that PKC positively regulates beta-catenin expression and stabilization in a glycogen synthase kinase 3beta-independent manner. Further, beta-catenin overexpression in PKC-deficient podocytes could restore the wild-type phenotype, similar to rescue with a PKC construct. This effect was mediated by up-regulation of P-cadherin and the beta-catenin downstream target fascin1. Zebrafish studies indicated three PKC-specific phosphorylation sites in beta-catenin that are required for full beta-catenin function. Co-immunoprecipitation and pulldown assays confirmed PKC and beta-catenin as binding partners and revealed that ablation of the three PKC phosphorylation sites weakens their interaction. In summary, we identified a novel pathway for regulation of beta-catenin levels and define PKC as an important beta-catenin interaction partner and signaling opponent of other PKC isoforms in podocytes. |
