Protein kinase C ϵ stabilizes β-catenin and regulates its subcellular localization in podocytes

Duong M, Yu X, Teng B, Schroder P, Haller H, Eschenburg S, Schiffer M (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Journal of Biological Chemistry American Society for Biochemistry and Molecular Biology

Book Volume: 292

Pages Range: 12100-12110

Journal Issue: 29

DOI: 10.1074/jbc.M117.775700

Abstract

Kidney disease has been linked to dysregulated signaling via 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 lower β-catenin expression compared with PKC wild-type mice, consistent with an altered phenotype of podocytes in culture. Remarkably, β-catenin showed a reversed subcellular localization pattern: Although 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 wild-type phenotype, similar to rescue with a PKCϵ construct. This effect was mediated by up-regulation 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.

Authors with CRIS profile

Mario Schiffer

Additional Organisation(s)

Lehrstuhl für Innere Medizin IV

Involved external institutions

Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) Mount Desert Island Biological Laboratory US United States (USA) (US)

How to cite

APA:

Duong, M., Yu, X., Teng, B., Schroder, P., Haller, H., Eschenburg, S., & Schiffer, M. (2017). Protein kinase C ϵ stabilizes β-catenin and regulates its subcellular localization in podocytes. Journal of Biological Chemistry, 292(29), 12100-12110. https://doi.org/10.1074/jbc.M117.775700

MLA:

Duong, Michelle, et al. "Protein kinase C ϵ stabilizes β-catenin and regulates its subcellular localization in podocytes." Journal of Biological Chemistry 292.29 (2017): 12100-12110.

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