PUBLICATION
Protein Kinase C ? Stabilizes ?-Catenin and Regulates Its Subcellular Localization in Podocytes
- Authors
- Duong, M., Yu, X., Teng, B., Schroder, P., Haller, H., Eschenburg, S., Schiffer, M.
- ID
- ZDB-PUB-170526-11
- Date
- 2017
- Source
- The Journal of biological chemistry 292(29): 12100-12110 (Journal)
- Registered Authors
- Keywords
- Wnt pathway, beta-catenin (B-catenin ), cadherin, cytoskeleton, glycogen synthase kinase 3 (GSK-3), kidney, podocytes, protein kinase C (PKC)
- MeSH Terms
-
- Carcinogens/toxicity
- Mutation
- Phosphorylation/drug effects
- Animals
- Mice, Knockout
- Biological Assay
- Protein Kinase C-epsilon/antagonists & inhibitors
- Protein Kinase C-epsilon/genetics
- Protein Kinase C-epsilon/metabolism*
- Recombinant Proteins/chemistry
- Recombinant Proteins/metabolism
- Tissue Culture Techniques
- Protein Processing, Post-Translational*/drug effects
- HEK293 Cells
- Mutagenesis, Site-Directed
- Glycogen Synthase Kinase 3 beta/metabolism
- Humans
- Active Transport, Cell Nucleus/drug effects
- Cell Line, Transformed
- Podocytes/cytology
- Podocytes/drug effects
- Podocytes/metabolism*
- Amino Acid Substitution
- beta Catenin/antagonists & inhibitors
- beta Catenin/chemistry
- beta Catenin/genetics
- beta Catenin/metabolism*
- Gene Expression Regulation/drug effects
- Tetradecanoylphorbol Acetate/analogs & derivatives
- Tetradecanoylphorbol Acetate/toxicity
- Protein Stability/drug effects
- PubMed
- 28539358 Full text @ J. Biol. Chem.
Citation
Duong, M., Yu, X., Teng, B., Schroder, P., Haller, H., Eschenburg, S., Schiffer, M. (2017) Protein Kinase C ? Stabilizes ?-Catenin and Regulates Its Subcellular Localization in Podocytes. The Journal of biological chemistry. 292(29):12100-12110.
Abstract
Kidney disease has been linked to dysregulated signaling via protein kinase C (PKC) in kidney cells such as podocytes. PKC? is a conventional isoform of PKC and a well-known binding partner of ?-catenin, which promotes its degradation. ?-Catenin is the main effector of the canonical Wnt pathway and is critical in cell adhesion. However, whether other PKC isoforms interact with ?-catenin has not been studied systematically. Here we demonstrate that PKC?-deficient mice, which develop proteinuria and glomerulosclerosis, display a lower ?-catenin expression compared to PKC wildtype mice, consistent with an altered phenotype of podocytes in culture. Remarkably, ?-catenin showed a reversed subcellular localization pattern: while ?-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 ?-catenin expression and stabilization in a glycogen synthase kinase-3? independent manner. Further, ?-catenin overexpression in PKC?-deficient podocytes could restore the wildtype phenotype, similar to the rescue with a PKC? construct. This effect was mediated by upregulation of P-cadherin and the ?-catenin downstream target fascin1. Zebrafish studies indicated three PKC?-specific phosphorylation sites in ?-catenin that are required for full ?-catenin function. Co-immunoprecipitation and pulldown assays confirmed PKC? and ?-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 ?-catenin levels and define PKC? as an important ?-catenin interaction partner and signaling opponent of other PKC isoforms in podocytes.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping