Mdm2-mediated ubiquitination of PKC?II in the nucleus mediates clathrin-mediated endocytic activity.

Cellular stimuli that increase diacylglycerol levels activate several protein kinase C (PKC) isoforms; however, prolonged stimulation depletes cells of PKCs. Ubiquitination is a critical cellular event that mediates the degradation of numerous proteins, including PKCs, but little is known of the molecular mechanisms involved in PKC ubiquitination. PKC?II is the ...
most widely expressed PKC isoform and regulates a variety of cellular functions. Here, we show that in response to stimulation of the Gq-coupled angiotensin II type 1 receptor or treatment with phorbol ester, Mdm2, E3 ubiquitin ligase, interacted with PKC?II isotype in the nucleus, resulting in ubiquitination of PKC?II at the C-terminal K668 and K672 residues and its subsequent downregulation. Ubiquitinated PKC?II mediated the clathrin-mediated endocytosis of G protein-coupled receptors like the D2 and D3 dopamine receptors; in contrast, non-ubiquitinated PKC?II mediated an as yet uncharacterized clathrin- and caveolar-independent endocytic pathway. In conclusion, we characterized the molecular mechanisms involved in the activity-dependent ubiquitination of PKC?II that determine its life span and endocytic roles. Considering that PKC?II plays an important role in the development of various diseases, including diabetic vasculitis, the results obtained in this study will contribute to better understanding the pathogenesis of PKC?II-related diseases.
Mesh Terms:
Amino Acid Sequence, Cell Nucleus, Clathrin, Endocytosis, HEK293 Cells, Humans, Protein Kinase C beta, Proto-Oncogene Proteins c-mdm2, Ubiquitination
Biochem Pharmacol
Date: Dec. 01, 2018
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