Search

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. PKCβII 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 PKCβII isotype in the nucleus, resulting in ubiquitination of PKCβII at the C-terminal K668 and K672 residues and its subsequent downregulation. Ubiquitinated PKCβII mediated the clathrin-mediated endocytosis of G protein-coupled receptors like the D 2 and D 3 dopamine receptors; in contrast, non-ubiquitinated PKCβII 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 PKCβII that determine its life span and endocytic roles. Considering that PKCβII 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 PKCβII-related diseases. [ABSTRACT FROM AUTHOR]