Mdm2-mediated ubiquitination of PKCβII in the nucleus mediates clathrin-mediated endocytic activity.

Cellular stimuli that increase diacylglycerol levels activate several protein kinase C isoforms; however, prolonged stimulation depletes cells of Ubiquitination is a critical cellular event that mediates the degradation of numerous proteins, including but little is known of the molecular mechanisms involved in ubiquitination. is the most widely expressed duanyu1531 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 duanyu1531βII isotype in the nucleus, resulting in ubiquitination of duanyu1531βII at the C-terminal K668 and K672 residues and its subsequent downregulation. Ubiquitinated duanyu1531βII mediated the clathrin-mediated endocytosis of G protein-coupled receptors like the D₂ and D₃ dopamine receptors; in contrast, non-ubiquitinated duanyu1531βII 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 duanyu1531βII that determine its life span and endocytic roles. Considering that duanyu1531βII 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 diseases.

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