| Protein kinase C(PKC) is a family of serine/threonine protein kinases which control major cellular function: differentiation, apoptosis, metabolism, cerebral ischemia, tumorigenesis through mediating many signal transduction pathways. PKC can be modified by multiple posttranslational modifications(PTMs), such as phosphorylation, ubiquitination and SUMOylation. Phosphorylation regulates PKC catalytic activity, stabilizes its active conformation, and is required for its mature. Phorbol esters(PMA) acutely activate and subsequently down-regulate PKC by triggering its proteolysis through ubiquitin-proteasome pathway.Previous study has been shown that PKC? was modified by SUMO1, and that deSUMOylation of PKC is essential for kainate-induced endocytosis of glycine receptors in spinal cord neurons. SUMOylation is one of the important PTMs, which play pivotal roles in cell signaling, protein trafficking and stability, thereby regulating a plethora of biological processes such as cell survival and neurodegeneration. As a protein can be modified by more than one type of PTMs, recent studies have provided evidence for a functional crosstalk and complex interplay between SUMOylation, ubiquitination and phosphorylation for a number of proteins. However, whether and how the interplay between PKC phosphorylation, SUMOylation and ubiquitination regulates its fate remains unknown.We herein have revealed a complex interplay between various PTMs that finely tune PKC functions and ultimately regulate its degradation via the proteasome pathway. We show that PKC is SUMOylated not only by SUMO1, but also by SUMO2/3. PKC promotes its SUMOylation and consequently inhibits its ubiquitination and degradation. These results provide evidence that activation-induced down-regulation of PKC is mediated by a novel regulatory mechanism through functional crosstalk between different types of PTM. The sequential cascade of PTMs may also participate in the down-regulation of in PKC? in cerebral ischemia. |
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