Min X, Zhang X, Wang S, Kim KM

Conventional members of protein kinase C (PKC) family, including PKC?II, are constitutively phosphorylated on three major motifs and located in the cytosol in a primed state. In response to cellular stimuli, PKC?II is activated through inducible phosphorylation and Mdm2-mediated ubiquitination. In this study, we aimed to identify the activation mechanism ...

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of PKC?II, focusing on the signaling cascade that regulate the phosphorylation and ubiquitination.Loss-of-function approaches and mutants of PDK1/PKC?II that display different regulatory properties were used to identify the cellular components and processes responsible for endocytosis.Phorbol 12-myristate 13-acetate (PMA)-induced phosphorylation and ubiquitination of PKC?II, which are needed for its translocation to the plasma membrane, required the presence of both G?? and 14-3-3?. G?? and 14-3-3? mediated the constitutive phosphorylation of PKC?II by scaffolding PI3K and PDK1 in the cytosol, which is an inactive but required state for the activation of PKC?II by subsequent signals. In response to PMA treatment, the signaling complex translocated to the nucleus with dissociation of PI3K from it. Thereafter, PDK1 stably interacted with 14-3-3? and was dephosphorylated; PKC?II interacted with Mdm2 along with G??, leading to its ubiquitination at two lysine residues on its C-tail. Finally, PDK1/14-3-3? and ubiquitinated PKC?II translocated to the plasma membrane.As PKC?II mediates a wide range of cellular functions and plays important roles in the pathogenesis of various diseases, our results will provide clues to understand the pathogenesis of PKC?II-related disorders and facilitate their treatment.

Date: Jan. 01, 2023

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