The von Hippel-Lindau tumor suppressor protein mediates ubiquitination of activated atypical protein kinase C.

The von Hippel-Lindau tumor-suppressor protein (pVHL) forms a protein complex (VCB-Cul2) with elongin C, elongin B, Cul-2, and Rbx1, which functions as a ubiquitin-protein ligase (E3). The alpha-subunits of the hypoxia-inducible factors have been identified as targets for the VCB-Cul2 ubiquitin ligase. However, a variety of cellular defects caused by ...
the depletion of pVHL cannot be explained solely by the ubiquitin-mediated degradation of hypoxia-inducible factor-alpha. We show here that a member of the atypical protein kinase C (PKC) group, PKClambda, is ubiquitinated by the pVHL-containing E3 enzyme. An active PKClambda mutant is ubiquitinated more extensively than wild-type PKClambda in HEK293 cells, and the ubiquitination is further enhanced by the overexpression of pVHL. The activation of wild-type PKClambda by serum stimulation of cells enhances the ubiquitination of the protein, supporting the notion that active PKClambda is preferentially ubiquitinated by VCB-Cul2 ubiquitin ligase. Furthermore, we show that PKClambda can be ubiquitinated in vitro in a cell-free ubiquitination assay using purified recombinant components including VCB-Cul2. Given the known function of aPKC in the regulation of cell polarity and cell growth, PKClambda may be a target of pVHL in its function as a tumor suppressor.
Mesh Terms:
Cell Line, Cysteine Endopeptidases, Cysteine Proteinase Inhibitors, Enzyme Activation, Humans, Hydrolysis, Isoenzymes, Ligases, Multienzyme Complexes, Proteasome Endopeptidase Complex, Protein Binding, Protein Kinase C, Tumor Suppressor Proteins, Ubiquitin, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein, von Hippel-Lindau Disease
J. Biol. Chem.
Date: Nov. 23, 2001
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