Role of the NEDD8 modification of Cul2 in the sequential activation of ECV complex.

ECV is an E3 ubiquitin ligase complex, which is composed of elongins B and C, Rbx1, Cul2, and the substrate-conferring von Hippel-Lindau (VHL) tumor-suppressor protein that targets the catalytic alpha subunit of hypoxia-inducible factor (HIF) for oxygen-dependent ubiquitin-mediated destruction. Mutations in VHL that compromise proper HIFalpha regulation through ECV have ...
been documented in the majority of renal cell carcinomas, underscoring the significance of the VHL-HIF pathway in renal epithelial oncogenesis. Recent evidence has shown that the modification of Cul2 by the ubiquitin-like molecule NEDD8 increases the activity of ECV to ubiquitylate HIFalpha. However, the underlying mechanism responsible for the NEDD8-mediated induction of ECV function is unknown. Here, we demonstrate that oxygen-dependent recognition of HIFalpha by VHL triggers Rbx1-dependent neddylation of Cul2, which preferentially engages the E2 ubiquitin-conjugating enzyme UbcH5a. These events establish a central role for the neddylation of Cul2 in a previously unrecognized, temporally coordinated activation of ECV with the recruitment of its substrate HIFalpha.
Mesh Terms:
Anoxia, Carrier Proteins, Catalytic Domain, Cell Line, Cullin Proteins, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Iron-Binding Proteins, Models, Biological, Mutation, Oxygen, Protein Binding, Protein Structure, Tertiary, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Ubiquitins
Neoplasia
Date: Nov. 01, 2006
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