Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL.
The hypoxia-regulated tumor-suppressor von Hippel-Lindau (VHL) is an E3 ligase that recognizes its substrates as part of an oxygen-dependent prolyl hydroxylase (PHD) reaction, with hypoxia-inducible factor α (HIFα) being its most notable substrate. Here we report that VHL has an equally important function distinct from its hypoxia-regulated activity. We find ... that Aurora kinase A (AURKA) is a novel, hypoxia-independent target for VHL ubiquitination. In contrast to its hypoxia-regulated activity, VHL mono-, rather than poly-ubiquitinates AURKA, in a PHD-independent reaction targeting AURKA for degradation in quiescent cells, where degradation of AURKA is required to maintain the primary cilium. Tumor-associated variants of VHL differentiate between these two functions, as a pathogenic VHL mutant that retains intrinsic ability to ubiquitinate HIFα is unable to ubiquitinate AURKA. Together, these data identify VHL as an E3 ligase with important cellular functions under both normoxic and hypoxic conditions.
Mesh Terms:
Aurora Kinase A, Carcinoma, Renal Cell, Cell Hypoxia, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Kidney Neoplasms, Mutation, Ubiquitination, Von Hippel-Lindau Tumor Suppressor Protein
Aurora Kinase A, Carcinoma, Renal Cell, Cell Hypoxia, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Kidney Neoplasms, Mutation, Ubiquitination, Von Hippel-Lindau Tumor Suppressor Protein
Oncogene
Date: Jun. 15, 2017
PubMed ID: 28114281
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