title: Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL.
abstract: 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.
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.|Department of Basic Oncology, Hacettepe University Cancer Institute, Sihhiye, Ankara, Turkey.
authors.forename: E
authors.initials: E
authors.lastname: Hasanov
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Chen
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.|Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Chowdhury
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Weldon
authors.affiliation: Department of Systems Biology, U.T. M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Department of Genitourinary Medical Oncology, U.T. M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Jonasch
authors.affiliation: Department of Translational Molecular Pathology, U.T. M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sen
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.|Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Walker
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.|Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Dere
mesh_terms: D064096:Aurora Kinase A / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D054875:Ubiquitination; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051794:Von Hippel-Lindau Tumor Suppressor Protein; C576917:AURKA protein, human; D064096:Aurora Kinase A; C497446:VHL protein, human