Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL

Creative Commons License

Hasanov E., Chen G., Chowdhury P., Weldon J., Ding Z., Jonasch E., ...Daha Fazla

ONCOGENE, cilt.36, sa.24, ss.3450-3463, 2017 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 36 Sayı: 24
  • Basım Tarihi: 2017
  • Doi Numarası: 10.1038/onc.2016.495
  • Dergi Adı: ONCOGENE
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.3450-3463
  • Hacettepe Üniversitesi Adresli: Hayır

Özet

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 a (HIF alpha) 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 HIFa is unable to ubiquitinate AURKA. Together, these data identify VHL as an E3 ligase with important cellular functions under both normoxic and hypoxic conditions.