TY - JOUR
T1 - Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL
AU - Hasanov, E.
AU - Chen, G.
AU - Chowdhury, P.
AU - Weldon, J.
AU - Ding, Z.
AU - Jonasch, E.
AU - Sen, S.
AU - Walker, C. L.
AU - Dere, R.
N1 - Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature.
PY - 2017/6/15
Y1 - 2017/6/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85010872096&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85010872096&partnerID=8YFLogxK
U2 - 10.1038/onc.2016.495
DO - 10.1038/onc.2016.495
M3 - Article
C2 - 28114281
AN - SCOPUS:85010872096
SN - 0950-9232
VL - 36
SP - 3450
EP - 3463
JO - Oncogene
JF - Oncogene
IS - 24
ER -