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J Biol Chem. 2016 Apr 1;291(14):7357-72. doi: 10.1074/jbc.M115.694562. Epub 2016 Feb 4.

Oxygen-dependent Regulation of Erythropoietin Receptor Turnover and Signaling.

Author information

1
From the Departments of Laboratory Medicine and Pathobiology and.
2
the Princess Margaret Cancer Centre, Toronto, Ontario M5G 1L7, Canada.
3
From the Departments of Laboratory Medicine and Pathobiology and Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8 and.
4
From the Departments of Laboratory Medicine and Pathobiology and Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8 and michael.ohh@utoronto.ca.

Abstract

von Hippel-Lindau (VHL) disease is a rare familial cancer predisposition syndrome caused by a loss or mutation in a single gene,VHL, but it exhibits a wide phenotypic variability that can be categorized into distinct subtypes. The phenotypic variability has been largely argued to be attributable to the extent of deregulation of the α subunit of hypoxia-inducible factor α, a well established target of VHL E3 ubiquitin ligase, ECV (Elongins/Cul2/VHL). Here, we show that erythropoietin receptor (EPOR) is hydroxylated on proline 419 and 426 via prolyl hydroxylase 3. EPOR hydroxylation is required for binding to the β domain of VHL and polyubiquitylation via ECV, leading to increased EPOR turnover. In addition, several type-specific VHL disease-causing mutants, including those that have retained proper binding and regulation of hypoxia-inducible factor α, showed a severe defect in binding prolyl hydroxylated EPOR peptides. These results identify EPOR as the secondbona fidehydroxylation-dependent substrate of VHL that potentially influences oxygen homeostasis and contributes to the complex genotype-phenotype correlation in VHL disease.

KEYWORDS:

E3 ubiquitin ligase; EPOR; PHD3; VHL; cell signaling; hypoxia; prolyl hydroxylation; protein degradation; ubiquitylation (ubiquitination)

PMID:
26846855
PMCID:
PMC4817168
DOI:
10.1074/jbc.M115.694562
[Indexed for MEDLINE]
Free PMC Article

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