Oxygen-dependent Regulation of Erythropoietin Receptor Turnover and Signaling.

Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE

Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology

Proteolysis* ; Signal Transduction* ; Ubiquitination*; Oxygen/*metabolism ; Receptors, Erythropoietin/*metabolism ; Von Hippel-Lindau Tumor Suppressor Protein/*metabolism; Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Cullin Proteins/genetics ; Cullin Proteins/metabolism ; HEK293 Cells ; Humans ; Receptors, Erythropoietin/genetics ; Von Hippel-Lindau Tumor Suppressor Protein/genetics ; von Hippel-Lindau Disease/genetics ; von Hippel-Lindau Disease/metabolism ; von Hippel-Lindau Disease/pathology

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.
(© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

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Canada Canadian Institutes of Health Research

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

0 (Basic Helix-Loop-Helix Transcription Factors)
0 (CUL2 protein, human)
0 (Cullin Proteins)
0 (Receptors, Erythropoietin)
EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein)
EC 6.3.2.- (VHL protein, human)
S88TT14065 (Oxygen)

Date Created: 20160206 Date Completed: 20160815 Latest Revision: 20210205

20250114

PMC4817168

10.1074/jbc.M115.694562

26846855