title: Oxygen-dependent Regulation of Erythropoietin Receptor Turnover and Signaling.
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.
authors: From the Departments of Laboratory Medicine and Pathobiology and.
authors: Pardeep
authors: P
authors: Heir
authors: the Princess Margaret Cancer Centre, Toronto, Ontario M5G 1L7, Canada.
authors: Tharan
authors: T
authors: Srikumar
authors: From the Departments of Laboratory Medicine and Pathobiology and.
authors: George
authors: G
authors: Bikopoulos
authors: From the Departments of Laboratory Medicine and Pathobiology and.
authors: Severa
authors: S
authors: Bunda
authors: From the Departments of Laboratory Medicine and Pathobiology and Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8 and.
authors: Betty P
authors: BP
authors: Poon
authors: From the Departments of Laboratory Medicine and Pathobiology and.
authors: Jeffrey E
authors: JE
authors: Lee
authors: the Princess Margaret Cancer Centre, Toronto, Ontario M5G 1L7, Canada.
authors: Brian
authors: B
authors: Raught
authors: From the Departments of Laboratory Medicine and Pathobiology and Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8 and michael.ohh@utoronto.ca.
authors: Michael
authors: M
authors: Ohh
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D010100:Oxygen / Q000378:metabolism*; D059748:Proteolysis; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D054875:Ubiquitination; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*; D006623:von Hippel-Lindau Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D044842:Cullin Proteins; D010100:Oxygen; D017467:Receptors, Erythropoietin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C105153:CUL2 protein, human; C497446:VHL protein, human
keywords: E3 ubiquitin ligase; EPOR; PHD3; VHL; cell signaling; hypoxia; prolyl hydroxylation; protein degradation; ubiquitylation (ubiquitination)