Oxygen-dependent Regulation of Erythropoietin Receptor Turnover and Signaling*
| Autor: | Severa Bunda, Jeffrey E. Lee, Brian Raught, Pardeep Heir, Betty P.K. Poon, Tharan Srikumar, George Bikopoulos, Michael Ohh |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cell signaling von Hippel-Lindau Disease endocrine system diseases Protein degradation Biology medicine.disease_cause urologic and male genital diseases Biochemistry 03 medical and health sciences 0302 clinical medicine Ubiquitin Oxygen homeostasis medicine Basic Helix-Loop-Helix Transcription Factors Receptors Erythropoietin Humans Molecular Biology neoplasms Mutation Ubiquitination food and beverages Cell Biology Cullin Proteins female genital diseases and pregnancy complications Cell biology Erythropoietin receptor Ubiquitin ligase Oxygen 030104 developmental biology HEK293 Cells Von Hippel-Lindau Tumor Suppressor Protein 030220 oncology & carcinogenesis Proteolysis biology.protein Signal transduction Signal Transduction |
| Popis: | 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 second bona fide hydroxylation-dependent substrate of VHL that potentially influences oxygen homeostasis and contributes to the complex genotype-phenotype correlation in VHL disease. |
| Databáze: | OpenAIRE |
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