dc.creator | Gkotinakou I.-M., Befani C., Simos G., Liakos P. | en |
dc.date.accessioned | 2023-01-31T07:43:03Z | |
dc.date.available | 2023-01-31T07:43:03Z | |
dc.date.issued | 2019 | |
dc.identifier | 10.1242/jcs.225698 | |
dc.identifier.issn | 00219533 | |
dc.identifier.uri | http://hdl.handle.net/11615/72506 | |
dc.description.abstract | Hypoxia-inducible factor 2 (HIF-2) is a principal component of the cellular response to oxygen deprivation (hypoxia). Its inducible subunit, HIF-2α (also known as EPAS1), is controlled by oxygen-dependent as well as oxygen-independent mechanisms, such as phosphorylation. We showhere that HIF-2α is phosphorylated under hypoxia (1%O2) by extracellular signal-regulated protein kinases 1 and 2 (ERK1/2; also known as MAPK3 and MAPK1, respectively) at serine residue 672, as identified by in vitro phosphorylation assays. Mutation of this site to an alanine residue or inhibition of the ERK1/2 pathway decreases HIF-2 transcriptional activity and causes HIF-2α to mislocalize to the cytoplasm without changing its protein expression levels. Localization, reporter gene and immunoprecipitation experiments further show that HIF-2α associates with the exportin chromosomal maintenance 1 (CRM1, also known as XPO1) in a phosphorylation-sensitive manner and identify two critical leucine residues as part of an atypical CRM1-dependent nuclear export signal (NES) neighboring serine 672. Inhibition of CRM1 or mutation of these residues restores nuclear accumulation and activity of HIF-2α lacking the ERK1/2-mediated modification. In summary, we reveal a novel regulatory mechanism of HIF-2, involving ERK1/2-dependent phosphorylation of HIF-2α, which controls its nucleocytoplasmic shuttling and the HIF-2 transcriptional activity. © 2019. Published by The Company of Biologists Ltd. | en |
dc.language.iso | en | en |
dc.source | Journal of Cell Science | en |
dc.source.uri | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85064558299&doi=10.1242%2fjcs.225698&partnerID=40&md5=00d0b332aa0f0dc40ae113a5813e32df | |
dc.subject | alanine | en |
dc.subject | exportin 1 | en |
dc.subject | hypoxia inducible factor 2alpha | en |
dc.subject | leucine | en |
dc.subject | mitogen activated protein kinase 1 | en |
dc.subject | mitogen activated protein kinase 3 | en |
dc.subject | serine | en |
dc.subject | basic helix loop helix transcription factor | en |
dc.subject | cell receptor | en |
dc.subject | endothelial PAS domain-containing protein 1 | en |
dc.subject | exportin 1 protein | en |
dc.subject | karyopherin | en |
dc.subject | MAPK3 protein, human | en |
dc.subject | mitogen activated protein kinase 3 | en |
dc.subject | serine | en |
dc.subject | Article | en |
dc.subject | cell hypoxia | en |
dc.subject | cellular distribution | en |
dc.subject | controlled study | en |
dc.subject | cytoplasm | en |
dc.subject | enzyme inhibition | en |
dc.subject | HeLa cell line | en |
dc.subject | Huh-7 cell line | en |
dc.subject | human | en |
dc.subject | human cell | en |
dc.subject | immunoprecipitation | en |
dc.subject | in vitro study | en |
dc.subject | MAPK signaling | en |
dc.subject | mutation | en |
dc.subject | nuclear export signal | en |
dc.subject | nucleocytoplasmic transport | en |
dc.subject | priority journal | en |
dc.subject | protein expression | en |
dc.subject | protein modification | en |
dc.subject | protein phosphorylation | en |
dc.subject | regulatory mechanism | en |
dc.subject | reporter gene | en |
dc.subject | transcription initiation | en |
dc.subject | transcription regulation | en |
dc.subject | cell nucleus | en |
dc.subject | genetics | en |
dc.subject | metabolism | en |
dc.subject | nucleocytoplasmic transport | en |
dc.subject | phosphorylation | en |
dc.subject | Active Transport, Cell Nucleus | en |
dc.subject | Basic Helix-Loop-Helix Transcription Factors | en |
dc.subject | Cell Nucleus | en |
dc.subject | HeLa Cells | en |
dc.subject | Humans | en |
dc.subject | Karyopherins | en |
dc.subject | Mitogen-Activated Protein Kinase 3 | en |
dc.subject | Mutation | en |
dc.subject | Phosphorylation | en |
dc.subject | Receptors, Cytoplasmic and Nuclear | en |
dc.subject | Serine | en |
dc.subject | Company of Biologists Ltd | en |
dc.title | ERK1/2 phosphorylates HIF-2α and regulates its activity by controlling its CRM1-dependent nuclear shuttling | en |
dc.type | journalArticle | en |