ArticleThe Journal of biological chemistry2009
Hypoxia-inducible factor prolyl-4-hydroxylase PHD2 protein abundance depends on integral membrane anchoring of FKBP38.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 72 citations in OpenAlex.
- Proline hydroxylase 2 (PHD2) promotes brown adipose thermogenesis by enhancing the hydroxylation of UCP1.Molecular metabolism · 2023Article
- EGLN1 prolyl hydroxylation of hypoxia-induced transcription factor HIF1α is repressed by SET7-catalyzed lysine methylation.The Journal of biological chemistry · 2022Article
- Molecular Characterization and Response of Prolyl Hydroxylase Domain (PHD) Genes to Hypoxia Stress inAnimals : an open access journal from MDPI · 2022Article
- Oxygen-sensing mechanisms in development and tissue repair.Development (Cambridge, England) · 2021Review
- The role of α-ketoglutarate and the hypoxia sensing pathway in the regulation of pancreatic β-cell function.Islets · 2020Review
- Contact-ID, a tool for profiling organelle contact sites, reveals regulatory proteins of mitochondrial-associated membrane formation.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Modulated Expression and Activities ofFrontiers in physiology · 2020Article
- Signal peptide peptidase promotes tumor progression via facilitating FKBP8 degradation.Oncogene · 2019Article
- Article
- Zonda is a novel early component of the autophagy pathway inMolecular biology of the cell · 2017Article
- Time-dependent inhibition of PHD2.Bioscience reports · 2017Article
- The structure of FKBP38 in complex with the MEEVD tetratricopeptide binding-motif of Hsp90.PloS one · 2017Article
- The Zinc Finger of Prolyl Hydroxylase Domain Protein 2 Is Essential for Efficient Hydroxylation of Hypoxia-Inducible Factor α.Molecular and cellular biology · 2016Article
- PHD2: from hypoxia regulation to disease progression.Hypoxia (Auckland, N.Z.) · 2016Review
- CDK-dependent phosphorylation of PHD1 on serine 130 alters its substrate preference in cells.Journal of cell science · 2016Article
- FK506-Binding Proteins and Their Diverse Functions.Current molecular pharmacology · 2015Review
- Role of the ANKMY2-FKBP38 axis in regulation of the Sonic hedgehog (Shh) signaling pathway.The Journal of biological chemistry · 2014Article
- Prolyl hydroxylase domain enzymes: important regulators of cancer metabolism.Hypoxia (Auckland, N.Z.) · 2014Review
- Oxygen sensing and hypoxia signalling pathways in animals: the implications of physiology for cancer.The Journal of physiology · 2013Review
- Prolyl hydroxylase domain protein 2 (PHD2) binds a Pro-Xaa-Leu-Glu motif, linking it to the heat shock protein 90 pathway.The Journal of biological chemistry · 2013Article
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Prolyl-4-hydroxylase domain (PHD) proteins are 2-oxoglutarate and dioxygen-dependent enzymes that mediate the rapid destruction of hypoxia-inducible factor alpha subunits. Whereas PHD1 and PHD3 proteolysis has been shown to be regulated by Siah2 ubiquitin E3 ligase-mediated polyubiquitylation and proteasomal destruction, protein regulation of the main oxygen sensor responsible for hypoxia-inducible factor alpha regulation, PHD2, remained unknown. We recently reported that the FK506-binding protein (FKBP) 38 specifically interacts with PHD2 and determines PHD2 protein stability in a peptidyl-prolyl cis-trans isomerase-independent manner. Using peptide array binding assays, fluorescence spectroscopy, and fluorescence resonance energy transfer analysis, we defined a minimal linear glutamate-rich PHD2 binding domain in the N-terminal part of FKBP38 and showed that this domain forms a high affinity complex with PHD2. Vice versa, PHD2 interacted with a non-linear N-terminal motif containing the MYND (myeloid, Nervy, and DEAF-1)-type Zn(2+) finger domain with FKBP38. Biochemical fractionation and immunofluorescence analysis demonstrated that PHD2 subcellular localization overlapped with FKBP38 in the endoplasmic reticulum and mitochondria. An additional fraction of PHD2 was found in the cytoplasm. In cellulo PHD2/FKBP38 association, as well as regulation of PHD2 protein abundance by FKBP38, is dependent on membrane- anchored FKBP38 localization mediated by the C-terminal transmembrane domain. Mechanistically our data indicate that PHD2 protein stability is regulated by a ubiquitin-independent proteasomal pathway involving FKBP38 as adaptor protein that mediates proteasomal interaction. We hypothesize that FKBP38-bound PHD2 is constantly degraded whereas cytosolic PHD2 is stable and able to function as an active prolyl-4-hydroxylase.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.