Affinage

EGLN1

Egl nine homolog 1 · UniProt Q9GZT9

Length
426 aa
Mass
46.0 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EGLN1 (PHD2) is the principal cellular oxygen sensor, functioning as a Fe(II)- and 2-oxoglutarate-dependent prolyl hydroxylase that hydroxylates HIF-α subunits to target them for VHL-mediated ubiquitination and proteasomal degradation, thereby serving as the master regulator of the hypoxic response across most cell types. PHD2 preferentially hydroxylates the CODD over the NODD of HIF-1α by ~20-fold through electrostatic interactions and β2β3 loop closure (PMID:23787140), and its activity is modulated by multiple inputs including competitive inhibition by lactate at the α-ketoglutarate binding site (PMID:36064857), persulfidation at Cys21/Cys33 by CBS-derived H₂S (PMID:32937467), ROS-induced disulfide dimerization (PMID:26740011), ERK-mediated phosphorylation (PMID:31285371), and SET7-catalyzed methylation at K297 (PMID:35452683). Beyond HIF-α, PHD2 hydroxylates non-HIF substrates including filamin A (regulating dendritic spine maturation) (PMID:26972007), B55α (PP2A subunit, controlling apoptosis under glucose starvation) (PMID:28329677), BRD4 (PMID:31239290), and AMPKα on mitochondria (enabling CaMKK2-dependent AMPK activation under hypoxia) (PMID:37661833). In vivo, PHD2 loss causes polycythemia rescued by HIF-2α but not HIF-1α haploinsufficiency (PMID:24121508), controls carotid body oxygen sensing and ventilatory responses through PHD2–HIF-2α coupling (PMID:26337139), and regulates macrophage polarization, arteriogenesis, and hematopoietic stem cell maintenance via NF-κB and HIF-dependent pathways (PMID:21983962, PMID:23667053).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2004 High

    Among the three PHD isoforms, the question of which is the dominant HIF-α regulator was resolved: PHD2 is the primary oxygen sensor setting steady-state HIF-α levels in most cell types, with non-redundant contributions from PHD1 and PHD3.

    Evidence siRNA knockdown of individual PHD isoforms with HIF-α protein and transcriptional readouts across multiple cell lines

    PMID:15247232

    Open questions at the time
    • Tissue-specific contributions of individual PHDs not fully delineated
    • Mechanism of isoform-specific substrate preference unknown
  2. 2005 High

    Two key aspects of PHD2 regulation were established: PHD2 is itself a direct HIF-1 target gene (negative feedback loop via HRE binding), and PHD2 can repress HIF-1α transcriptional activity independently of promoting its proteolysis.

    Evidence EMSA/reporter assays identifying HRE in PHD2 promoter; ectopic PHD2 expression in VHL-deficient cells showing transcriptional repression without protein level change

    PMID:15563275 PMID:16157596

    Open questions at the time
    • Mechanism of proteolysis-independent transcriptional repression not identified
    • Whether transcriptional repression operates in vivo unclear
  3. 2007 High

    The physiological importance of PHD2 was confirmed in vivo and a key binding partner identified: conditional PHD2 knockout in mice caused polycythemia and cardiomyopathy via EPO upregulation, while FKBP38 was identified as a specific PHD2 interactor that regulates its protein stability.

    Evidence Conditional Phd2 KO mice with EPO/hematologic readouts; yeast two-hybrid, Co-IP, and activity assays for FKBP38-PHD2 interaction

    PMID:17353276 PMID:18096761

    Open questions at the time
    • Whether FKBP38-mediated regulation is tissue-specific unknown
    • Mechanism of ubiquitin-independent proteasomal degradation of PHD2 not resolved
  4. 2009 High

    PHD2's subcellular dynamics and non-canonical signaling functions were mapped: PHD2 localizes to ER and mitochondria via FKBP38, uses a CRM1-dependent nuclear export signal, and regulates tumor angiogenesis through both HIF-dependent and NF-κB-dependent pathways; endothelial PHD2 haplodeficiency normalizes tumor vessels via HIF-driven VEGFR-1/VE-cadherin upregulation.

    Evidence FRET/fractionation for ER/mitochondrial localization; CRM1 inhibition and truncation mutants for nuclear export; PHD2 knockdown in cancer cells with NF-κB reporters and xenografts; PHD2+/- mice with vessel morphology analysis

    PMID:19217150 PMID:19477431 PMID:19546213 PMID:19631610

    Open questions at the time
    • Relative contribution of nuclear vs. cytoplasmic PHD2 to HIF regulation in vivo unknown
    • NF-κB regulation mechanism by PHD2 (direct substrate or indirect) not established
  5. 2011 High

    PHD2 was shown to function as an immune modulator: Phd2 haplodeficiency skews macrophage polarization toward a pro-arteriogenic M2-like phenotype through canonical NF-κB activation, promoting collateral vessel growth after ischemia.

    Evidence Phd2+/- and macrophage-specific Phd2 KO mice with hindlimb ischemia; NF-κB pathway analysis and smooth muscle cell recruitment assays

    PMID:21983962

    Open questions at the time
    • Direct PHD2 substrate in NF-κB pathway not identified
    • Whether macrophage PHD2 regulation is relevant in non-ischemic inflammation unclear
  6. 2012 Medium

    The compartmentalized regulation of PHD2 was refined: nuclear PHD2 is the primary pool interacting with and hydroxylating HIF-1α, with amino acids 196-205 required for nuclear import and amino acids 6-20 mediating CRM1-dependent export.

    Evidence NLS/NES mutant analysis; FRET detection of PHD2–HIF-1α interaction specifically in nucleus; activity assays of compartment-restricted mutants

    PMID:22946054

    Open questions at the time
    • Structural basis of non-classical nuclear import not resolved
    • Whether nuclear restriction holds for non-HIF substrates unknown
  7. 2013 High

    Three advances defined PHD2 substrate specificity and downstream isoform selectivity: PHD2 preferentially hydroxylates CODD over NODD by ~20-fold via electrostatic interactions and β2β3 loop dynamics; PHD2 erythrocytosis mutations act through HIF-2α (not HIF-1α) as demonstrated by genetic epistasis; and PHD2 regulates HSC self-renewal through HIF-1α/SMAD7.

    Evidence Kinetic competition assays and H/D exchange MS for CODD/NODD selectivity; P294R knock-in mice crossed with Hif2a+/- or Hif1a+/-; conditional Phd2 KO in hematopoietic precursors with competitive transplantation

    PMID:23667053 PMID:23787140 PMID:24121508

    Open questions at the time
    • Full structural basis of NODD vs. CODD discrimination not resolved at atomic level
    • Whether HSC phenotype involves non-HIF PHD2 substrates untested
  8. 2014 High

    The Tibetan high-altitude adaptation allele (D4E/C127S) was mechanistically explained: it drastically reduces PHD2 interaction with the HSP90 cochaperone p23 via a PXLE motif, impairing PHD2-mediated HIF downregulation, thus representing a natural loss-of-function variant.

    Evidence Pulldown and Co-IP with mutagenesis of D4E and C127S; functional HIF hydroxylation assays

    PMID:24711448

    Open questions at the time
    • Whether p23 assists PHD2 catalysis directly or via protein folding not determined
    • Contribution of other Tibetan variants beyond D4E/C127S not fully assessed
  9. 2015 High

    PHD2's role expanded beyond HIF-α: filamin A was identified as a direct non-HIF substrate hydroxylated at P2309/P2316 and targeted for VHL-dependent degradation, linking oxygen sensing to dendritic spine maturation; PHD2–HIF-2α was confirmed as the critical couple for carotid body oxygen sensing and ventilatory response.

    Evidence FLNA proline mutagenesis with VHL interaction assays and dendritic spine imaging; inducible Phd2 conditional KO with Hif-1α or Hif-2α co-inactivation and ventilatory response measurement

    PMID:26337139 PMID:26972007

    Open questions at the time
    • Physiological relevance of FLNA hydroxylation outside neuronal context unknown
    • Full repertoire of non-HIF PHD2 substrates not defined
  10. 2016 High

    A redox-sensitive regulatory mechanism was uncovered: ROS induces PHD2 inactivation through disulfide-mediated homodimerization of catalytic-domain cysteines, exploited by oncogenic H-Ras to drive aerobic glycolysis; separately, myeloid PHD2 deletion was shown to protect against hypertensive cardiovascular remodeling via HIF-α accumulation.

    Evidence Non-reducing SDS-PAGE with cysteine mutagenesis and metabolic assays in H-Ras(V12) cells; myeloid-specific Phd2 KO in L-NAME/Ang II hypertension model with digoxin rescue

    PMID:23778187 PMID:26740011

    Open questions at the time
    • Specific cysteines mediating dimerization not all individually resolved
    • Whether ROS-dimerization occurs in vivo under physiological conditions untested
  11. 2017 High

    PP2A regulatory subunit B55α was identified as another non-HIF PHD2 substrate: PHD2 hydroxylates B55α at Pro319 triggering its degradation, linking PHD2 to apoptotic signaling under glucose starvation in breast cancer.

    Evidence Site-directed mutagenesis of B55α Pro319; Co-IP; PHD2 siRNA with B55α protein measurement; xenograft models

    PMID:28329677

    Open questions at the time
    • Whether B55α hydroxylation affects PP2A holoenzyme activity directly not tested
    • Generalizability beyond breast cancer cells not established
  12. 2018 High

    BRD4 was identified as a PHD2 substrate and carotid body paraganglioma pathogenesis was mechanistically linked to PHD2: BRD4 proline hydroxylation alters its transcriptional interactome; PHD2 loss in Type I cells causes HIF-2α-dependent multilineage hyperplasia.

    Evidence Targeted proteomics for BRD4 hydroxylation; cell-type-specific Phd2 conditional KO with HIF-2α epistasis and ultrastructural analysis

    PMID:29917232 PMID:31239290

    Open questions at the time
    • Functional consequences of specific BRD4 hydroxylation sites on gene expression programs not mapped
    • Whether paraganglioma formation requires additional genetic hits beyond PHD2 loss unclear
  13. 2019 High

    ERK was identified as a direct kinase for PHD2, establishing a growth-factor-responsive post-translational regulatory layer: ERK phosphorylation prevents PHD2–HIF-1α binding, and TGFβ1 activates this axis to promote platinum resistance.

    Evidence In vitro kinase assay; mutagenesis; Co-IP of PHD2–HIF-1α; TGFβ1 inhibitor and xenograft experiments

    PMID:31285371

    Open questions at the time
    • Specific phosphorylation sites on PHD2 not all mapped
    • Whether other kinases converge on similar sites untested
  14. 2020 High

    Two new regulatory inputs to PHD2 were established: CBS-derived H₂S persulfidates PHD2 at Cys21/Cys33, augmenting its hydroxylase activity (with hypoxia reducing persulfidation); the Tibetan D4E/C127S allele was validated in knock-in mice as a loss-of-function allele causing augmented hypoxic ventilatory response through impaired p23 interaction.

    Evidence In vitro persulfidation with Cys mutagenesis and zebrafish CBS rescue; knock-in mice with Tibetan allele, p23 binding assays, and ventilatory measurements with Hif2a epistasis

    PMID:32414920 PMID:32937467

    Open questions at the time
    • Whether persulfidation and disulfide dimerization compete at the same cysteines not resolved
    • Contribution of p23 interaction to non-ventilatory PHD2 functions unknown
  15. 2022 High

    Two additional regulatory mechanisms were defined: lactate directly competes with α-ketoglutarate for binding to the PHD2 catalytic domain, providing a metabolite-sensing mechanism linking glycolytic flux to HIF stabilization; SET7 methylates PHD2 at K297, repressing its hydroxylase activity.

    Evidence Direct binding and competition assays for lactate; PHD2-deficient macrophages with IL-1β readout; in vitro methylation assay with K297 mutagenesis and cellular functional readouts

    PMID:35452683 PMID:36064857

    Open questions at the time
    • Whether lactate inhibition operates at physiological intracellular concentrations in all tissues not established
    • Structural basis of K297 methylation-mediated inhibition not resolved
  16. 2023 High

    PHD2's function expanded to mitochondrial metabolic regulation: PHD2 accumulates on mitochondria under hypoxia via its β2β3 loop, where it hydroxylates AMPKα under normoxia to prevent activation; under hypoxia, loss of hydroxylation stabilizes a CaMKK2–PHD2–AMPKα complex that activates AMPK for metabolic adaptation. Separately, osteocyte PHD2 was identified as a critical regulator of FGF23 production through HIF-1α.

    Evidence Mitochondrial proteomics; β2β3 loop mutagenesis; in vitro hydroxylation of AMPKα; CaMKK2 complex pulldown; breast tumor xenografts; osteocyte-specific Phd2 KO mice with ATACseq/RNAseq and HIF-1α blockade

    PMID:36650133 PMID:37661833

    Open questions at the time
    • How PHD2 is targeted to mitochondria (receptor, membrane insertion mechanism) not structurally defined
    • Whether AMPKα hydroxylation is tissue-specific unknown
    • Full scope of osteocyte PHD2 targets beyond FGF23 not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • The complete non-HIF substrate repertoire of PHD2, the structural basis of its multi-compartment targeting, and how its diverse post-translational modifications are integrated to tune activity in different physiological contexts remain incompletely understood.
  • Systematic identification of non-HIF prolyl hydroxylation substrates not performed
  • No high-resolution structure of full-length PHD2 with regulatory N-terminal domain
  • How persulfidation, methylation, phosphorylation, and ROS-dimerization are hierarchically coordinated in vivo is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016491 oxidoreductase activity 3
Localization
GO:0005634 nucleus 2 GO:0005739 mitochondrion 2 GO:0005829 cytosol 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-8953897 Cellular responses to stimuli 7 R-HSA-392499 Metabolism of proteins 5 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-5357801 Programmed Cell Death 1
Partners
EPAS1FKBP38FLNAHIF1APPP2R2APRKAA1PTGES3VHL
Complex memberships
CaMKK2-EglN1-AMPKα complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 PHD1, PHD2 (EGLN1), and PHD3 each contribute non-redundantly to the regulation of both HIF-1α and HIF-2α subunits via prolyl hydroxylation; PHD2 is the dominant oxygen sensor in most cell types, and the three isoforms show specificity for different prolyl hydroxylation sites within each HIF-α subunit. siRNA knockdown of individual PHD isoforms with HIF-α protein level and transcriptional activity readouts in multiple cell lines The Journal of biological chemistry High 15247232
2005 EGLN1/PHD2 specifically represses HIF-1α transcriptional activity in hypoxia independently of promoting its proteolysis; ectopic EGLN1 inhibited HIF-1α transcriptional activity without altering HIF-1α protein levels in VHL-deficient cells, suggesting a discrete transcriptional repression activity. Ectopic EGLN1 expression in VHL-deficient cells; siRNA silencing of EGLN1; HIF-1α transcriptional reporter assays The Journal of biological chemistry Medium 16157596
2005 PHD2 (EGLN1) is a direct HIF target gene: HIF-1 binds a functional hypoxia-responsive element (HRE) in the CpG island downstream promoter of the PHD2 gene, establishing a negative feedback loop. EMSA demonstrating HIF-1 binding to HRE; luciferase reporter assays; identification of functional promoter by deletion analysis The Biochemical journal High 15563275
2006 TGFβ1 stabilizes HIF-1α by selectively decreasing PHD2 mRNA and protein levels via the Smad signaling pathway, thereby impairing HIF-1α prolyl hydroxylation and degradation. mRNA/protein quantification of PHD2 after TGFβ treatment; reporter assay with ODD domain; siRNA and inhibitor experiments; furin inhibition The Journal of biological chemistry High 16815840
2007 FK506-binding protein 38 (FKBP38) specifically interacts with PHD2 (not PHD1 or PHD3) via their N-terminal regions; FKBP38 depletion increases PHD2 hydroxylase activity and decreases HIF-α levels; FKBP38 regulates PHD2 protein stability through a peptidyl prolyl cis/trans isomerase-independent mechanism. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, co-localization, mammalian two-hybrid, stable RNAi, PHD hydroxylation activity assay Molecular and cellular biology High 17353276
2007 PHD2 is the primary HIF prolyl hydroxylase setting steady-state HIF-α levels in vivo; conditional inactivation of PHD2 in mice activates HIF target genes including erythropoietin, causing polycythemia and dilated cardiomyopathy. Conditional Phd2 knockout mice; measurement of EPO levels, red blood cell counts, cardiac pathology Blood High 18096761
2009 FKBP38 regulates PHD2 protein abundance through membrane-anchored interaction; PHD2 colocalizes with FKBP38 at the endoplasmic reticulum and mitochondria; PHD2 protein stability is regulated by a ubiquitin-independent proteasomal pathway with FKBP38 as adaptor. Peptide array binding, fluorescence spectroscopy, FRET, biochemical fractionation, immunofluorescence, cellular co-IP The Journal of biological chemistry High 19546213
2009 PHD2 haplodeficiency in endothelial cells normalizes the endothelial lining and vessel maturation via HIF-driven upregulation of soluble VEGFR-1 and VE-cadherin, redirecting tip cell specification to a quiescent phalanx formation and inhibiting tumor metastasis. Tumor implantation in PHD2+/- mice; vessel morphology, perfusion and oxygenation assays; molecular analysis of VEGFR-1 and VE-cadherin Cell High 19217150
2009 PHD2 regulates tumor angiogenesis through both HIF-dependent and HIF-independent but NF-κB-dependent pathways controlling IL-8 and angiogenin expression, which drive complementary angiogenesis and bone marrow-derived cell mobilization. PHD2 knockdown in cancer cells; cytokine profiling; xenograft tumor models; NF-κB reporter assays Cancer cell Medium 19477431
2011 Phd2 haplodeficiency skews macrophage polarization toward an M2-like pro-arteriogenic phenotype via activation of the canonical NF-κB pathway, promoting collateral artery growth independent of vessel density changes. Phd2+/- mice with hindlimb ischemia; macrophage-specific Phd2 deletion; NF-κB pathway analysis; smooth muscle cell recruitment assays Nature High 21983962
2011 PHD2 reacts with nitric oxide at both its catalytic Fe(II) center and cysteine residues, providing a mechanism by which NO may regulate the hypoxic response by directly inhibiting HIF hydroxylase activity. Biochemical and biophysical studies including EPR spectroscopy; reaction of purified PHD2 with NO donors Journal of molecular biology Medium 21601578
2012 PHD2 subcellular localization is dynamically regulated: amino acids 196-205 are required for nuclear import while amino acids 6-20 mediate nuclear export via CRM1; PHD2-HIF-1α interaction and hydroxylation occur predominantly in the nucleus, as cytoplasm-restricted PHD2 mutant shows reduced interaction with HIF-1α and lower prolyl hydroxylase activity. NLS/NES mutant analysis; FRET to detect PHD2-HIF-1α interaction in nucleus vs. cytoplasm; functional prolyl hydroxylase activity assays of compartment-restricted mutants Journal of cell science Medium 22946054
2009 PHD2 nuclear import is independent of classical importin α/β receptors, while its nuclear export requires CRM1 and the N-terminal 100 amino acids of the protein. Subcellular fractionation; importin inhibitors; CRM1 inhibition with leptomycin B; truncation mutants Biochemical and biophysical research communications Medium 19631610
2013 PHD2 preferentially hydroxylates the C-terminal oxygen-dependent degradation domain (CODD) of HIF-1α over the N-terminal domain (NODD) by ~20-fold, with electrostatic interactions and β2β3 loop closure being the dominant structural contributors to substrate selectivity. Kinetic competition assays; varied ionic strength experiments; amide H/D exchange mass spectrometry of PHD2 conformation Journal of inorganic biochemistry High 23787140
2013 PHD2 is the key regulator of hematopoietic stem cell (HSC) maintenance; conditional loss of PHD2 in early hematopoietic precursors promotes self-renewal of multipotent progenitors in a HIF1α- and SMAD7-dependent manner. Conditional Phd2 knockout in hematopoietic precursors; competitive bone marrow transplantation; whole BM transfer experiments Blood High 23667053
2014 The Tibetan PHD2 haplotype (D4E/C127S) drastically diminishes PHD2 interaction with the HSP90 cochaperone p23 via a PXLE motif in p23, resulting in impaired PHD2-mediated downregulation of the HIF pathway; both substitutions are required for this defective binding. Pulldown assays; co-immunoprecipitation; mutagenesis of D4E and C127S; functional HIF hydroxylation assays The Journal of biological chemistry High 24711448
2013 A P294R knock-in mutation in PHD2 causes erythrocytosis through haploinsufficiency; the erythrocytosis is rescued by Hif2a+/- but not Hif1a+/- background, identifying HIF-2α as the specific downstream mediator of PHD2-regulated red cell mass. Knock-in mouse model; genetic epistasis with Hif1a+/- and Hif2a+/- backgrounds; conditional Phd2 KO with cell-type-specific Cre lines The Journal of biological chemistry High 24121508
2015 PHD2 hydroxylates proline residues P2309 and P2316 in filamin A (FLNA) under normoxia, targeting FLNA for VHL-mediated ubiquitination and proteasomal degradation; PHD2 inactivation in hypoxia causes FLNA upregulation, leading to immature filopodium-like dendritic spines and reduced synapse density independently of HIF signaling. PHD2 knockdown; chemical PHD inhibition; identification of FLNA as substrate; site-directed mutagenesis of FLNA proline residues; VHL interaction assays; dendritic spine imaging Cell reports High 26972007
2016 Oxidative stress induces disulfide bond-mediated PHD2 homodimerization at cysteine residues in the catalytic double-stranded β-helix fold, causing PHD2 inactivation and consequent HIF-1α stabilization; oncogenic H-Ras(V12) promotes this ROS-dependent PHD2 dimerization to drive aerobic glycolysis. Non-reducing SDS-PAGE to detect dimers; site-directed mutagenesis of cysteines; ROS scavenger experiments; PHD2 knockdown in H-Ras(V12) cells; metabolic assays Scientific reports Medium 26740011
2015 PHD2 inactivation in cancer-associated fibroblasts (CAFs) phenocopies hypoxia-induced deactivation: HIF-1α stabilization reduces αSMA and periostin expression and myosin II activity, reducing contractile force, ECM remodeling, and tumor stiffness, thereby impairing metastasis. PHD2 siRNA in CAFs; PHD inhibitor DMOG in orthotopic breast cancer model; PHD2 KO CAF co-injection with tumor cells; traction force microscopy EMBO reports High 26323721
2015 PHD2/HIF-2α (not HIF-1α) is the critical enzyme-substrate couple controlling ventilatory sensitivity to hypoxia and carotid body proliferation; PHD2 inactivation-driven phenotypes are strongly rescued by HIF-2α co-inactivation but not HIF-1α co-inactivation. Inducible and constitutive Phd2 conditional KO mice; concomitant Hif-1α or Hif-2α inactivation; measurement of hypoxic ventilatory responses; BrdU incorporation for carotid body proliferation The Journal of physiology High 26337139
2017 PHD2 is identified as a direct binding partner of EGFR and regulates EGFR protein stability and downstream signaling in breast cancer cells. Co-immunoprecipitation of PHD2 and EGFR; PHD2 knockdown with EGFR stability assays; analysis of breast cancer patient samples Oncotarget Medium 28038470
2017 PHD2 hydroxylates the PP2A regulatory subunit B55α at proline 319, triggering its degradation; in glucose starvation, PHD2-mediated B55α hydroxylation drives apoptosis of breast cancer cells, identifying B55α as a non-HIF PHD2 substrate. Site-directed mutagenesis of B55α Pro319; co-immunoprecipitation; PHD2 siRNA with B55α protein level measurement; xenograft models with glucose competitor Cell reports High 28329677
2018 PHD2 hydroxylates BRD4 at proline residues; PHD2 is the key regulatory enzyme of BRD4 proline hydroxylation, and this modification significantly affects BRD4 interactions with key transcription factors and BRD4-mediated transcriptional activation. Parallel-reaction monitoring targeted proteomics; quantitative interactome analysis; biochemical validation of PHD2-BRD4 substrate relationship Molecular & cellular proteomics Medium 31239290
2018 DAP5 regulates HIF-1α abundance by promoting eIF2β-dependent translation of PHD2 during hypoxia-associated protein synthesis repression, acting as a safeguard to reverse HIF-1α accumulation. DAP5 depletion with HIF-1α and PHD2 protein level measurement; ribosome profiling/translation assays; DAP5:eIF2β binding requirement demonstrated by mutagenesis Molecular and cellular biology Medium 29530922
2019 ERK directly phosphorylates PHD2, preventing PHD2 binding to HIF-1α and inhibiting HIF-1α hydroxylation and degradation; TGFβ1 activates this ERK/PHD2 axis to stabilize HIF-1α and promote platinum resistance in ovarian cancer. In vitro kinase assay showing ERK phosphorylates PHD2; co-immunoprecipitation of PHD2 and HIF-1α; site-directed mutagenesis; TGFβ1 inhibitor experiments; xenograft models Clinical cancer research High 31285371
2020 Cystathionine β-synthase (CBS)-derived H2S persulfidates PHD2 at Cys21 and Cys33 in the zinc finger motif, augmenting PHD2 prolyl hydroxylase activity toward HIF-1α; hypoxia or CBS inhibition reduces persulfidation and PHD2 activity, stabilizing HIF-1α. In vitro persulfidation assays; site-directed mutagenesis of Cys21 and Cys33; CBS knockdown/inhibition; zebrafish CBS depletion rescue with H2S Science advances High 32937467
2020 The Tibetan PHD2 D4E/C127S allele is a loss-of-function allele that impairs p23 interaction; mice with the Tibetan Phd2 allele display augmented hypoxic ventilatory response, phenocopied by a p23 mutation that abrogates PHD2:p23 interaction. Knockin mouse model with Tibetan PHD2 allele; p23 binding assays; hypoxic ventilatory response measurement; Hif2a haploinsufficiency epistasis Proceedings of the National Academy of Sciences High 32414920
2022 Lactate directly binds to the catalytic domain of PHD2 in competition with α-ketoglutarate, inhibiting PHD2 activity and stabilizing HIF-1α; lactate-induced IL-1β production in macrophages was abolished in PHD2-deficient macrophages. Direct binding assay of lactate to PHD2 catalytic domain; competitive binding with α-ketoglutarate; PHD2-deficient macrophages with inflammatory cytokine readout; adipocyte-selective Ldha deletion mouse model Nature communications High 36064857
2022 SET7 lysine methyltransferase catalyzes EGLN1 monomethylation at lysine 297, repressing EGLN1 prolyl hydroxylase activity toward HIF-1α; a methylation-mimic EGLN1 mutant fails to suppress HIF signaling, enhancing cell proliferation and oxygen consumption. In vitro methylation assay; site-directed mutagenesis of K297; HIF-1α hydroxylation activity assay; cell proliferation and oxygen consumption rate measurement The Journal of biological chemistry High 35452683
2023 EglN1 (PHD2) accumulates on mitochondria under hypoxia via its β2β3 loop substrate-binding region; mitochondrial EglN1 prolyl-hydroxylates AMPKα under normoxia causing their dissociation, while hypoxia stabilizes EglN1-AMPKα interaction on mitochondria, enabling CaMKK2-EglN1-AMPKα complex formation and AMPKα activation for metabolic homeostasis. Mitochondrial proteomic profiling; EglN1 β2β3 loop mutagenesis; co-immunoprecipitation of EglN1-AMPKα; in vitro prolyl hydroxylation assay; CaMKK2 complex pulldown; breast tumor xenograft models The EMBO journal High 37661833
2023 Phd2 in osteocytes is a critical regulator of FGF23 production: osteocyte-specific Phd2 loss constitutively activates Fgf23 in a HIF-1α-dependent manner, and Phd2-KO cells lose iron-mediated suppression of Fgf23; this effect is not compensated by Phd1 or Phd3. Conditional osteocyte-specific Phd2 KO mice; CRISPR Phd2-KO osteocyte cell line; ATACseq/RNAseq; HIF-1α blockade rescue; iron manipulation experiments Bone research High 36650133
2016 PHD2 deletion in myeloid lineage reduces hypertensive cardiovascular remodeling through HIF-α accumulation in macrophages, decreasing inflammation- and fibrosis-associated gene expression; the protective effects are reversed by HIF-α synthesis inhibition with digoxin. Myeloid-specific Phd2 KO (LysM-Cre); hypertension model with L-NAME/Ang II; echocardiography; HIF-α inhibitor (digoxin) reversal experiment Journal of the American Heart Association High 23778187
2018 PHD2 inactivation in Type I cells of the carotid body (via Phd2 conditional KO) induces multilineage hyperplasia and paraganglioma-like changes dependent on HIF-2α but not HIF-1α, establishing PHD2-HIF-2α as the critical couple for carotid body oxygen-sensing and adaptive functions. Cell lineage tracing; Type I cell-specific Phd2 conditional KO; concurrent HIF-1α and HIF-2α inactivation; ultrastructural and proliferation analyses The Journal of physiology High 29917232

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. The Journal of biological chemistry 901 15247232
2009 Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 643 19217150
2006 Transforming growth factor beta1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression. The Journal of biological chemistry 276 16815840
2011 Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis. Nature 250 21983962
2007 Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood 245 18096761
2009 Tumor vasculature is regulated by PHD2-mediated angiogenesis and bone marrow-derived cell recruitment. Cancer cell 194 19477431
2005 Regulation of the prolyl hydroxylase domain protein 2 (phd2/egln-1) gene: identification of a functional hypoxia-responsive element. The Biochemical journal 173 15563275
2016 Oxidative Dimerization of PHD2 is Responsible for its Inactivation and Contributes to Metabolic Reprogramming via HIF-1α Activation. Scientific reports 143 26740011
2022 Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2. Nature communications 139 36064857
2015 Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis. EMBO reports 137 26323721
2014 Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia. Journal of molecular medicine (Berlin, Germany) 106 25263965
2012 Gene-targeting of Phd2 improves tumor response to chemotherapy and prevents side-toxicity. Cancer cell 106 22897855
2007 The peptidyl prolyl cis/trans isomerase FKBP38 determines hypoxia-inducible transcription factor prolyl-4-hydroxylase PHD2 protein stability. Molecular and cellular biology 94 17353276
2009 Binding of the CHD4 PHD2 finger to histone H3 is modulated by covalent modifications. The Biochemical journal 93 19624289
2005 Suppression of hypoxia-inducible factor 1alpha (HIF-1alpha) transcriptional activity by the HIF prolyl hydroxylase EGLN1. The Journal of biological chemistry 91 16157596
2015 Hypoxia-inducible miR-182 enhances HIF1α signaling via targeting PHD2 and FIH1 in prostate cancer. Scientific reports 87 26205124
2015 Regulation of ventilatory sensitivity and carotid body proliferation in hypoxia by the PHD2/HIF-2 pathway. The Journal of physiology 75 26337139
2010 Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis. Oncogene 68 20856199
2015 The Cancer Cell Oxygen Sensor PHD2 Promotes Metastasis via Activation of Cancer-Associated Fibroblasts. Cell reports 66 26235614
2006 Induction of human endometrial cancer cell senescence through modulation of HIF-1alpha activity by EGLN1. International journal of cancer 65 16161047
2014 Defective Tibetan PHD2 binding to p23 links high altitude adaption to altered oxygen sensing. The Journal of biological chemistry 62 24711448
2017 Gain-of-function EGLN1 prolyl hydroxylase (PHD2 D4E:C127S) in combination with EPAS1 (HIF-2α) polymorphism lowers hemoglobin concentration in Tibetan highlanders. Journal of molecular medicine (Berlin, Germany) 61 28233034
2009 Hypoxia-inducible factor prolyl-4-hydroxylase PHD2 protein abundance depends on integral membrane anchoring of FKBP38. The Journal of biological chemistry 61 19546213
2016 PHD2: from hypoxia regulation to disease progression. Hypoxia (Auckland, N.Z.) 60 27800508
2010 PHD2 in tumour angiogenesis. British journal of cancer 60 20461086
2019 Hydrogen sulfide inhibits cigarette smoke-induced inflammation and injury in alveolar epithelial cells by suppressing PHD2/HIF-1α/MAPK signaling pathway. International immunopharmacology 57 31771816
2016 Regulation of ATP13A2 via PHD2-HIF1α Signaling Is Critical for Cellular Iron Homeostasis: Implications for Parkinson's Disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 57 26818499
2016 Increased EPO Levels Are Associated With Bone Loss in Mice Lacking PHD2 in EPO-Producing Cells. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 56 27082941
2011 Studies on the reaction of nitric oxide with the hypoxia-inducible factor prolyl hydroxylase domain 2 (EGLN1). Journal of molecular biology 56 21601578
2016 miR-17/20 Controls Prolyl Hydroxylase 2 (PHD2)/Hypoxia-Inducible Factor 1 (HIF1) to Regulate Pulmonary Artery Smooth Muscle Cell Proliferation. Journal of the American Heart Association 52 27919930
2016 The Oxygen Sensor PHD2 Controls Dendritic Spines and Synapses via Modification of Filamin A. Cell reports 51 26972007
2012 Oxygen sensing by the prolyl-4-hydroxylase PHD2 within the nuclear compartment and the influence of compartmentalisation on HIF-1 signalling. Journal of cell science 50 22946054
2020 Cystathione β-synthase regulates HIF-1α stability through persulfidation of PHD2. Science advances 48 32937467
2018 PHD2 inactivation in Type I cells drives HIF-2α-dependent multilineage hyperplasia and the formation of paraganglioma-like carotid bodies. The Journal of physiology 48 29917232
2007 Hypoxia-inducible factor prolyl-hydroxylase: purification and assays of PHD2. Methods in enzymology 48 17998047
2019 Association of EGLN1 gene with high aerobic capacity of Peruvian Quechua at high altitude. Proceedings of the National Academy of Sciences of the United States of America 47 31712437
2017 Localized Delivery of shRNA against PHD2 Protects the Heart from Acute Myocardial Infarction through Ultrasound-Targeted Cationic Microbubble Destruction. Theranostics 47 28042316
2020 Inhibition of Endothelial PHD2 Suppresses Post-Ischemic Kidney Inflammation through Hypoxia-Inducible Factor-1. Journal of the American Society of Nephrology : JASN 45 31996410
2016 Class I and IIa HDACs Mediate HIF-1α Stability Through PHD2-Dependent Mechanism, While HDAC6, a Class IIb Member, Promotes HIF-1α Transcriptional Activity in Nucleus Pulposus Cells of the Intervertebral Disc. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 45 26765925
2013 A knock-in mouse model of human PHD2 gene-associated erythrocytosis establishes a haploinsufficiency mechanism. The Journal of biological chemistry 44 24121508
2011 Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia. Haematologica 44 21933857
2019 ERK Regulates HIF1α-Mediated Platinum Resistance by Directly Targeting PHD2 in Ovarian Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 43 31285371
2014 The role of PHD2 mutations in the pathogenesis of erythrocytosis. Hypoxia (Auckland, N.Z.) 43 27774468
2019 Genome-Wide Interrogation of Human Cancers Identifies EGLN1 Dependency in Clear Cell Ovarian Cancers. Cancer research 40 30898838
2013 EGLN1 variants influence expression and SaO2 levels to associate with high-altitude pulmonary oedema and adaptation. Clinical science (London, England : 1979) 40 23130672
2009 The prolyl-hydroxylase EGLN3 and not EGLN1 is inactivated by methylation in plasma cell neoplasia. European journal of haematology 40 19737309
2019 Convergent evolution on the hypoxia-inducible factor (HIF) pathway genes EGLN1 and EPAS1 in high-altitude ducks. Heredity 39 30631144
2013 Gambogic acid inhibits angiogenesis through inhibiting PHD2-VHL-HIF-1α pathway. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 39 23501055
2013 HIF prolyl hydroxylase 2 (PHD2) is a critical regulator of hematopoietic stem cell maintenance during steady-state and stress. Blood 39 23667053
2014 Intermediary metabolite precursor dimethyl-2-ketoglutarate stabilizes hypoxia-inducible factor-1α by inhibiting prolyl-4-hydroxylase PHD2. PloS one 37 25420025
2003 SM-20, EGL-9, and the EGLN family of hypoxia-inducible factor prolyl hydroxylases. Molecules and cells 37 14503838
2022 Adipose-Derived Mesenchymal Stem Cells Reprogram M1 Macrophage Metabolism via PHD2/HIF-1α Pathway in Colitis Mice. Frontiers in immunology 35 35757749
2019 PHD2 exerts anti-cancer and anti-inflammatory effects in colon cancer xenografts mice via attenuating NF-κB activity. Life sciences 35 31838134
2002 Angiotensin II's antiproliferative effects mediated through AT2-receptors depend on down-regulation of SM-20. Laboratory investigation; a journal of technical methods and pathology 35 12379765
2020 Tibetan PHD2, an allele with loss-of-function properties. Proceedings of the National Academy of Sciences of the United States of America 34 32414920
2013 Erythropoietin inhibits HIF-1α expression via upregulation of PHD-2 transcription and translation in an in vitro model of hypoxia-ischemia. Translational stroke research 34 24323731
2012 Screening chelating inhibitors of HIF-prolyl hydroxylase domain 2 (PHD2) and factor inhibiting HIF (FIH). Journal of inorganic biochemistry 34 22687491
2011 Prolyl hydroxylase domain protein 2 (PHD2) mediates oxygen-induced retinopathy in neonatal mice. The American journal of pathology 34 21435465
2009 Cellular oxygen sensing: Importins and exportins are mediators of intracellular localisation of prolyl-4-hydroxylases PHD1 and PHD2. Biochemical and biophysical research communications 34 19631610
2017 Hypoxia-inducible factor prolyl hydroxylase 2 (PHD2) is a direct regulator of epidermal growth factor receptor (EGFR) signaling in breast cancer. Oncotarget 32 28038470
2014 HIF-1-PHD2 axis controls expression of syndecan 4 in nucleus pulposus cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 24558194
2014 Conditional disruption of the prolyl hydroxylase domain-containing protein 2 (Phd2) gene defines its key role in skeletal development. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 32 24753072
2018 GLA supplementation regulates PHD2 mediated hypoxia and mitochondrial apoptosis in DMBA induced mammary gland carcinoma. The international journal of biochemistry & cell biology 31 29355756
2018 Acceleration of Diabetic Wound Healing with PHD2- and miR-210-Targeting Oligonucleotides. Tissue engineering. Part A 30 29644938
2013 Deletion of phd2 in myeloid lineage attenuates hypertensive cardiovascular remodeling. Journal of the American Heart Association 30 23778187
2000 Mapping, characterization, and expression analysis of the SM-20 human homologue, c1orf12, and identification of a novel related gene, SCAND2. Genomics 30 11056053
2020 Myocardium-targeted transplantation of PHD2 shRNA-modified bone mesenchymal stem cells through ultrasound-targeted microbubble destruction protects the heart from acute myocardial infarction. Theranostics 29 32308762
2011 Prolyl hydroxylase-2 (PHD2) exerts tumor-suppressive activity in pancreatic cancer. Cancer 28 21792862
2019 Systemic silencing of PHD2 causes reversible immune regulatory dysfunction. The Journal of clinical investigation 27 31162141
2017 PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner. Cell reports 27 28329677
2015 Molecular characterization and mRNA expression of HIF-prolyl hydroxylase-2 (phd2) in hypoxia-sensing pathways from Megalobrama amblycephala. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 27 25868626
2014 Epidermal or dermal specific knockout of PHD-2 enhances wound healing and minimizes ischemic injury. PloS one 27 24695462
2011 An activator of PHD2, KRH102140, decreases angiogenesis via inhibition of HIF-1α. Cell biochemistry and function 26 21287578
2019 Genetic variants at the EGLN1 locus associated with high-altitude adaptation in Tibetans are absent or found at low frequency in highland Andeans. Annals of human genetics 25 30719713
2018 A redox ruthenium compound directly targets PHD2 and inhibits the HIF1 pathway to reduce tumor angiogenesis independently of p53. Cancer letters 25 30339780
2018 Gamma linolenic acid regulates PHD2 mediated hypoxia and mitochondrial apoptosis in DEN induced hepatocellular carcinoma. Drug design, development and therapy 23 30587920
2019 Targeted and Interactome Proteomics Revealed the Role of PHD2 in Regulating BRD4 Proline Hydroxylation. Molecular & cellular proteomics : MCP 22 31239290
2014 Variants of the low oxygen sensors EGLN1 and HIF-1AN associated with acute mountain sickness. International journal of molecular sciences 22 25431923
2021 Gain-of-function Tibetan PHD2D4E;C127S variant suppresses monocyte function: A lesson in inflammatory response to inspired hypoxia. EBioMedicine 20 34102396
2018 Regulation of Hypoxia-Inducible Factor 1α during Hypoxia by DAP5-Induced Translation of PHD2. Molecular and cellular biology 20 29530922
2015 Tetramethylpyrazine protects CoCl2-induced apoptosis in human umbilical vein endothelial cells by regulating the PHD2/HIF/1α-VEGF pathway. Molecular medicine reports 20 26676934
2016 Prolyl hydroxylase 2 (PHD2) inhibition protects human renal epithelial cells and mice kidney from hypoxia injury. Oncotarget 19 27527871
2017 Conditional Deletion of the Phd2 Gene in Articular Chondrocytes Accelerates Differentiation and Reduces Articular Cartilage Thickness. Scientific reports 18 28349987
2023 Osteocyte Egln1/Phd2 links oxygen sensing and biomineralization via FGF23. Bone research 17 36650133
2021 PHD2 attenuates high-glucose-induced blood retinal barrier breakdown in human retinal microvascular endothelial cells by regulating the Hif-1α/VEGF pathway. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 17 34773469
2016 Short Hairpin RNA Silencing of PHD-2 Improves Neovascularization and Functional Outcomes in Diabetic Wounds and Ischemic Limbs. PloS one 16 26967994
2009 Defects in embryonic development of EGLN1/PHD2 knockdown transgenic mice are associated with induction of Igfbp in the placenta. Biochemical and biophysical research communications 16 19683511
2023 A mitochondrial EglN1-AMPKα axis drives breast cancer progression by enhancing metabolic adaptation to hypoxic stress. The EMBO journal 15 37661833
2022 A novel PHD2 inhibitor acteoside from Cistanche tubulosa induces skeletal muscle mitophagy to improve cancer-related fatigue. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 15 35658245
2018 Inhibition of the Oxygen Sensor PHD2 Enhances Tissue-Engineered Endochondral Bone Formation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 15 30452097
2016 Erythrocytosis due to PHD2 Mutations: A Review of Clinical Presentation, Diagnosis, and Genetics. Case reports in hematology 15 27034858
2013 Substrate preference of the HIF-prolyl hydroxylase-2 (PHD2) and substrate-induced conformational change. Journal of inorganic biochemistry 15 23787140
2021 Endothelial cell PHD2-HIF1α-PFKFB3 contributes to right ventricle vascular adaptation in pulmonary hypertension. American journal of physiology. Lung cellular and molecular physiology 14 34346780
2016 Prolyl Hydroxylase Domain-Containing Protein 2 (Phd2) Regulates Chondrocyte Differentiation and Secondary Ossification in Mice. Scientific reports 14 27775044
2013 Novel complex crystal structure of prolyl hydroxylase domain-containing protein 2 (PHD2): 2,8-Diazaspiro[4.5]decan-1-ones as potent, orally bioavailable PHD2 inhibitors. Bioorganic & medicinal chemistry 14 24055079
2023 Characterization of genetic variants in the EGLN1/PHD2 gene identified in a European collection of patients with erythrocytosis. Haematologica 13 37317877
2022 EGLN1 prolyl hydroxylation of hypoxia-induced transcription factor HIF1α is repressed by SET7-catalyzed lysine methylation. The Journal of biological chemistry 13 35452683
2021 Developmental role of PHD2 in the pathogenesis of pseudohypoxic pheochromocytoma. Endocrine-related cancer 13 34658364
2018 Loss of Phd2 cooperates with BRAFV600E to drive melanomagenesis. Nature communications 13 30575721
2015 Ultrasound-targeted microbubble destruction (UTMD) assisted delivery of shRNA against PHD2 into H9C2 cells. PloS one 13 26267649