Affinage

EGLN3

Prolyl hydroxylase EGLN3 · UniProt Q9H6Z9

Length
239 aa
Mass
27.3 kDa
Annotated
2026-06-09
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EGLN3/PHD3 is an iron- and 2-oxoglutarate-dependent prolyl hydroxylase that functions both as an oxygen sensor in the HIF pathway and as a broad post-translational regulator of substrate stability, interactions, and activity across diverse cellular processes (PMID:12181324, PMID:17434750, PMID:21620138). In its canonical role it hydroxylates conserved prolines in HIF-1α and HIF-2α within the LXXLAP motif, contributing non-redundantly to oxygen-dependent HIF-α turnover, and is itself transcriptionally induced by HIF through an intronic hypoxia-response element, establishing a negative-feedback loop (PMID:15247232, PMID:15823097, PMID:19720742). Beyond HIF, PHD3 hydroxylates an expanding substrate repertoire — PKM2 to promote its HIF-1 coactivator function and aerobic glycolysis, ACC2 to activate it and suppress fatty acid oxidation in muscle and leukemia cells, ATF-4, the β2-adrenergic receptor and p53 to govern their VHL- or deubiquitinase-dependent stability, HCLK2 to enable ATR/CHK1/p53 DNA-damage signaling, actin to limit polymerization and motility, and ERK3 to block its chaperone-mediated autophagy — thereby coupling oxygen and nutrient status to metabolism, apoptosis, and genome maintenance (PMID:21620138, PMID:27635760, PMID:32663458, PMID:17684156, PMID:19584355, PMID:30067985, PMID:22797300, PMID:25079693, PMID:35124697). A major branch of PHD3 biology is catalysis-independent: it acts as a scaffold or co-activator by binding IKKγ/NEMO and p65 to modulate NF-κB signaling, Eps15 to drive EGFR internalization, occludin to protect tight junctions from Itch-mediated degradation, and myogenin to oppose VHL-mediated destabilization during myogenesis (PMID:23732909, PMID:22948157, PMID:25420589, PMID:26124271, PMID:17344222). PHD3 drives developmental neuronal apoptosis downstream of c-Jun and upstream of KIF1Bβ and BIM-EL, a function relevant to sympathoadrenal development and pheochromocytoma (PMID:16098468, PMID:18334619, PMID:18332118, PMID:31375625). Its abundance and activity are tightly controlled by Siah2-, CDC20/APC-, and MAEA-mediated ubiquitination, USP9X-mediated deubiquitination, SUMOylation, p62-driven aggregation, and STAT1/IFNγ-dependent transcription (PMID:16958618, PMID:33039559, PMID:36882523, PMID:34112167, PMID:25380826, PMID:23345396, PMID:19574556).

Mechanistic history

Synthesis pass · year-by-year structured walk · 39 steps
  1. 2002 High

    Established the molecular basis of PHD3 substrate recognition by defining the proline acceptor within the HIF-1α LXXLAP motif and showing PHD3 has restricted specificity relative to PHD2.

    Evidence In vitro prolyl hydroxylase assay with mutant HIF-1α peptides and sequence analysis

    PMID:12181324

    Open questions at the time
    • Did not define full substrate range beyond HIF-1α
    • Structural basis of restricted specificity not resolved
  2. 2004 High

    Showed PHD3 contributes non-redundantly to oxygen-dependent regulation of both HIF-1α and HIF-2α with site and isoform selectivity, distinguishing its cellular role from other PHDs.

    Evidence siRNA knockdown of individual PHD isoforms across multiple cell types and conditions

    PMID:15247232

    Open questions at the time
    • Relative quantitative contribution per cell type not fully resolved
    • Does not address non-HIF substrates
  3. 2005 High

    Placed PHD3 in a HIF-driven negative feedback loop by identifying a functional intronic HRE bound by HIF in vivo.

    Evidence HRE bioinformatics, reporter assays, and ChIP for HIF binding

    PMID:15823097

    Open questions at the time
    • Quantitative impact of feedback on HIF dynamics not modeled
  4. 2005 High

    Defined a HIF-independent proapoptotic role: PHD3 acts downstream of c-Jun and is uniquely required for neuronal apoptosis on NGF withdrawal, feedback-inhibited by succinate, linking SDH/metabolism to developmental apoptosis.

    Evidence Genetic epistasis in sympathetic neuronal progenitors with NGF withdrawal and succinate supplementation

    PMID:16098468

    Open questions at the time
    • Substrate mediating apoptosis not identified at this stage
    • Catalytic requirement vs scaffold role unresolved here
  5. 2007 High

    Expanded the PHD3 substrate repertoire beyond HIF by identifying ATF-4 hydroxylation within a novel ODD domain in a PHD3-specific, pVHL-independent manner.

    Evidence Co-IP, isoform-specific siRNA, substrate proline mutagenesis, and PHD inhibitor treatment

    PMID:17684156

    Open questions at the time
    • Downstream physiological consequences of ATF-4 stabilization not fully mapped
    • E3 ligase for hydroxylated ATF-4 not defined
  6. 2007 High

    Demonstrated a HIF-independent scaffold function in myogenesis: PHD3 binds and stabilizes myogenin, opposing VHL-mediated degradation during myoblast differentiation.

    Evidence Co-IP, ubiquitination assay, EGLN3 loss/gain-of-function and rescue of VHL-mediated degradation in C2C12 cells

    PMID:17344222

    Open questions at the time
    • Whether myogenin stabilization requires hydroxylase activity not resolved here
    • In vivo muscle relevance not tested
  7. 2007 High

    Confirmed PHD3 as a bona fide iron/2-OG dioxygenase by reconstituting recombinant enzyme and identifying an additional HIF-1α hydroxylation site (Pro567).

    Evidence E. coli expression, purification, in vitro hydroxylation assay, and mass spectrometry verification

    PMID:17434750

    Open questions at the time
    • Physiological significance of Pro567 hydroxylation not established
  8. 2006 High

    Identified Morg1 as a WD-repeat scaffold partner that modulates PHD3 suppression of HIF activity.

    Evidence Yeast two-hybrid, reciprocal co-IP, co-localization, and HIF reporter assays with siRNA

    PMID:16407229

    Open questions at the time
    • Structural interface and stoichiometry not defined
    • Whether Morg1 targets PHD3 to specific substrates unknown
  9. 2008 High

    Established in vivo that PHD3 drives sympathoadrenal developmental apoptosis specifically through HIF-2α, validating the neuronal pathway genetically.

    Evidence PHD3-/- mice with HIF-1α+/- and HIF-2α+/- genetic intercrosses and neuronal apoptosis assays

    PMID:18332118

    Open questions at the time
    • Molecular mechanism downstream of HIF-2α in this context not fully detailed
  10. 2008 High

    Defined the apoptotic effector axis by placing KIF1Bβ genetically downstream of EglN3 as necessary and sufficient for NGF-withdrawal apoptosis.

    Evidence Unbiased shRNA screen and epistasis with knockdown/overexpression in neuronal progenitors

    PMID:18334619

    Open questions at the time
    • Direct biochemical link between PHD3 catalysis and KIF1Bβ not established
  11. 2008 High

    Explained isoform-selective PHD3 turnover: Siah2 targets PHD3 because it lacks the N-terminal extension of PHD1/2, and a low-mass PHD3 form has higher HIF-1α activity.

    Evidence Co-IP, size-exclusion fractionation, in vitro hydroxylation, and N-terminal deletion mutagenesis

    PMID:16958618

    Open questions at the time
    • Cellular triggers regulating Siah2-PHD3 turnover not fully defined
  12. 2008 Medium

    Described activity-dependent PHD3 aggresome-like aggregation under normoxia coupled to apoptosis, linking localization to function.

    Evidence PHD3-GFP imaging, fractionation, co-localization with proteasome/ubiquitin markers, and active-site mutants

    PMID:18337469

    Open questions at the time
    • Single lab; physiological role of aggregation not confirmed in vivo
    • Composition of aggregates incompletely defined
  13. 2009 High

    Broadened prolyl hydroxylation signaling to GPCRs by showing PHD3 hydroxylates β2AR at Pro382/Pro395 to enable pVHL-mediated degradation, oxygen-dependently.

    Evidence Co-IP, MS site identification, proline mutagenesis, pVHL ubiquitylation assay, and hypoxia experiments

    PMID:19584355

    Open questions at the time
    • Physiological adrenergic consequences in vivo not fully characterized
  14. 2009 High

    Demonstrated in vivo that Phd3 participates in a HIF feedback loop and partially compensates for Phd2 loss.

    Evidence Phd2/Phd3 double-knockout mice with HIF target analysis and histopathology

    PMID:19720742

    Open questions at the time
    • Tissue-specific compensation thresholds not delineated
  15. 2009 Medium

    Identified a HIF-independent transcriptional input: IFNγ induces PHD3 specifically via JAK/STAT1, linking inflammatory signaling to PHD3 levels.

    Evidence JAK inhibitor, STAT1 siRNA, and ChIP for STAT1 at the PHD3 promoter in endothelial cells

    PMID:19574556

    Open questions at the time
    • Single lab; functional consequence of IFNγ-induced PHD3 not defined
    • Cell-type generality untested
  16. 2010 High

    Established that PHD3's NF-κB-suppressive activity in myogenesis requires catalytic activity, distinguishing it from scaffold roles.

    Evidence Pharmacological PHD inhibition, catalytically inactive EGLN3, and dominant-negative epistasis with NF-κB reporters

    PMID:20089853

    Open questions at the time
    • Direct hydroxylation target in the NF-κB axis in this context not identified
  17. 2010 Medium

    Identified PRP19 as a hypoxia-enhanced partner that suppresses PHD3-dependent cell death.

    Evidence Co-IP, domain-deletion mapping, siRNA/overexpression, and caspase/cell death assays with double-silencing rescue

    PMID:20599946

    Open questions at the time
    • Single lab; mechanism by which PRP19 restrains PHD3-driven death unclear
  18. 2011 High

    Connected PHD3 to cancer metabolism by showing PKM2 hydroxylation enhances its HIF-1 coactivator role and aerobic glycolysis.

    Evidence MS/anti-hydroxyproline site identification, co-IP, knockdown, and metabolic flux assays with PKM1/PKM2 comparison

    PMID:21620138

    Open questions at the time
    • In vivo tumor relevance of PKM2 hydroxylation not detailed here
  19. 2011 High

    Defined a HIF-independent survival role: PHD3 uniquely prolongs neutrophil survival in hypoxia via Siva1/Bcl-xL, with in vivo inflammatory consequences.

    Evidence Phd3-/- neutrophils, apoptosis assays, Siva1/Bcl-xL measurement, and acute lung injury/colitis models

    PMID:21317538

    Open questions at the time
    • Whether PHD3 catalysis or scaffolding mediates the effect not resolved
  20. 2012 High

    Linked PHD3 to the DNA-damage response by showing HCLK2 hydroxylation is required for ATR binding and ATR/CHK1/p53 activation.

    Evidence Co-IP, DMOG/hypoxia inhibition, PHD3-/- mice, thymic apoptosis, and CHK1/p53 phosphorylation assays

    PMID:22797300

    Open questions at the time
    • HCLK2 hydroxylation site not mapped here
    • Crosstalk with HIF pathway in DDR unaddressed
  21. 2012 High

    Established a hydroxylase-independent NF-κB co-activator function via physical interaction with p65 in nucleus pulposus catabolism.

    Evidence Co-IP, co-localization, shRNA knockdown, NF-κB and HRE reporters confirming HIF-independence

    PMID:22948157

    Open questions at the time
    • Structural basis of p65 interaction undefined
    • Apparent context-dependent opposite NF-κB effects vs catalytic suppression unreconciled
  22. 2013 High

    Defined a catalysis-independent NF-κB-suppressive mechanism: EGLN3 binds IKKγ/NEMO and competes with cIAP1 to block K63 ubiquitination.

    Evidence Co-IP, K63 ubiquitination assay, catalytic mutant, cIAP1 competition, and isoform comparison

    PMID:23732909

    Open questions at the time
    • Reconciliation with co-activator p65 role context-dependent and not fully explained
  23. 2013 Medium

    Showed p62/SQSTM1 controls PHD3 by promoting normoxic aggregation/degradation, tuning PHD3-HIF-α engagement with oxygen.

    Evidence Co-IP, p62 siRNA, PHD3 localization imaging, and HIF-α level measurement

    PMID:23345396

    Open questions at the time
    • Single lab; molecular trigger for hypoxic p62 decrease unclear
  24. 2013 High

    Revealed an in vivo HIF-2α-specific metabolic axis: hepatic Phd3 loss improves insulin sensitivity via HIF-2α-driven Irs2 induction.

    Evidence Acute hepatic Phd3 knockout, glucose/insulin tolerance tests, Akt phosphorylation, and HIF-2α/Irs2 double-knockdown epistasis

    PMID:24037093

    Open questions at the time
    • Whether direct HIF-2α hydroxylation or other mechanism drives selectivity not resolved
  25. 2014 High

    Demonstrated a scaffold role in receptor trafficking: PHD3 binds Eps15 to promote EGFR internalization, restraining EGFR signaling independent of catalysis, HIF, and NF-κB.

    Evidence Co-IP, EGFR internalization assay, knockdown, catalytic mutant, and EGFR phosphorylation measurement

    PMID:25420589

    Open questions at the time
    • Structural basis of Eps15 interaction not defined
  26. 2014 High

    Extended hydroxylation to the cytoskeleton: PHD3 hydroxylates actin at Pro307/Pro322 to inhibit polymerization and motility.

    Evidence MS site identification, co-IP, knockdown/overexpression, F-/G-actin fractionation, DMOG, and migration assays

    PMID:25079693

    Open questions at the time
    • In vivo relevance of actin hydroxylation untested
  27. 2014 Medium

    Linked PHD3 to mitochondrial metabolism via interaction with PDH-E1β and stabilization of the PDH complex.

    Evidence MS interactome, co-IP, and PDH activity/stability assays in PHD3-depleted cells and -/- MEFs

    PMID:25088999

    Open questions at the time
    • Single lab; whether interaction is direct or catalytic unclear
  28. 2014 High

    Defined a hydroxylase-independent barrier-protective role: PHD3 shields occludin from Itch, with intestinal Phd3 loss causing spontaneous colitis.

    Evidence Intestinal epithelial-specific Phd3 knockout, co-IP of PHD3/occludin/Itch, permeability assays, and hydroxylase-dead mutant

    PMID:26124271

    Open questions at the time
    • Mechanism of Itch competition not structurally defined
  29. 2014 Medium

    Identified a catalysis-independent SUMOylation mechanism repressing HIF-1 transcriptional activity without affecting HIF-1α stability.

    Evidence SUMOylation assay, lysine cluster mutagenesis, HIF-1 reporter, and hydroxylase activity controls

    PMID:25380826

    Open questions at the time
    • Single lab; SUMO E3 ligase and downstream effector not identified
  30. 2015 Medium

    Connected PHD3 to cell cycle control by HIF-independent reduction of p27 half-life via reduced Ser10 phosphorylation, promoting G1/S entry.

    Evidence Knockdown, flow cytometry, cycloheximide chase, phospho-S10 antibody, and p27-S10A mutant

    PMID:26223520

    Open questions at the time
    • Single lab; molecular intermediary linking PHD3 to p27-S10 phosphorylation unknown
  31. 2016 High

    Established PHD3 as a nutrient-responsive metabolic brake: ACC2 hydroxylation activates ACC2 to suppress fatty acid oxidation, with consequences for leukemia proliferation.

    Evidence Knockdown/overexpression, ACC2 hydroxylation assay, isotopic FAO tracing, and leukemia proliferation assay

    PMID:27635760

    Open questions at the time
    • ACC2 hydroxylation site not mapped here
  32. 2018 High

    Showed PHD3 hydroxylates p53 at Pro359 to regulate USP7/USP10 binding and thus p53 stability.

    Evidence Co-IP, MS site identification, USP7/USP10 interaction and ubiquitination assays with mRNA controls

    PMID:30067985

    Open questions at the time
    • In vivo p53-dependent phenotypes of this hydroxylation not defined
  33. 2019 High

    Resolved the apoptotic effector mechanism: EglN3 hydroxylates BIM-EL to enable VHL binding that blocks ERK-Ser69 phosphorylation, stabilizing BIM-EL; VHL type 2C mutants fail, linking to pheochromocytoma.

    Evidence Co-IP, hydroxylation/phosphorylation assays, genetic inactivation, VHL mutant panel, and ERK-inhibitor rescue

    PMID:31375625

    Open questions at the time
    • Integration with the KIF1Bβ axis not fully reconciled
  34. 2019 High

    Uncovered a cell-type-specific reversal: in ccRCC, PHD3 silencing lowers HIF-2α by destabilizing HIF2A mRNA, opposite to the canonical pathway.

    Evidence Isoform-specific siRNA, protein/mRNA measurement, mRNA stability assay, and rescue with cell-type comparison

    PMID:30617181

    Open questions at the time
    • Single lab; mechanism by which PHD3 affects HIF2A mRNA stability unknown
  35. 2020 High

    Validated the ACC2 metabolic axis in vivo: tissue-specific PHD3 loss abolishes ACC2 hydroxylation, elevates FAO, and enhances endurance exercise capacity.

    Evidence Whole-body and muscle-specific PHD3 knockout mice, ACC2 hydroxylation/FAO measurement, treadmill and AMPK assays

    PMID:32663458

    Open questions at the time
    • Interplay between hydroxylation and AMPK phosphorylation of ACC2 not fully mechanistic
  36. 2020 Medium

    Identified CDC20/APC-mediated D-box-dependent PHD3 degradation that stabilizes HIF-1α and promotes VEGF in HCC.

    Evidence Co-IP, ubiquitination assay, CDC20 ablation/inhibition, non-degradable D-box mutant rescue, and xenograft

    PMID:33039559

    Open questions at the time
    • Single lab; cell-cycle context of PHD3 destruction not detailed
  37. 2021 Medium

    Showed USP9X deubiquitinates EGLN3 to prevent degradation, sustaining the apoptotic KIF1Bβ pathway and restraining cholangiocarcinoma growth.

    Evidence Co-IP, ubiquitination assay, USP9X/EGLN3 knockdown, xenograft, and KIF1Bβ measurement

    PMID:34112167

    Open questions at the time
    • Single lab; deubiquitination site not mapped
  38. 2022 High

    Demonstrated PHD3 catalysis blocks chaperone-mediated autophagy of ERK3 by preventing LAMP2A/HSC70 binding.

    Evidence Co-IP, catalytically inactive EGLN3 knock-in mice, CMA-lysosome assays, and interaction rescue

    PMID:35124697

    Open questions at the time
    • ERK3 hydroxylation site not defined here
    • Physiological context of ERK3 regulation broad
  39. 2023 Medium

    Identified MAEA as an E3 ligase ubiquitinating PHD3 at K159 to stabilize HIF-1α and promote glioblastoma stemness and temozolomide resistance.

    Evidence TMT proteomics, co-IP, K48 ubiquitination assay, K159 mutagenesis, and xenograft

    PMID:36882523

    Open questions at the time
    • Single lab; regulation of MAEA-PHD3 axis upstream unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the cell selects between PHD3's catalytic substrate hydroxylation and its catalysis-independent scaffold/co-activator functions, and what determines the cell-type-specific and context-dependent (even opposite) outcomes on HIF-2α and NF-κB.
  • No unifying structural model distinguishing catalytic from scaffold engagement
  • Determinants of cell-type-specific HIF-2α regulation unknown
  • Reconciliation of opposing NF-κB effects across tissues lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016491 oxidoreductase activity 5 GO:0060090 molecular adaptor activity 4 GO:0140110 transcription regulator activity 1
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 2
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-1430728 Metabolism 5 R-HSA-5357801 Programmed Cell Death 4 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-162582 Signal Transduction 3 R-HSA-73894 DNA Repair 2
Partners
ACC2EPS15HIF1AIKBKGOCLNPKM2TP53VHL

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 PHD3 (EGLN3) hydroxylates specific proline residues in HIF-1α within a conserved LXXLAP sequence motif; the hydroxylacceptor proline itself is the only obligatory residue for this reaction. PHD2 shows highest specific activity toward the primary hydroxylation site, while PHD3 shows restricted substrate specificity. In vitro prolyl hydroxylase assay with mutant HIF-1α peptides; sequence analysis The Journal of biological chemistry High 12181324
2004 PHD3 contributes in a non-redundant manner to oxygen-dependent regulation of both HIF-1α and HIF-2α subunits; PHD isoforms show specificity for different prolyl hydroxylation sites within HIF-α subunits and a degree of selectivity between HIF-1α and HIF-2α. siRNA-mediated knockdown of individual PHD isoforms followed by measurement of HIF-α protein levels in multiple cell types under various culture conditions The Journal of biological chemistry High 15247232
2004 PHD3 interacts with the cytosolic chaperonin TRiC (TCP-1 ring complex), identified by co-purification and mass spectrometry, suggesting PHD3 is a TRiC substrate and that TRiC may regulate PHD3 activity. Co-purification of PHD3 from cell extracts followed by mass spectrometry identification of TRiC subunits FEBS letters Medium 15251459
2005 EglN3 (PHD3) acts downstream of c-Jun and is specifically required among EglN family members for neuronal apoptosis when NGF becomes limiting; EglN3 proapoptotic activity is feedback-inhibited by succinate (a product of SDH), placing EglN3 in a pathway linking SDH activity to developmental apoptosis. Genetic epistasis in sympathetic neuronal progenitor cells: selective EglN3 knockdown, NGF withdrawal apoptosis assay, succinate supplementation inhibition Cancer cell High 16098468
2005 A functional hypoxia response element (HRE) located in the first intron of the EGLN3 gene (12 kb downstream of transcription start) binds HIF in vivo and drives HIF-dependent transcriptional induction of EGLN3 under hypoxia, establishing a negative feedback loop. Bioinformatics HRE identification, reporter gene assays, chromatin immunoprecipitation (ChIP) The Biochemical journal High 15823097
2006 PHD3 physically interacts with the novel WD-repeat scaffold protein Morg1 (MAPK organizer 1); co-expression of Morg1 with PHD3 decreases HIF-mediated reporter gene activity, and siRNA knockdown of either Morg1 or PHD3 increases HIF-1 activity. Both proteins co-localize in the cytoplasm and nucleus. Yeast two-hybrid screen, in vitro and in vivo co-immunoprecipitation, confocal microscopy co-localization, HIF reporter assay with siRNA knockdown The Journal of biological chemistry High 16407229
2007 PHD3 interacts with the zipper II domain of ATF-4 and hydroxylates ATF-4 within a novel oxygen-dependent degradation (ODD) domain; siRNA knockdown of PHD3 (but not PHD2) stabilizes ATF-4 under normoxia, identifying ATF-4 as a PHD3-specific substrate independent of pVHL. Co-IP, siRNA knockdown of PHD isoforms, mutational analysis of ATF-4 prolyl residues (5-proline mutations stabilize ATF-4), PHD inhibitor treatment Blood High 17684156
2007 EGLN3 levels increase during C2C12 skeletal myoblast differentiation; EGLN3 interacts with and stabilizes myogenin protein, while VHL associates with and destabilizes myogenin via the ubiquitin-proteasome pathway. Overexpression of EGLN3 reverses VHL-mediated myogenin degradation, revealing a novel HIF-independent role for EGLN3 in myogenic differentiation. siRNA/antisense knockdown of EGLN3, co-immunoprecipitation of EGLN3 with myogenin, ubiquitination assay, EGLN3 overexpression rescue of VHL-mediated myogenin degradation The Journal of biological chemistry High 17344222
2007 Catalytically active human PHD3 was expressed and purified from E. coli; the enzyme hydroxylates Pro567 (a novel site) in addition to the canonical Pro564 of HIF-1α. PHD3 activity is inhibited by Zn2+, desferrioxamine, and imidazole, consistent with its iron- and 2-oxoglutarate-dependent dioxygenase mechanism. Heterologous expression in E. coli, Ni-affinity chromatography purification, in vitro hydroxylation assay with HIF-1α-derived peptide, mass spectrometry verification of hydroxylation Protein expression and purification High 17434750
2008 PHD3 forms oxygen-dependent subcellular aggregates under normoxia in an activity-dependent manner; aggregates contain 26S proteasome components, chaperones, and ubiquitin (aggresome-like features); forced expression of active PHD3 induces protein aggregation and apoptosis. Aggregate formation depends on microtubular integrity and is reversed by hypoxia or PHD3 catalytic inactivation. Fluorescence microscopy of PHD3-GFP aggregates, fractionation, co-localization with proteasome/ubiquitin markers, pharmacological inhibition, active-site mutant comparison Molecular biology of the cell Medium 18337469
2008 PHD3 knockout mice (PHD3−/−) show reduced apoptosis in superior cervical ganglion (SCG) neurons, increased SCG and adrenal medulla cell numbers, and hypofunctional sympathoadrenal development. Genetic intercrossing with HIF-1α+/− and HIF-2α+/− mice demonstrates a PHD3–HIF-2α interaction (but not HIF-1α) in sympathoadrenal development. PHD3−/− mouse generation, neuronal apoptosis assay (cultured SCG neurons), genetic epistasis (PHD3−/− × HIF-1α+/−; PHD3−/− × HIF-2α+/−), sympathoadrenal functional assays Molecular and cellular biology High 18332118
2008 The kinesin KIF1Bβ acts downstream of EglN3 in the NGF-withdrawal apoptotic pathway; KIF1Bβ is both necessary and sufficient for neuronal apoptosis when NGF becomes limiting, placing it genetically downstream of EglN3. Unbiased shRNA screen, epistasis analysis in neuronal progenitor cells with EglN3 and KIF1Bβ knockdown/overexpression, apoptosis assays Genes & development High 18334619
2008 Siah2 E3 ligase preferentially targets PHD3 for degradation because PHD3 lacks the N-terminal extension present in PHD1/PHD2; deletion of this extension from PHD1/PHD2 renders them susceptible to Siah2-mediated degradation. PHD3 homo- and hetero-multimerizes with other PHDs; the lower-molecular-mass PHD3 form has higher specific activity toward HIF-1α hydroxylation and co-localizes with Siah2. Co-immunoprecipitation, size-exclusion fractionation, in vitro HIF-1α hydroxylation assay with different PHD3 complexes, N-terminal deletion mutagenesis of PHD1/PHD2 The Biochemical journal High 16958618
2009 EGLN3 directly interacts with the β2-adrenergic receptor (β2AR) and hydroxylates it at proline-382 and proline-395, enabling recognition and ubiquitylation by pVHL, leading to proteasomal degradation of β2AR. Hypoxia reduces receptor hydroxylation, attenuating receptor degradation, thereby expanding the functional scope of prolyl hydroxylation beyond HIF. Co-IP of EGLN3 with β2AR, mass spectrometry identification of hydroxylation sites, mutagenesis of proline residues, pVHL ubiquitylation assay, hypoxic condition experiments, endogenous receptor abundance measurement Science signaling High 19584355
2009 Phd3 loss in mice exacerbates HIF activation, hepatic steatosis, dilated cardiomyopathy, and premature mortality caused by Phd2 loss alone, demonstrating that Phd3 participates in a HIF-regulatory feedback loop in vivo and can partially compensate for Phd2. Phd2/Phd3 double-knockout mice, HIF target gene expression analysis, histopathology Molecular and cellular biology High 19720742
2010 EGLN3 prolyl hydroxylase activity is required to suppress canonical NF-κB signaling during skeletal myoblast differentiation; catalytically inactive EGLN3 fails to inhibit NF-κB, and NF-κB activation (via DMOG, hypoxia, or EGLN3 knockdown) blocks myogenic differentiation through a HIF-independent mechanism. Pharmacological PHD inhibition (DMOG, DFO, hypoxia), HIF dominant-negative/siRNA (to confirm HIF independence), IκBα dominant-negative, wild-type vs. catalytically-inactive EGLN3 overexpression, NF-κB reporter assay The Journal of biological chemistry High 20089853
2011 PKM2 (but not PKM1) is hydroxylated by PHD3 at proline-403/408; this hydroxylation enhances PKM2 binding to HIF-1α and promotes PKM2 coactivator function for HIF-1 target genes. PHD3 knockdown inhibits PKM2 coactivator activity, reduces glucose uptake and lactate production, and increases O2 consumption in cancer cells. Mass spectrometry and anti-hydroxyproline antibody identification of PKM2 hydroxylation sites, Co-IP of PHD3/PKM2/HIF-1α, PHD3 knockdown, glucose uptake/lactate/O2 consumption assays, PKM1 vs PKM2 comparison Cell High 21620138
2011 PHD3 is uniquely required among PHD isoforms for prolonging neutrophil survival during hypoxia; PHD3-deficient neutrophils show increased apoptosis associated with upregulation of proapoptotic Siva1 and loss of Bcl-xL binding, independent of altered HIF transcriptional activity. In vivo, PHD3-deficient mice show increased neutrophil clearance in acute lung injury and reduced neutrophilic inflammation in colitis. Phd3−/− mouse neutrophils, apoptosis assays, Siva1/Bcl-xL expression measurement, HIF transcriptional activity assay, acute lung injury model, colitis model The Journal of clinical investigation High 21317538
2012 PHD3 hydroxylates HCLK2 (human CLK-2), an essential component of the ATR/CHK1 signaling pathway; HCLK2 hydroxylation is required for its interaction with ATR and subsequent ATR/CHK1/p53 activation. PHD3 inhibition (pharmacologically with DMOG or genetically) prevents ATR/CHK1/p53 pathway activation and decreases DNA-damage-induced apoptosis. PHD3−/− mice are resistant to ionizing radiation. Co-IP of PHD3 with HCLK2 and ATR, DMOG/hypoxia inhibition, PHD3 knockout mice, thymic apoptosis assay, CHK1/p53 phosphorylation western blot The Journal of clinical investigation High 22797300
2012 PHD3 acts as a co-activator of NF-κB/p65 signaling in nucleus pulposus cells independently of its hydroxylase activity; PHD3 physically interacts with and co-localizes with p65. PHD3 silencing decreases TNF-α-induced expression of catabolic markers (ADAMTS5, MMP13, COX2) and restores aggrecan/collagen type II expression. Co-IP and co-localization of PHD3 with p65, lentiviral shRNA knockdown, NF-κB reporter assay, cytokine gene expression measurement, HRE reporter confirming HIF-independence The Journal of biological chemistry High 22948157
2013 EGLN3 specifically interacts with IKKγ (NEMO) and inhibits K63-linked ubiquitination of IKKγ by competing with cIAP1 for IKKγ binding; this suppresses IKK-NF-κB signaling. The effect is independent of EGLN3 hydroxylase activity but requires physical interaction with IKKγ. EGLN1 and EGLN2 do not share this function. Co-IP of EGLN3 with IKKγ, ubiquitination assay (K63-linked), EGLN3 catalytic mutant comparison, cIAP1 competition assay, NF-κB reporter assay with EGLN isoform comparison Molecular and cellular biology High 23732909
2013 p62/SQSTM1 interacts with PHD3 in normoxic cytosolic aggregates, promotes PHD3 aggregation and degradation under normoxia, and limits PHD3 activity. Under hypoxia, p62 decreases, allowing PHD3 to distribute evenly in cells and interact more with HIF-α. Loss of p62 elevates PHD3 levels and reduces HIF-α via enhanced PHD3–HIF-α interaction. Co-IP of p62 with PHD3, siRNA knockdown of p62, fluorescence microscopy of PHD3 localization, HIF-α protein level measurement Journal of cell science Medium 23345396
2013 Acute hepatic deletion of Phd3 in mice improves insulin sensitivity and ameliorates diabetes by specifically stabilizing HIF-2α (not HIF-1α), which increases Irs2 transcription and insulin-stimulated Akt activation. Both HIF-2α and Irs2 are required for the metabolic benefit of Phd3 knockout. Acute hepatic Phd3 knockout, glucose tolerance/insulin tolerance tests, Akt phosphorylation, shRNA knockdown of HIF-2α and Irs2 (epistasis), comparison with other PHD isoforms Nature medicine High 24037093
2014 PHD3 interacts with the endocytic adaptor Eps15 and promotes internalization of EGFR as a scaffolding protein, independent of its hydroxylase activity; loss of PHD3 suppresses EGFR internalization and hyperactivates EGFR signaling to enhance cell proliferation and survival. This is independent of HIF and NF-κB. Co-IP of PHD3 with Eps15, EGFR internalization assay, PHD3 siRNA/shRNA knockdown, EGFR phosphorylation measurement, PHD3 catalytic mutant Nature communications High 25420589
2014 PHD3-mediated prolyl hydroxylation of nonmuscle actin at proline-307 and proline-322 inhibits actin polymerization and cell motility; PHD3 knockdown increases F-actin assembly and cell migration velocity, while PHD3 overexpression reverses this effect. Mass spectrometry identification of actin hydroxylation sites, Co-IP of PHD3 with actin, shRNA knockdown, PHD3 overexpression, F-actin/G-actin fractionation, pharmacological PHD inhibition (DMOG), cell migration assay Molecular biology of the cell High 25079693
2014 PHD3 interacts with pyruvate dehydrogenase E1β subunit (PDH-E1β); PHD3 depletion destabilizes the PDH complex (PDC) and decreases cellular PDH activity without affecting PDH subunit expression or E1α phosphorylation status. Proteomics (MS) to identify PHD3-interacting proteins, co-IP validation of PHD3–PDH-E1β interaction, PDH activity assay in PHD3-depleted cells and PHD3−/− MEFs, PDH complex stability measurement Biochemical and biophysical research communications Medium 25088999
2014 PHD3 stabilizes the tight junction protein occludin by preventing interaction between the E3 ligase Itch and occludin, in a hydroxylase-independent manner; intestinal epithelial-specific Phd3 knockout in mice leads to decreased occludin levels and spontaneous colitis. Intestinal epithelial-specific Phd3 knockout mice, Co-IP of PHD3/occludin/Itch, tight junction/permeability assays, hydroxylase-independent PHD3 mutant The Journal of biological chemistry High 26124271
2014 PHD3 SUMOylation at a C-terminal cluster of four lysines (by SUMO2/SUMO3) represses HIF-1 transcriptional activity without affecting PHD3 hydroxylase activity or HIF-1α stability, revealing a catalysis-independent mechanism of HIF-1 regulation; hypoxia modulates PHD3 SUMOylation inversely with HIF-1 activation. SUMOylation assay, lysine cluster mutagenesis, HIF-1 reporter assay, HIF-1α protein level measurement, hydroxylase activity assay Journal of cell science Medium 25380826
2015 PHD3 decreases the half-life of CDK inhibitor p27/CDKN1B under hypoxia via a mechanism involving reduced p27 phosphorylation at serine-10, promoting G1/S cell cycle entry; this effect is HIF-independent and requires intact p27-Ser10. PHD3 siRNA/shRNA knockdown, flow cytometry cell cycle analysis, cycloheximide chase for p27 half-life, phospho-specific antibody for p27-S10, p27-S10A mutant, HIF-independence confirmed Molecular cancer Medium 26223520
2016 PHD3 hydroxylates acetyl-CoA carboxylase 2 (ACC2) at a proline residue in response to nutrient abundance, activating ACC2 to suppress fatty acid oxidation (FAO); loss of PHD3 prevents ACC2 hydroxylation and enables elevated FAO. Overexpressing PHD3 limits FAO and impedes leukemia cell proliferation. PHD3 knockdown/overexpression, ACC2 hydroxylation assay, fatty acid oxidation measurement (isotopic tracing), PHD3-null cancer cell analysis, AML/leukemia proliferation assay Molecular cell High 27635760
2018 PHD3 hydroxylates p53 at proline-359, a residue in the p53-DUB binding domain; this hydroxylation regulates p53 interaction with deubiquitinases USP7 and USP10. Inhibiting PHD3 decreases p53 association with USP7/USP10, increases p53 ubiquitination, and rapidly reduces p53 protein levels independent of mRNA. Co-IP of PHD3 with p53, mass spectrometry identification of Pro359 hydroxylation, USP7/USP10 interaction assay, ubiquitination assay, mRNA expression control Cell reports High 30067985
2019 EglN3 hydroxylates BIM-EL (proapoptotic BH3-only protein); hydroxylated BIM-EL is subsequently bound by VHL, which inhibits ERK-mediated phosphorylation at Ser69, allowing BIM-EL to escape proteasomal degradation and enhance EglN3-induced apoptosis. VHL type 2C mutants fail to bind hydroxylated BIM-EL, linking this pathway to pheochromocytoma pathogenesis. Co-IP of BIM-EL with VHL and EglN3, hydroxylation assay, phosphorylation assay (ERK/Ser69), genetic EglN3 inactivation, VHL mutant panel, cisplatin resistance assay, ERK inhibitor rescue Proceedings of the National Academy of Sciences of the United States of America High 31375625
2019 In clear cell renal cell carcinoma (ccRCC) cells, PHD3 silencing leads to downregulation of HIF-2α protein and mRNA (opposite to canonical pathway), by reducing HIF2A mRNA stability. This effect is PHD3-specific (other PHD family members have no effect) and cell-type-specific (non-RCC cells show expected HIF-2α increase upon PHD3 knockdown). siRNA-mediated PHD3 knockdown, HIF-2α protein/mRNA measurement by immunoblot and qRT-PCR, mRNA stability assay, comparison with PHD1/PHD2 knockdown, forced HIF-2α expression rescue The Journal of biological chemistry High 30617181
2020 PHD3 hydroxylates ACC2; in skeletal muscle, ACC2 hydroxylation and AMPK-mediated phosphorylation of ACC2 occur inversely. PHD3-null mice show loss of ACC2 hydroxylation in heart and skeletal muscle, elevated fatty acid oxidation, and enhanced endurance exercise capacity. Skeletal muscle-specific PHD3 loss is sufficient to enhance exercise capacity. PHD3 whole-body and skeletal muscle-specific knockout mice, ACC2 hydroxylation measurement, fatty acid oxidation measurement, endurance exercise treadmill assay, AMPK phosphorylation comparison Cell metabolism High 32663458
2020 CDC20 binds to a destruction-box (D-box) motif in PHD3 protein and promotes its polyubiquitination and proteasomal degradation via the APC/CDC20 complex, thereby stabilizing HIF-1α and promoting VEGF secretion in hepatocellular carcinoma cells. Co-IP of CDC20 with PHD3, ubiquitination assay, genetic ablation and pharmacological inhibition of CDC20, HIF-1α/VEGF measurement, non-degradable PHD3 D-box mutant rescue, xenograft tumor assay Cancer letters Medium 33039559
2021 USP9X deubiquitinates EGLN3, preventing its proteasomal degradation; loss of USP9X leads to EGLN3 degradation, reducing the apoptotic KIF1Bβ pathway and promoting cholangiocarcinoma proliferation. Co-IP of USP9X with EGLN3, ubiquitination assay, shRNA knockdown of USP9X and EGLN3, xenograft tumor model, KIF1Bβ expression measurement Journal of biomedical science Medium 34112167
2022 EGLN3 hydroxylates ERK3, preventing its interaction with LAMP2A and HSC70 (core CMA components), thereby blocking chaperone-mediated autophagy (CMA)-lysosomal degradation of ERK3; inactivation of EGLN3 catalytic activity promotes ERK3 degradation via CMA. Co-IP of ERK3 with HSC70 and LAMP2A, EGLN3 catalytically inactive knock-in mice, CMA-lysosome inhibition assay, hydroxylation assay, LAMP2A/ERK3 interaction rescue experiment Oncogene High 35124697
2023 MAEA E3 ligase targets PHD3 at lysine-159 to promote K48-linked polyubiquitination and proteasomal degradation of PHD3, thereby stabilizing HIF-1α and upregulating CD133 to promote glioblastoma stemness and temozolomide resistance. TMT-based quantitative proteomics, co-IP of MAEA with PHD3, ubiquitination assay (K48-linked), K159 mutagenesis, HIF-1α/CD133 protein level measurement, xenograft tumor assay Oncogene Medium 36882523
2009 IFNγ induces PHD3 (but not PHD1 or PHD2) expression in human endothelial cells through a JAK/STAT1-dependent mechanism, as demonstrated by pharmacological inhibition of JAK, siRNA knockdown of STAT1, and chromatin immunoprecipitation showing STAT1 binding to the PHD3 promoter. This induction is independent of HIF-1α. qRT-PCR, immunoblotting, JAK inhibitor, STAT1 siRNA knockdown, chromatin immunoprecipitation (ChIP) for STAT1 at PHD3 promoter Arteriosclerosis, thrombosis, and vascular biology Medium 19574556
2010 Human PRP19 interacts with PHD3 via its C-terminal WD40 region; interaction is enhanced under hypoxia through PRP19's N-terminal coiled-coil domain. PRP19 overexpression suppresses PHD3-dependent cell death under prolonged hypoxia; PRP19 silencing increases caspase activity and cell death, and this is rescued by co-silencing PHD3. Co-IP of PHD3 with PRP19, domain deletion mapping, siRNA knockdown and overexpression, caspase activity assay, cell death assay Experimental cell research Medium 20599946
2005 An alternatively spliced PHD3 transcript (PHD3Δ4) retains prolyl hydroxylase activity as demonstrated in transfection experiments; a second variant (PHD3Δ1) is also expressed ubiquitously, while PHD3Δ4 expression appears restricted to primary cancer tissues. RT-PCR identification of splice variants, transfection-based functional hydroxylase activity assay Cancer letters Low 16473674

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 1213 21620138
2004 Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. The Journal of biological chemistry 905 15247232
2005 Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer cell 439 16098468
2008 The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes & development 275 18334619
2002 Sequence determinants in hypoxia-inducible factor-1alpha for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3. The Journal of biological chemistry 258 12181324
2005 Identification of a functional hypoxia-responsive element that regulates the expression of the egl nine homologue 3 (egln3/phd3) gene. The Biochemical journal 185 15823097
2007 Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor. Blood 178 17684156
2008 Abnormal sympathoadrenal development and systemic hypotension in PHD3-/- mice. Molecular and cellular biology 169 18332118
2010 Pro isomerization in MLL1 PHD3-bromo cassette connects H3K4me readout to CyP33 and HDAC-mediated repression. Cell 166 20541251
2011 Prolyl hydroxylase 3 (PHD3) is essential for hypoxic regulation of neutrophilic inflammation in humans and mice. The Journal of clinical investigation 155 21317538
2009 A feedback loop involving the Phd3 prolyl hydroxylase tunes the mammalian hypoxic response in vivo. Molecular and cellular biology 138 19720742
2016 PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2. Molecular cell 134 27635760
2009 Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL. Science signaling 130 19584355
2013 Cross-talk between hypoxia and insulin signaling through Phd3 regulates hepatic glucose and lipid metabolism and ameliorates diabetes. Nature medicine 125 24037093
2020 Hypoxic gastric cancer-derived exosomes promote progression and metastasis via MiR-301a-3p/PHD3/HIF-1α positive feedback loop. Oncogene 118 32826951
2008 Overexpression of the oxygen sensors PHD-1, PHD-2, PHD-3, and FIH Is associated with tumor aggressiveness in pancreatic endocrine tumors. Clinical cancer research : an official journal of the American Association for Cancer Research 78 18927305
2010 Binding of the MLL PHD3 finger to histone H3K4me3 is required for MLL-dependent gene transcription. Journal of molecular biology 77 20452361
2005 Use of novel monoclonal antibodies to determine the expression and distribution of the hypoxia regulatory factors PHD-1, PHD-2, PHD-3 and FIH in normal and neoplastic human tissues. Histopathology 76 16324198
2012 Expression of prolyl hydroxylases (PHDs) is selectively controlled by HIF-1 and HIF-2 proteins in nucleus pulposus cells of the intervertebral disc: distinct roles of PHD2 and PHD3 proteins in controlling HIF-1α activity in hypoxia. The Journal of biological chemistry 70 22451659
2012 Loss of the oxygen sensor PHD3 enhances the innate immune response to abdominal sepsis. Journal of immunology (Baltimore, Md. : 1950) 70 22786772
2007 EGLN3 prolyl hydroxylase regulates skeletal muscle differentiation and myogenin protein stability. The Journal of biological chemistry 68 17344222
2010 PHD3 regulates differentiation, tumour growth and angiogenesis in pancreatic cancer. British journal of cancer 66 20978507
2012 PHD3-dependent hydroxylation of HCLK2 promotes the DNA damage response. The Journal of clinical investigation 64 22797300
2010 Prolyl hydroxylase EGLN3 regulates skeletal myoblast differentiation through an NF-kappaB-dependent pathway. The Journal of biological chemistry 64 20089853
2020 APCCDC20-mediated degradation of PHD3 stabilizes HIF-1a and promotes tumorigenesis in hepatocellular carcinoma. Cancer letters 60 33039559
2015 PHD3 Stabilizes the Tight Junction Protein Occludin and Protects Intestinal Epithelial Barrier Function. The Journal of biological chemistry 59 26124271
2014 Loss of PHD3 allows tumours to overcome hypoxic growth inhibition and sustain proliferation through EGFR. Nature communications 59 25420773
2012 Prolyl hydroxylase 3 (PHD3) modulates catabolic effects of tumor necrosis factor-α (TNF-α) on cells of the nucleus pulposus through co-activation of nuclear factor κB (NF-κB)/p65 signaling. The Journal of biological chemistry 57 22948157
2006 The novel WD-repeat protein Morg1 acts as a molecular scaffold for hypoxia-inducible factor prolyl hydroxylase 3 (PHD3). The Journal of biological chemistry 57 16407229
2018 PHD3 Regulates p53 Protein Stability by Hydroxylating Proline 359. Cell reports 56 30067985
2011 MicroRNA-20a inhibits stress-induced cardiomyocyte apoptosis involving its novel target Egln3/PHD3. Journal of molecular and cellular cardiology 56 22182733
2020 Circular RNA circ-EGLN3 promotes renal cell carcinoma proliferation and aggressiveness via miR-1299-mediated IRF7 activation. Journal of cellular biochemistry 55 31904147
2008 Prolyl hydroxylase PHD3 activates oxygen-dependent protein aggregation. Molecular biology of the cell 53 18337469
2010 The PHD3 domain of MLL acts as a CYP33-regulated switch between MLL-mediated activation and repression . Biochemistry 51 20677832
2007 Hypoxia-induced assembly of prolyl hydroxylase PHD3 into complexes: implications for its activity and susceptibility for degradation by the E3 ligase Siah2. The Biochemical journal 51 16958618
2014 PHD3 regulates EGFR internalization and signalling in tumours. Nature communications 48 25420589
2004 The HIF prolyl hydroxylase PHD3 is a potential substrate of the TRiC chaperonin. FEBS letters 47 15251459
2015 Depletion of PHD3 protects heart from ischemia/reperfusion injury by inhibiting cardiomyocyte apoptosis. Journal of molecular and cellular cardiology 46 25633836
2012 The prolyl hydroxylase PHD3 identifies proinflammatory macrophages and its expression is regulated by activin A. Journal of immunology (Baltimore, Md. : 1950) 46 22778395
2017 α-Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 45 28939592
2019 MicroRNA-1205, encoded on chromosome 8q24, targets EGLN3 to induce cell growth and contributes to risk of castration-resistant prostate cancer. Oncogene 44 30808975
2014 ERα upregulates Phd3 to ameliorate HIF-1 induced fibrosis and inflammation in adipose tissue. Molecular metabolism 44 25161887
2013 Expression and DNA methylation levels of prolyl hydroxylases PHD1, PHD2, PHD3 and asparaginyl hydroxylase FIH in colorectal cancer. BMC cancer 44 24195777
2018 PHD3 Controls Lung Cancer Metastasis and Resistance to EGFR Inhibitors through TGFα. Cancer research 43 29339541
2015 Distinct breast cancer stem/progenitor cell populations require either HIF1α or loss of PHD3 to expand under hypoxic conditions. Oncotarget 43 26372732
2009 The prolyl-hydroxylase EGLN3 and not EGLN1 is inactivated by methylation in plasma cell neoplasia. European journal of haematology 40 19737309
2010 Molecular mechanism of MLL PHD3 and RNA recognition by the Cyp33 RRM domain. Journal of molecular biology 39 20460131
2020 ESC-sEVs Rejuvenate Aging Hippocampal NSCs by Transferring SMADs to Regulate the MYT1-Egln3-Sirt1 Axis. Molecular therapy : the journal of the American Society of Gene Therapy 38 33038325
2017 Inhibition of PHD3 by salidroside promotes neovascularization through cell-cell communications mediated by muscle-secreted angiogenic factors. Scientific reports 38 28266625
2013 The regulation, localization, and functions of oxygen-sensing prolyl hydroxylase PHD3. Biological chemistry 38 23380539
2011 Aberrant promoter CpG methylation is a mechanism for impaired PHD3 expression in a diverse set of malignant cells. PloS one 38 21297970
2011 Prolyl hydroxylase PHD3 enhances the hypoxic survival and G1 to S transition of carcinoma cells. PloS one 38 22087251
2013 EGLN3 inhibition of NF-κB is mediated by prolyl hydroxylase-independent inhibition of IκB kinase γ ubiquitination. Molecular and cellular biology 34 23732909
2019 Hypoxia-inducible factor (HIF)-prolyl hydroxylase 3 (PHD3) maintains high HIF2A mRNA levels in clear cell renal cell carcinoma. The Journal of biological chemistry 32 30617181
2014 Deletion of prolyl hydroxylase domain proteins (PHD1, PHD3) stabilizes hypoxia inducible factor-1 alpha, promotes neovascularization, and improves perfusion in a murine model of hind-limb ischemia. Microvascular research 32 25446011
2014 Prolyl-4-hydroxylase domain 3 (PHD3) is a critical terminator for cell survival of macrophages under stress conditions. Journal of leukocyte biology 31 24626957
2022 Inactivation of EGLN3 hydroxylase facilitates Erk3 degradation via autophagy and impedes lung cancer growth. Oncogene 30 35124697
2005 An alternatively spliced transcript of the PHD3 gene retains prolyl hydroxylase activity. Cancer letters 30 16473674
2020 PHD3 Loss Promotes Exercise Capacity and Fat Oxidation in Skeletal Muscle. Cell metabolism 29 32663458
2017 PHD3 is a transcriptional coactivator of HIF-1α in nucleus pulposus cells independent of the PKM2-JMJD5 axis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 29 28495754
2014 Prolyl-hydroxylase PHD3 interacts with pyruvate dehydrogenase (PDH)-E1β and regulates the cellular PDH activity. Biochemical and biophysical research communications 29 25088999
2008 Identification of an immunogenic CTL epitope of HIFPH3 for immunotherapy of renal cell carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 28 18980986
2017 HIF prolyl hydroxylase PHD3 regulates translational machinery and glucose metabolism in clear cell renal cell carcinoma. Cancer & metabolism 27 28680592
2013 Simvastatin treatment inhibits hypoxia inducible factor 1-alpha-(HIF-1alpha)-prolyl-4-hydroxylase 3 (PHD-3) and increases angiogenesis after myocardial infarction in streptozotocin-induced diabetic rat. International journal of cardiology 26 23590933
2015 Hypoxia inducible prolyl hydroxylase PHD3 maintains carcinoma cell growth by decreasing the stability of p27. Molecular cancer 25 26223520
2013 p62/SQSTM1 regulates cellular oxygen sensing by attenuating PHD3 activity through aggregate sequestration and enhanced degradation. Journal of cell science 25 23345396
2014 PHD3-mediated prolyl hydroxylation of nonmuscle actin impairs polymerization and cell motility. Molecular biology of the cell 24 25079693
2009 Interferon-gamma induces prolyl hydroxylase (PHD)3 through a STAT1-dependent mechanism in human endothelial cells. Arteriosclerosis, thrombosis, and vascular biology 24 19574556
2010 Human PRP19 interacts with prolyl-hydroxylase PHD3 and inhibits cell death in hypoxia. Experimental cell research 23 20599946
2014 PHD3-SUMO conjugation represses HIF1 transcriptional activity independently of PHD3 catalytic activity. Journal of cell science 22 25380826
2023 CIRP attenuates acute kidney injury after hypothermic cardiovascular surgery by inhibiting PHD3/HIF-1α-mediated ROS-TGF-β1/p38 MAPK activation and mitochondrial apoptotic pathways. Molecular medicine (Cambridge, Mass.) 20 37127576
2017 Estrogen receptor β2 induces proliferation and invasiveness of triple negative breast cancer cells: association with regulation of PHD3 and HIF-1α. Oncotarget 20 29100336
2021 USP9X promotes apoptosis in cholangiocarcinoma by modulation expression of KIF1Bβ via deubiquitinating EGLN3. Journal of biomedical science 19 34112167
2018 PHD3 regulates glucose metabolism by suppressing stress-induced signalling and optimising gluconeogenesis and insulin signalling in hepatocytes. Scientific reports 19 30250231
2017 Loss of PHD3 in myeloid cells dampens the inflammatory response and fibrosis after hind-limb ischemia. Cell death & disease 19 28796258
2010 DNA methylation analysis of the HIF-1α prolyl hydroxylase domain genes PHD1, PHD2, PHD3 and the factor inhibiting HIF gene FIH in invasive breast carcinomas. Histopathology 17 20727020
2023 E3 ligase MAEA-mediated ubiquitination and degradation of PHD3 promotes glioblastoma progression. Oncogene 16 36882523
2017 PHD3 affects gastric cancer progression by negatively regulating HIF1A. Molecular medicine reports 15 28901473
2014 Increased expression of PHD3 represses the HIF-1 signaling pathway and contributes to poor neovascularization in pancreatic ductal adenocarcinoma. Journal of gastroenterology 15 25542265
2019 EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance. Proceedings of the National Academy of Sciences of the United States of America 13 31375625
2016 Prolyl hydroxylase 3 (PHD3) expression augments the development of regulatory T cells. Molecular immunology 13 27331863
2007 Expression and purification of catalytically active human PHD3 in Escherichia coli. Protein expression and purification 13 17434750
2022 Chronic intermittent hypoxia accelerates cardiac dysfunction and cardiac remodeling during cardiac pressure overload in mice and can be alleviated by PHD3 overexpression. Frontiers in cardiovascular medicine 12 36172572
2021 Circular RNA EGLN3 silencing represses renal cell carcinoma progression through the miR-1224-3p/HMGXB3 axis. Acta histochemica 12 34274607
2020 Zebrafish phd3 Negatively Regulates Antiviral Responses via Suppression of Irf7 Transactivity Independent of Its Prolyl Hydroxylase Activity. Journal of immunology (Baltimore, Md. : 1950) 12 32669312
2017 Immunohistochemical analysis of PDK1, PHD3 and HIF-1α expression defines the hypoxic status of neuroblastoma tumors. PloS one 12 29117193
2015 Alternative splicing transcription of Megalobrama amblycephala HIF prolyl hydroxylase PHD3 and up-regulation of PHD3 by HIF-1α. Biochemical and biophysical research communications 11 26697748
2023 Methylene blue targets PHD3 expression in murine microglia to mitigate lipopolysaccharide-induced neuroinflammation and neurocognitive impairments. International immunopharmacology 10 37210913
2023 Deletion of prolyl hydroxylase domain-containing enzyme 3 (phd3) in zebrafish facilitates hypoxia tolerance. The Journal of biological chemistry 10 37923141
2018 PHD3 Acts as Tumor Suppressor in Mouse Osteosarcoma and Influences Tumor Vascularization via PDGF-C Signaling. Cancers 10 30563292
2013 In silico investigation of PHD-3 specific HIF1-α proline 567 hydroxylation: a new player in the VHL/HIF-1α interaction pathway? FEBS letters 10 23886708
2010 Double immunohistochemical staining method for HIF-1alpha and its regulators PHD2 and PHD3 in formalin-fixed paraffin-embedded tissues. Applied immunohistochemistry & molecular morphology : AIMM 10 20216402
2022 Modulating the Siah2-PHD3-HIF1α axis and/or autophagy potentially retard colon cancer proliferation possibly, due to the damping of colon cancer stem cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 9 35994813
2025 Sirtuin1 mitigates hypoxia-induced cardiomyocyte apoptosis in myocardial infarction via PHD3/HIF-1α. Molecular medicine (Cambridge, Mass.) 8 40087582
2023 DPP-4i versus SGLT2i as modulators of PHD3/HIF-2α pathway in the diabetic kidney. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 8 37804810
2021 PHD3 mediates denervation skeletal muscle atrophy through Nf-κB signal pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 8 33749901
2020 Circ_101341 Deteriorates the Progression of Clear Cell Renal Cell Carcinoma Through the miR- 411/EGLN3 Axis. Cancer management and research 8 33408523
2019 Interactions between PHD3-Bromo of MLL1 and H3K4me3 Revealed by Single-Molecule Magnetic Tweezers in a Parallel DNA Circuit. Bioconjugate chemistry 8 31714753
2018 Polymorphisms in the Egl nine homolog 3 (EGLN3) and Peroxisome proliferator activated receptor-alpha (PPARα) genes and their correlation with hypoxia adaptation in Tibetan chickens. PloS one 8 29543898
2024 Trans-resveratrol mitigates miR-204-3p mediated progression of allergic rhinitis by regulating the EGLN3/HIF-1α/IL33/ST2 signalling pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 7 39226709

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