Affinage

EGLN2

Prolyl hydroxylase EGLN2 · UniProt Q96KS0

Length
407 aa
Mass
43.6 kDa
Annotated
2026-06-09
75 papers in source corpus 29 papers cited in narrative 29 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

EGLN2/PHD1 is a nuclear iron(II)- and 2-oxoglutarate-dependent prolyl hydroxylase that initiates regulated proteolysis of its substrates and broadly couples oxygen/metabolic status to cell-cycle, metabolic, and stress-response programs (PMID:12039559, PMID:12181324). Its founding activity is hydroxylation of conserved prolines in HIF-1α/HIF-2α within the LXXLAP motif, marking HIF-α for ubiquitin-mediated degradation; PHD1 contributes non-redundantly with PHD2/PHD3, and its catalytic core depends on the 2His-1-carboxylate iron motif and the 2-oxoglutarate-binding arginine (PMID:12039559, PMID:12181324, PMID:15247232, PMID:14695194). Beyond HIF, PHD1 hydroxylates a defined set of substrates to control proteostasis and complex assembly: it hydroxylates FOXO3a to block USP9x-mediated deubiquitination and drive FOXO3a degradation, relieving repression of Cyclin D1 in estrogen-dependent breast cancer in a HIF-independent, catalysis-dependent manner (PMID:19878873, PMID:24990963); it hydroxylates Cep192 at Pro1717 to recruit SCF(Skp2) for centrosome-duplication control (PMID:23932902); it hydroxylates Beclin1 at Pro54 to enable VHL binding and suppress autophagy initiation (PMID:38360997); and it hydroxylates RepoMan/CDCA2 at Pro604 to regulate PP2A-B56γ interaction and mitotic progression [PMID:bio_10.1101_2025.05.06.652400]. PHD1 also acts through hydroxylation-independent routes—stabilizing leucyl tRNA synthetase to sustain leucine-driven mTORC1 signaling and muscle mass (PMID:31924757), and associating with the NRF1-PGC1α complex on chromatin to promote mitochondrial gene transcription and respiration (PMID:26492917). Substrate selectivity is gated by CDK2/4/6 phosphorylation at Ser130, which lowers activity toward HIF1α while raising activity toward Cep192 (PMID:26644182), and PHD1 abundance is controlled by the E3 ligases SPOP, FBW7, and MDM2 (PMID:28089830, PMID:28036276, PMID:34687132). Physiologically, Phd1 loss reprograms glucose metabolism toward anaerobic/pentose-phosphate flux to protect muscle and neurons against ischemia (PMID:18176562, PMID:26774962), and a germline loss-of-function mutation in PHD1 is associated with pheochromocytoma/paraganglioma and polycythemia (PMID:25263965).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 2002 High

    Established that EGLN2/PHD1 is an enzyme rather than a passive HIF binder, defining the catalytic chemistry that links oxygen availability to HIF-α fate.

    Evidence In vitro enzymatic assays with active-site mutagenesis and oxygen isotope tracing; reconstituted LXXLAP-motif mutagenesis across PHD isoforms

    PMID:12039559 PMID:12181324

    Open questions at the time
    • Did not resolve PHD1-specific substrate preference beyond HIF
    • Cellular contribution relative to other isoforms untested in this work
  2. 2004 High

    Showed that PHD isoforms act non-redundantly with abundance-dependent and site-specific contributions, framing PHD1 as one functionally distinct arm of HIF regulation.

    Evidence Individual siRNA knockdown of each PHD across multiple cell types with site-specific hydroxylation readouts

    PMID:15247232

    Open questions at the time
    • Did not define non-HIF substrates
    • Mechanism of isoform site selectivity unresolved
  3. 2003 Medium

    Demonstrated that PHD1 gain-of-function suppresses HIF/VEGF output and tumor growth, establishing a tumor-relevant consequence of HIF hydroxylation.

    Evidence PHD1 overexpression in colon carcinoma cells with xenograft tumor model and microvessel/HIF immunostaining

    PMID:14695194

    Open questions at the time
    • Gain-of-function only
    • Endogenous PHD1 contribution not isolated
  4. 2006 Medium

    Revealed that PHD1 is produced as two alternatively initiated isoforms differing in stability and regulation, indicating layered control of PHD1 protein levels.

    Evidence Start-codon mutagenesis, activity/stability assays, and Co-IP with Siah ligases

    PMID:16509823

    Open questions at the time
    • Dominant degradation pathway under physiological conditions unresolved
    • Functional distinction between isoforms in vivo untested
  5. 2008 High

    Identified PHD1 as a metabolic regulator in vivo, showing that Phd1 loss reprograms muscle glucose metabolism to confer ischemia tolerance largely independent of HIF-driven angiogenesis.

    Evidence Phd1 knockout mice with metabolic profiling, Hif-2α epistasis, and ischemic muscle histology

    PMID:18176562

    Open questions at the time
    • Direct PPARα-pathway substrate of PHD1 not defined
    • Tissue-specificity of the metabolic switch unresolved
  6. 2008 High

    Provided the first phospho-regulatory layer on PHD1, showing PKCα phosphorylation sites tune catalytic activity.

    Evidence Recombinant PHD1 with in vitro kinase assays, site-directed mutagenesis, and activity measurements

    PMID:18710826

    Open questions at the time
    • In vivo relevance of these sites not established
    • Did not link phosphorylation to substrate selectivity
  7. 2009 Medium

    Defined PHD1 as an exclusively nuclear hydroxylase imported via importin α/β, distinguishing its compartment from cytoplasm-cycling PHD2 and rationalizing nuclear substrate access.

    Evidence Subcellular fractionation, importin inhibition, NLS mutagenesis, and microscopy

    PMID:19631610

    Open questions at the time
    • Whether localization is regulated by signaling untested
    • Link to specific nuclear substrates not made here
  8. 2009 High

    Uncovered a HIF-independent oncogenic function: PHD1 catalytic activity sustains Cyclin D1 and estrogen-dependent breast tumorigenesis.

    Evidence EglN2 knockout mice, breast cancer siRNA, catalytic-mutant studies, and Cyclin D1 rescue

    PMID:19878873

    Open questions at the time
    • Direct hydroxylation substrate linking PHD1 to Cyclin D1 not yet identified in this work
  9. 2011 Medium

    Showed PHD1 can act as a non-catalytic protein partner, stabilizing and repressing ATF4 without hydroxylating it, broadening PHD1 function beyond proline hydroxylation.

    Evidence Reciprocal Co-IP, negative in vitro hydroxylation assay, and ATF4 reporter/stability assays

    PMID:21951999

    Open questions at the time
    • Structural basis of PHD1-ATF4 binding unknown
    • Physiological context of ATF4 repression untested
  10. 2013 High

    Identified Cep192 as a direct hydroxylation substrate coupling PHD1 to centrosome duplication and ciliogenesis via SCF(Skp2)-mediated degradation.

    Evidence Loss-of-function, MS site identification, P1717 mutagenesis, SCF(Skp2) Co-IP, and centrosome/cilia imaging

    PMID:23932902

    Open questions at the time
    • Oxygen-dependence of Cep192 hydroxylation in vivo not defined
    • Crosstalk with cell-cycle phosphorylation not yet linked
  11. 2014 High

    Connected PHD1 catalysis to its Cyclin D1 phenotype by showing FOXO3a hydroxylation blocks USP9x binding and drives FOXO3a degradation, relieving Cyclin D1 repression.

    Evidence In vitro hydroxylation with MS site mapping, FOXO3a-USP9x Co-IP, stability assays, and Cyclin D1 readouts

    PMID:24990963

    Open questions at the time
    • Quantitative contribution of FOXO3a vs other substrates to Cyclin D1 unresolved
  12. 2015 High

    Identified CDK2/4/6 phosphorylation at Ser130 as a substrate-switch that biases PHD1 away from HIF1α toward Cep192, integrating PHD1 into cell-cycle control.

    Evidence In vitro CDK kinase assays, phospho-S130 antibody, cell-cycle synchronization, Co-IP, and substrate activity assays

    PMID:26644182

    Open questions at the time
    • Whether S130 also reroutes activity to FOXO3a/Beclin1/RepoMan untested
    • Relation to PKCα sites unclear
  13. 2015 High

    Defined a hydroxylation-independent transcriptional co-activator role, with EglN2 joining the NRF1-PGC1α complex on chromatin to drive mitochondrial gene expression and respiration.

    Evidence Reciprocal Co-IP, ChIP, expression profiling, respiration and mtDNA measurements with siRNA

    PMID:26492917

    Open questions at the time
    • Whether chromatin association requires catalytic residues untested
    • Direct DNA/chromatin contacts undefined
  14. 2015 Medium

    Linked PHD1 to genotoxic stress response, showing it reinforces p53-p38α interaction and p53 activation enabling nucleotide excision repair after chemotherapy.

    Evidence Isoform-specific siRNA, p53-p38α Co-IP, phospho-p53 S15 westerns, XPB interaction, and 5-FU xenograft

    PMID:26290450

    Open questions at the time
    • Whether PHD1 hydroxylates a component of this complex unknown
    • Mechanism of p53-p38α reinforcement undefined
  15. 2014 Medium

    Provided human disease genetics linking a germline PHD1 loss-of-function mutation to pheochromocytoma/paraganglioma and polycythemia through reduced stability/activity.

    Evidence Patient sequencing, stability and catalytic activity assays, and erythroid progenitor EPO-sensitivity assay

    PMID:25263965

    Open questions at the time
    • Single-variant evidence with limited mechanistic follow-up
    • Causal substrate driving the tumor/polycythemia phenotype unspecified
  16. 2016 High

    Extended the neuroprotective metabolic role, showing PHD1 deficiency boosts pentose-phosphate flux and redox buffering to protect neurons from ischemia.

    Evidence PHD1 knockout mice, brain ischemia model, metabolic flux and ROS analysis, and antisense oligonucleotide rescue

    PMID:26774962

    Open questions at the time
    • Direct molecular target controlling the metabolic shift not defined
    • Cell-type contribution within brain unresolved
  17. 2016 Medium

    Showed PHD1 activity can be drug-induced to degrade HIF-1α, linking docetaxel/JNK2 signaling to PHD1-driven HIF turnover and cancer cell death under hypoxia.

    Evidence JNK2 and PHD1 siRNA, pharmacological inhibition, HIF-1α ubiquitination/reporter assays, and xenograft

    PMID:27263528

    Open questions at the time
    • Mechanism by which JNK2 activates PHD1 undefined
    • Whether activation involves a known phospho-site untested
  18. 2017 Medium

    Identified SPOP and androgen-receptor signaling as a degradation/transcription axis controlling EglN2 abundance in prostate cancer.

    Evidence SPOP-EglN2 Co-IP, ubiquitination assays, SPOP mutants, AR transcription assays, and tumor models

    PMID:28089830

    Open questions at the time
    • Degron in EglN2 recognized by SPOP not mapped
    • Downstream substrate consequences of EglN2 accumulation untested
  19. 2017 Medium

    Added FBW7 as a GSK3β-dependent E3 ligase for EglN2 relevant to breast tumorigenesis, multiplying the routes controlling PHD1 stability.

    Evidence FBW7 overexpression/knockdown, GSK3β inhibition, stability assays, Co-IP, and transgenic mouse model

    PMID:28036276

    Open questions at the time
    • Phosphodegron priming sites not mapped
    • Interplay with SPOP/MDM2 unresolved
  20. 2017 Medium

    Provided a structural view of the PHD1 active site, defining a monodentate iron-coordinating inhibitor binding mode and an Asn315 hydrogen-bond contact.

    Evidence X-ray crystallography of PHD1-inhibitor complex and structure-activity analysis

    PMID:28594552

    Open questions at the time
    • No substrate-bound structure
    • Basis of substrate selectivity not addressed structurally
  21. 2020 High

    Established a hydroxylation-independent scaffolding role coupling PHD1 to nutrient signaling: PHD1 stabilizes leucyl tRNA synthetase to sustain leucine-driven mTORC1 and muscle mass.

    Evidence PHD1-LRS Co-IP, catalytic-dead mutant, PHD1KO mice, leucine-specific mTORC1 assays, and human muscle biopsies

    PMID:31924757

    Open questions at the time
    • Structural basis of PHD1-LRS protection undefined
    • Mechanism linking oxygen/amino-acid depletion to the interaction unresolved
  22. 2021 Medium

    Added MDM2 as an E3 ligase mediating K48-linked ubiquitination of EGLN2 via its N-terminus, further defining the proteostatic network governing PHD1.

    Evidence EGLN2-MDM2 Co-IP, K48-linkage ubiquitination assay, stability assays, and domain mapping

    PMID:34687132

    Open questions at the time
    • Physiological/cell-context where MDM2 dominates unclear
    • Relationship to SPOP and FBW7 pathways untested
  23. 2023 Medium

    Linked PHD1 to bone biology, showing alpha-ketoglutarate suppresses RANKL-induced osteoclastogenesis through PHD1-dependent NF-κB inhibition.

    Evidence Isoform-specific siRNA, NF-κB reporter, osteoclast differentiation assay, and DMOG treatment

    PMID:36771407

    Open questions at the time
    • Direct PHD1 substrate in NF-κB pathway not identified
    • Whether catalytic activity is required not tested here
  24. 2024 High

    Defined PHD1 control of autophagy, showing Beclin1 Pro54 hydroxylation enables VHL binding that blocks Beclin1-VPS34 association with ATG14L to inhibit autophagy initiation.

    Evidence In vitro hydroxylation, VHL-Beclin1 Co-IP, P54A mutagenesis, complex-assembly assays, autophagy flux, and xenografts

    PMID:38360997

    Open questions at the time
    • Oxygen-tension dependence of this regulation under physiology not fully defined
    • Crosstalk with PHD1's metabolic roles unresolved
  25. 2024 Medium

    Implicated EGLN2 in neurodegeneration, showing its loss protects motor neurons in ALS models and restores STING-mediated astrocytic interferon responses.

    Evidence Egln2 knockout/ASO knockdown in zebrafish and mouse ALS models, snRNA-seq, and patient iPSC-astrocyte experiments

    PMID:39255062

    Open questions at the time
    • Direct PHD1 substrate in the STING/interferon axis unidentified
    • Catalytic dependence of the effect untested
  26. 2025 Medium

    Extended PHD1's mitotic role, showing RepoMan/CDCA2 Pro604 hydroxylation governs RepoMan-PP2A-B56γ interaction and faithful chromosome segregation.

    Evidence MS site identification, isoform-specific siRNA, P604A mutagenesis, PP2A-B56γ Co-IP, H3T3 phospho-imaging, and live-cell mitosis imaging (preprint)

    PMID:bio_10.1101_2025.05.06.652400

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Integration with Cep192-based mitotic control unresolved
  27. 2025 Medium

    Added a catalysis-dependent route by which PHD1/PHD2 lower IKKα/β levels and dampen NF-κB target expression, complementing the osteoclast NF-κB findings.

    Evidence PHD-IKKα/β Co-IP, active-site mutants, IL-1β mRNA measurement, and IKK protein-level assays

    PMID:40024754

    Open questions at the time
    • Whether IKKα/β are direct hydroxylation substrates not shown
    • PHD1 vs PHD2 relative contribution unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CDK/PKC phosphorylation, multiple competing E3 ligases, and oxygen/metabolite levels are integrated to choose among PHD1's many catalytic and non-catalytic substrates in a given cell remains unresolved.
  • No unified model of substrate prioritization
  • No substrate-bound structures to explain selectivity
  • Tissue-specific dominant substrates not defined

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 GO:0016787 hydrolase activity 2 GO:0098772 molecular function regulator activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 1 GO:0005730 nucleolus 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 1
Partners
BECN1CDCA2CEP192FOXO3HIF1ALARSMDM2NRF1
Complex memberships
NRF1-PGC1α transcriptional complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 PHD1 (EGLN2) is an iron(II)- and 2-oxoglutarate-dependent oxygenase that hydroxylates proline residues in HIF-1α; mutation of the arginine proposed to bind 2-oxoglutarate and of the 2His-1-carboxylate iron(II) binding motif dramatically reduces activity; the oxygen of the product alcohol derives >95% from dioxygen. In vitro enzymatic assay with active-site mutagenesis; isotope labeling to trace oxygen source Bioorganic & medicinal chemistry letters High 12039559
2002 PHD1, PHD2, and PHD3 hydroxylate specific prolines in HIF-1α within the LXXLAP motif; PHD2 has the highest specific activity toward the primary hydroxylation site; the hydroxylacceptor proline itself is the only obligatory residue in the motif, with mutations tolerated at the -5, -2, and -1 positions. In vitro prolyl hydroxylation assay with systematic LXXLAP motif mutants; specific activity comparisons across PHD isoforms The Journal of biological chemistry High 12181324
2004 PHD1, PHD2, and PHD3 each contribute in a non-redundant manner to the regulation of both HIF-1α and HIF-2α; the relative contribution of each PHD isoform depends on its cellular abundance; isoforms show specificity for different prolyl hydroxylation sites within HIF-α subunits and a degree of selectivity between HIF-1α and HIF-2α. siRNA knockdown of each PHD isoform individually in multiple cell types; measurement of HIF-α levels and site-specific hydroxylation The Journal of biological chemistry High 15247232
2003 Ectopic expression of PHD1 (EGLN2) suppresses HIF-1α accumulation and VEGF secretion under hypoxia-mimetic conditions and inhibits tumor growth in vivo, associated with increased necrosis and decreased microvessel density. Overexpression of mPHD1 in colon carcinoma cells; xenograft tumor model in nude mice; immunostaining for HIF-1α and microvessel density Cancer research Medium 14695194
2006 PHD1 exists as two isoforms generated by alternative translational initiation; both isoforms are biologically active with similar HIF prolyl hydroxylase activity but differ in their responses to estrogen, cell confluence, and proteasomal inhibition, and differ markedly in protein stability. Both isoforms have the potential to interact with Siah ubiquitin ligase family members, though genetic studies indicated other proteolytic mechanisms control their stability under examined conditions. Characterization of isoforms by mutagenesis of start codons; HIF prolyl hydroxylase activity assays; protein stability assays; co-immunoprecipitation with Siah proteins The Biochemical journal Medium 16509823
2008 Loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to anaerobic ATP production through activation of a PPARα pathway; this metabolic adaptation provides acute protection of myofibers against lethal ischemia; hypoxia tolerance relies primarily on Hif-2α and is not due to HIF-dependent angiogenesis, erythropoiesis, or vasodilation, but to reduced oxidative stress preserving mitochondrial respiration. Phd1 knockout mice; metabolic profiling; genetic epistasis with Hif-2α; histology of ischemic muscle; measurement of oxidative stress Nature genetics High 18176562
2008 Human PHD1 purified from E. coli is an Fe2+- and 2-oxoglutarate-dependent enzyme with EC50 for Fe2+ of 0.64 μM; it is phosphorylated in vitro by protein kinase Cα at Ser-132, Ser-226, and Ser-234; mutation of Ser-132 or Ser-234 to Asp/Glu diminishes enzymatic activity to 25–60%, whereas mutation of Ser-226 has little effect. Recombinant protein purification; in vitro kinase assay with PKCα, PKA, CKI/II, Erk2; site-directed mutagenesis; prolyl hydroxylase activity assay Journal of biochemistry High 18710826
2008 EGLN2 overexpression in renal oncocytoma increases ubiquitin-mediated destruction of HIF and concomitantly suppresses the expression of HIF-target genes including the pro-death BNIP3L gene. Gene expression profiling; functional overexpression studies in renal oncocytoma cells; ubiquitination assays for HIF PLoS genetics Medium 18773095
2009 Nuclear import of PHD1 occurs in an importin α/β-dependent manner and relies on a nuclear localization signal (NLS); PHD1 is located exclusively in the nucleus, in contrast to PHD2 which cycles between nucleus and cytoplasm. Subcellular fractionation; importin α/β inhibition; fluorescence microscopy; NLS mutagenesis Biochemical and biophysical research communications Medium 19631610
2009 EglN2 (PHD1) is estrogen-inducible in breast carcinoma cells; EglN2 inactivation decreases Cyclin D1 levels and suppresses mammary gland proliferation in vivo in a HIF-independent manner; loss of EglN2 catalytic activity inhibits estrogen-dependent breast cancer tumorigenesis, rescued by exogenous Cyclin D1. EglN2 knockout mice; siRNA knockdown in breast cancer cells; mammary gland histology; Cyclin D1 rescue experiment; catalytic mutant studies Cancer cell High 19878873
2011 PHD1 interacts with ATF4 (but not PHD2) through the central region of ATF4; co-expression of PHD1 stabilizes ATF4 (opposite to PHD3 which destabilizes it); PHD1 represses the transcriptional activity of ATF4; ATF4 does not serve as a prolyl hydroxylation substrate of PHD1 (negative finding for hydroxylation); the interaction and transcriptional repression occur without prolyl hydroxylation of ATF4. Co-immunoprecipitation; in vitro prolyl hydroxylation assay; reporter assay for ATF4 transcriptional activity; protein stability assays; proline-to-alanine mutagenesis of ATF4 Experimental cell research Medium 21951999
2013 PHD1 is required for centrosome duplication and maturation through hydroxylation of the centrosomal protein Cep192 on proline 1717; this hydroxylation promotes binding of the E3 ubiquitin ligase SCF(Skp2), which ubiquitinates Cep192 and targets it for proteasomal degradation; PHD1 is also required for primary cilia formation. PHD1 loss-of-function; mass spectrometry identification of Cep192 as substrate; site-directed mutagenesis of Cep192 P1717; co-immunoprecipitation with SCF(Skp2); ubiquitination assay; centrosome/cilia imaging Developmental cell High 23932902
2014 EglN2 hydroxylates FOXO3a on two specific prolyl residues in vitro and in vivo; hydroxylation of these sites prevents binding of the USP9x deubiquitinase, thereby promoting proteasomal degradation of FOXO3a; failure to hydroxylate FOXO3a promotes its accumulation, which suppresses Cyclin D1 transcription (because FOXO transcription factors can repress Cyclin D1). In vitro prolyl hydroxylation assay; mass spectrometry identification of hydroxylation sites; co-immunoprecipitation of FOXO3a with USP9x; protein stability assays; Cyclin D1 reporter/expression analysis Genes & development High 24990963
2014 A germline loss-of-function mutation in PHD1 causes reduced protein stability and compromised catalytic activity, associated with pheochromocytoma/paraganglioma and polycythemia, with inappropriate hypersensitivity of erythroid progenitors to EPO. Sequencing of patient samples; protein stability assays; in vitro catalytic activity measurement; erythroid progenitor EPO sensitivity assay Journal of molecular medicine (Berlin, Germany) Medium 25263965
2015 PHD1 activity reinforces p53 binding to p38α kinase in a hydroxylation-dependent manner; following p53-p38α interaction and chemotherapeutic damage, p53 is phosphorylated at serine 15 and activated; active p53 interacts with the DNA helicase XPB to allow nucleotide excision repair; PHD1 knockdown (but not PHD2 or PHD3) prevents p53 activation upon chemotherapy in CRC cells. siRNA knockdown of PHD isoforms; co-immunoprecipitation of p53 with p38α; phospho-specific western blotting (p53 S15); interaction assay with XPB; mouse xenograft with 5-FU treatment EMBO molecular medicine Medium 26290450
2015 PHD1 is phosphorylated by CDK2, CDK4, and CDK6 at serine 130; this phosphorylation fluctuates with the cell cycle and can be induced by oncogenic activation; S130 phosphorylation does not alter PHD1's intrinsic enzymatic activity but decreases its interaction with HIF1α (reducing PHD1 activity toward HIF1α) while increasing PHD1's activity toward Cep192. In vitro kinase assays with CDK2/4/6; phospho-specific antibody to pS130; cell cycle synchronization; co-immunoprecipitation of PHD1 with HIF1α; substrate activity assays toward HIF1α and Cep192 Journal of cell science High 26644182
2015 EglN2 associates with the NRF1-PGC1α complex on chromatin under hypoxic conditions and promotes transcription of ferredoxin reductase (FDXR); EglN2 depletion decreases mitochondrial respiration and mitochondrial DNA content in breast cancer cells in a HIF1/2α-independent manner. Co-immunoprecipitation of EglN2 with NRF1 and PGC1α; chromatin immunoprecipitation (ChIP); gene expression profiling; mitochondrial respiration measurements; mtDNA quantification; siRNA knockdown The EMBO journal High 26492917
2016 PHD1 deficiency in neurons reprograms glucose metabolism by enhancing flux through the oxidative pentose phosphate pathway (away from glycolysis), increasing redox buffering capacity to scavenge oxygen radicals; this provides neuroprotection against ischemia independently of collateral vessel network changes. PHD1 knockout mice; permanent brain ischemia model; metabolic flux analysis; ROS measurements; intracerebroventricular antisense oligonucleotide injection Cell metabolism High 26774962
2016 Docetaxel activates PHD1 under hypoxic conditions through JNK2 signaling; activated PHD1 promotes polyubiquitination and proteasomal degradation of HIF-1α; pharmacological inhibition or siRNA knockdown of PHD1 prevents docetaxel-induced HIF-1α degradation and cancer cell death under hypoxia. JNK2 siRNA knockdown; PHD1 siRNA knockdown; pharmacological PHD1 inhibition; HIF-1α polyubiquitination assay; luciferase reporter for HIF-1 transcriptional activity; xenograft model Scientific reports Medium 27263528
2017 The E3 ubiquitin ligase SPOP (Cullin 3-based complex) recognizes and ubiquitinates EglN2, targeting it for proteasomal degradation; androgen receptor (AR) transcriptionally upregulates EglN2; SPOP loss-of-function mutations or AR amplification (common in prostate cancer) accumulate EglN2 protein. Co-immunoprecipitation of SPOP and EglN2; ubiquitination assay; SPOP loss-of-function mutants; AR ChIP/transcription assays; in vivo tumor models Cancer letters Medium 28089830
2017 EglN2 acts as an FBW7 ubiquitin ligase substrate contributing to breast tumorigenesis; FBW7 overexpression leads to EglN2 downregulation in a GSK3β-dependent manner; depletion of FBW7 leads to EglN2 upregulation. FBW7 overexpression and knockdown; GSK3β inhibition; protein stability assays; co-immunoprecipitation; C3Tag transgenic mouse model Oncotarget Medium 28036276
2020 PHD1 interacts with leucyl tRNA synthetase (LRS) and stabilizes it in a hydroxylation-independent manner; this interaction is promoted during oxygen and amino acid depletion and protects LRS from degradation; PHD1 knockout mice show impaired mTORC1 activation in response to leucine (but not growth factors or eccentric contractions), reduced muscle mass, and decreased LRS protein content. Co-immunoprecipitation of PHD1 with LRS; PHD1 catalytic mutant (hydroxylation-dead); PHD1KO mice; mTORC1 activity assays; leucine stimulation experiments; LRS activity measurements in human muscle biopsies Nature communications High 31924757
2021 EGLN2 is a substrate of the E3 ubiquitin ligase MDM2, which interacts with the N-terminal of EGLN2 and mediates its K48-linked poly-ubiquitination, thereby facilitating proteasomal degradation of EGLN2. Co-immunoprecipitation of EGLN2 with MDM2; ubiquitination assay (K48 linkage); protein stability assays; domain mapping (N-terminal EGLN2) Journal of cellular and molecular medicine Medium 34687132
2024 PHD1 hydroxylates Beclin1 on proline 54; VHL directly binds Beclin1 after PHD1-mediated hydroxylation; this binding inhibits the association of Beclin1-VPS34 complexes with ATG14L, thereby inhibiting autophagy initiation in response to nutrient deficiency; expression of non-hydroxylatable Beclin1 P54A abrogates VHL-mediated autophagy inhibition. In vitro hydroxylation assay; co-immunoprecipitation of VHL with Beclin1; P54A mutagenesis of Beclin1; Beclin1-VPS34-ATG14L complex assays; autophagy flux measurements; xenograft tumor models The EMBO journal High 38360997
2024 Loss of EGLN2 in ALS models protects motor neurons and induces an astrocyte-specific downregulation of interferon-stimulated genes mediated via the STING protein; genetic deletion of EGLN2 restores this interferon response in patient iPSC-derived astrocytes. Egln2 genetic knockout; antisense oligonucleotide knockdown; zebrafish and mouse ALS models; single-nucleus RNA sequencing; iPSC-derived astrocyte experiments; STING pathway analysis Cell reports Medium 39255062
2025 PHD1 hydroxylates RepoMan (CDCA2) on proline 604; siRNA depletion of PHD1 (but not PHD2) increases H3T3 phosphorylation in prometaphase-arrested cells; the non-hydroxylatable RepoMan P604A mutant reduces interaction of RepoMan with PP2A-B56γ, delays completion of mitosis, causes defects in chromosome alignment and segregation, and increases cell death. Mass spectrometry identification of P604 hydroxylation; siRNA depletion of PHD1/PHD2; RepoMan P604A mutagenesis; co-immunoprecipitation of RepoMan with PP2A-B56γ; H3T3 phosphorylation immunostaining; live-cell imaging of mitosis bioRxivpreprint Medium bio_10.1101_2025.05.06.652400
2017 PHD1 inhibitors were identified with a novel monodentate binding mode; X-ray crystallography showed the triazolo N1 atom coordinates in a monodentate interaction with the active site Fe2+ ion, while the benzonitrile group accepts a hydrogen bond from Asn315. X-ray crystallography of PHD1-inhibitor complex; structure-activity relationship analysis Journal of medicinal chemistry Medium 28594552
2023 Elevation of intracellular alpha-ketoglutarate inhibits RANKL-induced osteoclastogenesis by suppressing NF-κB signaling in a PHD1 (EGLN2)-dependent manner; blockade of PHD1 expression (but not PHD2 or PHD3) reverses this suppression of RANKL-activated NF-κB signaling and antagonizes the inhibitory effects on osteoclastogenesis. PHD1/PHD2/PHD3 siRNA knockdown; NF-κB reporter assay; RANKL-induced osteoclast differentiation assay; DMOG (PHD competitive inhibitor) treatment Nutrients Medium 36771407
2025 PHD1 (all three PHD isoforms) interacts with IKKα/β; overexpression of PHD1 and PHD2 (but PHD3 to a lesser extent) markedly reduces IKKα/β protein levels in a manner requiring PHD1/PHD2 active sites; PHD1 overexpression decreases mRNA levels of IL-1β, a downstream NF-κB target; FIH-1 does not interact with IKKα/β (negative finding). Co-immunoprecipitation of PHDs with IKKα/β; active-site mutants of PHD1/2/3; IL-1β mRNA measurement; IKKα/β protein level assays after PHD overexpression The Journal of toxicological sciences Medium 40024754

Source papers

Stage 0 corpus · 75 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 905 15247232
2008 Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nature genetics 392 18176562
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
2020 PHD1 controls muscle mTORC1 in a hydroxylation-independent manner by stabilizing leucyl tRNA synthetase. Nature communications 255 31924757
1994 Induction of pseudohyphal growth by overexpression of PHD1, a Saccharomyces cerevisiae gene related to transcriptional regulators of fungal development. Molecular and cellular biology 221 8114741
2009 Control of cyclin D1 and breast tumorigenesis by the EglN2 prolyl hydroxylase. Cancer cell 117 19878873
2014 Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase. Genes & development 112 24990963
2009 Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury. Gastroenterology 109 19818783
2014 Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia. Journal of molecular medicine (Berlin, Germany) 108 25263965
2002 The use of dioxygen by HIF prolyl hydroxylase (PHD1). Bioorganic & medicinal chemistry letters 98 12039559
2003 Expression of prolyl-hydroxylase-1 (PHD1/EGLN2) suppresses hypoxia inducible factor-1alpha activation and inhibits tumor growth. Cancer research 91 14695194
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
2016 Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism. Cell metabolism 76 26774962
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
2013 PHD1 links cell-cycle progression to oxygen sensing through hydroxylation of the centrosomal protein Cep192. Developmental cell 74 23932902
2015 EglN2 associates with the NRF1-PGC1α complex and controls mitochondrial function in breast cancer. The EMBO journal 70 26492917
2012 Exploring PHD fingers and H3K4me0 interactions with molecular dynamics simulations and binding free energy calculations: AIRE-PHD1, a comparative study. PloS one 70 23077531
2011 Disruption of hypoxia-inducible transcription factor-prolyl hydroxylase domain-1 (PHD-1-/-) attenuates ex vivo myocardial ischemia/reperfusion injury through hypoxia-inducible factor-1α transcription factor and its target genes in mice. Antioxidants & redox signaling 68 21083501
2011 The stress response factors Yap6, Cin5, Phd1, and Skn7 direct targeting of the conserved co-repressor Tup1-Ssn6 in S. cerevisiae. PloS one 67 21552514
2008 Somatic pairing of chromosome 19 in renal oncocytoma is associated with deregulated EGLN2-mediated [corrected] oxygen-sensing response. PLoS genetics 55 18773095
2015 PHD1 regulates p53-mediated colorectal cancer chemoresistance. EMBO molecular medicine 47 26290450
2013 Expression and DNA methylation levels of prolyl hydroxylases PHD1, PHD2, PHD3 and asparaginyl hydroxylase FIH in colorectal cancer. BMC cancer 44 24195777
2006 Characterization of different isoforms of the HIF prolyl hydroxylase PHD1 generated by alternative initiation. The Biochemical journal 43 16509823
2017 Tumor suppressor SPOP ubiquitinates and degrades EglN2 to compromise growth of prostate cancer cells. Cancer letters 41 28089830
2020 Mucosal inflammation downregulates PHD1 expression promoting a barrier-protective HIF-1α response in ulcerative colitis patients. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 35 31944416
2019 EGLN2 DNA methylation and expression interact with HIF1A to affect survival of early-stage NSCLC. Epigenetics 35 30665327
2016 Docetaxel induced-JNK2/PHD1 signaling pathway increases degradation of HIF-1α and causes cancer cell death under hypoxia. Scientific reports 35 27263528
2011 Cdk8 regulates stability of the transcription factor Phd1 to control pseudohyphal differentiation of Saccharomyces cerevisiae. Molecular and cellular biology 35 22124158
2010 Expression of key hypoxia sensing prolyl-hydroxylases PHD1, -2 and -3 in pancreaticobiliary cancer. Histopathology 34 20497244
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
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
2013 Variants in two adjacent genes, EGLN2 and CYP2A6, influence smoking behavior related to disease risk via different mechanisms. Human molecular genetics 28 24045616
2011 PHD1 interacts with ATF4 and negatively regulates its transcriptional activity without prolyl hydroxylation. Experimental cell research 28 21951999
2012 Deficiency of the oxygen sensor PHD1 augments liver regeneration after partial hepatectomy. Langenbeck's archives of surgery 27 22961008
2016 Hypoxia-inducible factor prolyl hydroxylase 1 (PHD1) deficiency promotes hepatic steatosis and liver-specific insulin resistance in mice. Scientific reports 26 27094951
2019 Overexpression of long non-coding RNA NORAD promotes invasion and migration in malignant melanoma via regulating the MIR-205-EGLN2 pathway. Cancer medicine 24 30843652
2020 Long non-coding RNA LINC00662 promotes proliferation and migration of breast cancer cells via regulating the miR-497-5p/EglN2 axis. Acta biochimica Polonica 23 32558530
2008 Expression of prolyl-hydroxylases PHD-1, 2 and 3 and of the asparagine hydroxylase FIH in non-small cell lung cancer relates to an activated HIF pathway. Cancer letters 22 18187257
2024 VHL suppresses autophagy and tumor growth through PHD1-dependent Beclin1 hydroxylation. The EMBO journal 20 38360997
2017 EglN2 contributes to triple negative breast tumorigenesis by functioning as a substrate for the FBW7 tumor suppressor. Oncotarget 20 28036276
2017 1,2,4-Triazolo-[1,5-a]pyridine HIF Prolylhydroxylase Domain-1 (PHD-1) Inhibitors With a Novel Monodentate Binding Interaction. Journal of medicinal chemistry 20 28594552
2021 LncRNA MIAT enhances cerebral ischaemia/reperfusion injury in rat model via interacting with EGLN2 and reduces its ubiquitin-mediated degradation. Journal of cellular and molecular medicine 19 34687132
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
1998 phd1+, a histone deacetylase gene of Schizosaccharomyces pombe, is required for the meiotic cell cycle and resistance to trichostatin A. FEBS letters 16 9781677
2015 CDK-dependent phosphorylation of PHD1 on serine 130 alters its substrate preference in cells. Journal of cell science 15 26644182
2024 Hypoxia-mediated attenuation of EGLN2 inhibition of the NF-κB signaling pathway leads to the formation of a loop between HIF-1α and MUC1-C promoting chemoresistance in bladder cancer. Molecular carcinogenesis 13 38634741
2023 Elevation of Intracellular Alpha-Ketoglutarate Levels Inhibits Osteoclastogenesis by Suppressing the NF-κB Signaling Pathway in a PHD1-Dependent Manner. Nutrients 13 36771407
2017 Double Knockdown of PHD1 and Keap1 Attenuated Hypoxia-Induced Injuries in Hepatocytes. Frontiers in physiology 13 28539891
2004 Hypoxia-dependent regulation of PHD1: cloning and characterization of the human PHD1/EGLN2 gene promoter. FEBS letters 13 15178343
2021 Recognition of Histone H3 Methylation States by the PHD1 Domain of Histone Demethylase KDM5A. ACS chemical biology 12 33621062
2012 The conserved PHD1-PHD2 domain of ZFP-1/AF10 is a discrete functional module essential for viability in Caenorhabditis elegans. Molecular and cellular biology 12 23263989
2014 Polymorphism in PHD1 gene and risk of non-small cell lung cancer in a Chinese population. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 10 24894671
2022 Modulation of miR-205/ EGLN2 by rosuvastatin mitigates colistin-induced nephrotoxicity in rats: Involvement of ATF4/ CHOP and Nrf2 pathways. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 9 36436490
2017 An insertion/deletion polymorphism within the promoter of EGLN2 is associated with susceptibility to colorectal cancer. The International journal of biological markers 9 28218358
2015 EGLN2 and RNF150 genetic variants are associated with chronic obstructive pulmonary disease risk in the Chinese population. International journal of chronic obstructive pulmonary disease 9 25609945
2024 Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response. Cell reports 8 39255062
2012 Molecular cloning of phd1 and comparative analysis of phd1, 2, and 3 expression in Xenopus laevis. TheScientificWorldJournal 8 22645445
2008 Expression, purification and characterization of human PHD1 in Escherichia coli. Journal of biochemistry 7 18710826
2024 PHD1-3 oxygen sensors in vivo-lessons learned from gene deletions. Pflugers Archiv : European journal of physiology 6 38509356
2022 Lack of Skeletal Effects in Mice with Targeted Disruptionof Prolyl Hydroxylase Domain 1 (Phd1) Gene Expressed in Chondrocytes. Life (Basel, Switzerland) 6 36676055
2015 Augmented 5-HT Secretion in Pulmonary Neuroepithelial Bodies from PHD1 Null Mice. Advances in experimental medicine and biology 6 26303495
2015 EglN2 positively regulates mitochondrial function in breast cancer. Molecular & cellular oncology 6 27308620
2018 Effects of Simultaneous Downregulation of PHD1 and Keap1 on Prevention and Reversal of Liver Fibrosis in Mice. Frontiers in pharmacology 5 29899699
2018 The molecular characterization, expression pattern and alternative initiation of Megalobrama amblycephala Hif prolyl hydroxylase Phd1. Gene 5 30086363
2024 YAP1 Overexpression Enhances the Aerobic Glycolysis Process via Suppression of EGLN2 in Pancreatic Ductal Adenocarcinoma. The journal of gene medicine 4 39647834
2020 Exploring the Ligand Preferences of the PHD1 Domain of Histone Demethylase KDM5A Reveals Tolerance for Modifications of the Q5 Residue of Histone 3. ACS chemical biology 3 33314922
2025 EGLN2 attenuates ovarian cancer malignancy via ferroptosis activation. Neoplasma 2 40958522
2024 Mass Spectrometry-Based Protein Footprinting Defines the Binding Pocket of Crotonylated H3K14 in the PHD1 Domain of BAF45D within the BAF Chromatin Remodeling Complex. ACS bio & med chem Au 2 39184054
2025 Prolyl hydroxylase domain enzymes (isoforms 1-3, PHD1-3), but not factor-inhibiting HIF-1 (FIH-1), interact with the IKK complex and attenuate LPS-activated NF-kappa-B. The Journal of toxicological sciences 1 40024754
2025 Hypoxia-driven ferroptosis escape mediates lung injury induced by nickel-refining fumes via oxygen-sensing signaling PHD1/HIF-1α. Environmental pollution (Barking, Essex : 1987) 1 41082962
2024 Zebrafish phd1 enhances mavs-mediated antiviral responses in a hydroxylation-independent manner. Journal of virology 1 39162481
2023 Identifying ligands for the PHD1 finger of KDM5A through high-throughput screening. RSC chemical biology 1 38456036
2026 Exosomal lncRNA ENSSSCG00000049656 regulates porcine oocyte maturation via the ssc-miR-500-3p/EGLN2 axis. Theriogenology 0 41643377
2026 Targeted Degradation of Prolyl Hydroxylase Domain Enzyme 1 (PHD1) as a Novel Therapeutic Strategy for Acetaminophen-Induced Acute Liver Injury. Journal of medicinal chemistry 0 42126822
2026 Chrysin reshapes ferroptosis sensitivity to reverse nickel refining fumes-induced lung injury via the miR-210/ANGPTL4 signaling axis mediated by the PHD1/HIF-1α pathway. Ecotoxicology and environmental safety 0 42127541

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