Affinage

NT5E

5'-nucleotidase · UniProt P21589

Length
574 aa
Mass
63.4 kDa
Annotated
2026-04-29
100 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NT5E (CD73) is a GPI-anchored, homodimeric ecto-5′-nucleotidase that hydrolyzes extracellular AMP to adenosine and inorganic phosphate, serving as a master regulator of purinergic signaling across immune, vascular, neural, and epithelial compartments. Structurally, the enzyme undergoes a ~114° domain rotation between open and closed conformations that governs substrate selectivity for monophosphate nucleotides, and its catalytic activity requires proper N-linked glycosylation at C-terminal residues N311 and N333 (PMID:23142347, PMID:31592495). The adenosine generated by CD73 signals through A1, A2A, or A2B adenosine receptors to mediate cardioprotection during ischemic preconditioning, inhibit nociception in spinal circuits, maintain epithelial barrier integrity via CDC42/N-WASP/ARP2/3-dependent cortical actin remodeling, suppress macrophage inflammatory responses, and protect against diabetic nephropathy and vascular inflammation (PMID:17353435, PMID:20147550, PMID:26642367, PMID:28060378, PMID:24262796, PMID:16636171). CD73 protein turnover is controlled by TRIM21-mediated K48-linked polyubiquitylation at residues K133/K208/K262/K321, and an alternatively spliced catalytically inactive isoform (CD73S) promotes proteasomal degradation of canonical CD73L; transcriptionally, NT5E is activated by c-Jun/AP-1 downstream of MAPK signaling, by HIF-1α, and by TET2-mediated promoter demethylation downstream of AHR (PMID:36608132, PMID:25298403, PMID:28652246, PMID:36314527).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Early work established that CD73 is a GPI-anchored ectoenzyme localized to the apical surface of epithelia within lipid raft/caveolar domains, converting neutrophil-derived 5′-AMP to adenosine to activate A2B receptors and drive epithelial chloride secretion — defining its core paracrine signaling axis.

    Evidence PI-PLC release, sucrose gradient fractionation, confocal microscopy, and AOPCP pharmacological blockade on T84 intestinal epithelial monolayers

    PMID:9113412 PMID:9169488

    Open questions at the time
    • Whether lipid raft partitioning quantitatively regulates enzymatic output was not determined
    • Costimulatory function for T cells was shown to be enzyme-independent but the non-enzymatic mechanism was not identified
  2. 2006 High

    Genetic deletion of CD73 in mice revealed that vascular CD73-generated adenosine signals through A2A receptors to limit endothelial NF-κB activation, VCAM-1 expression, and monocyte recruitment, establishing CD73 as an anti-inflammatory checkpoint in vasculature.

    Evidence CD73−/− mice, wire injury neointima model, flow adhesion assay, ChIP for NF-κB p65, A2A agonist rescue

    PMID:16636171

    Open questions at the time
    • Relative contributions of endothelial vs. leukocyte CD73 were not fully resolved by tissue-specific deletion
    • Downstream adenosine receptor coupling in smooth muscle cells was not examined
  3. 2007 High

    CD73 was shown to be essential for ischemic preconditioning-mediated cardioprotection, with genetic and pharmacological evidence converging on A2B adenosine receptor as the downstream effector selectively induced during preconditioning.

    Evidence cd73−/− and A2B AR KO mice, AOPCP inhibition, exogenous 5′-nucleotidase reconstitution, infarct size measurement

    PMID:17353435

    Open questions at the time
    • Cellular source of AMP substrate during ischemia was not identified
    • Whether CD73 contributes to post-conditioning or remote conditioning was not tested
  4. 2010 High

    NT5E was identified as a principal ectonucleotidase on nociceptive neurons, where it generates adenosine that acts through A1 receptors to inhibit pain signaling — establishing its neuronal analgesic role distinct from immune functions.

    Evidence Nt5e−/− and Pap/Nt5e double-KO mice, AMP histochemistry, fast-scan cyclic voltammetry in lamina II, behavioral pain models, A1R KO epistasis

    PMID:20147550 PMID:22011440

    Open questions at the time
    • Whether NT5E activity is dynamically regulated in nociceptors by injury or inflammation was not addressed
    • Relative contributions of NT5E vs. PAP differ by pain modality and remain incompletely parsed
  5. 2012 High

    Crystal structures of human CD73 resolved the catalytic mechanism, revealing a dramatic ~114° inter-domain rotation that controls active-site access and selectivity for monophosphate nucleotides, and identified a druggable auxiliary pocket in the open conformation.

    Evidence X-ray crystallography of apo, adenosine-bound, and AMPCP-bound human CD73 dimers

    PMID:23142347

    Open questions at the time
    • Structures were obtained in detergent-solubilized form without the GPI anchor or membrane environment
    • Transition-state intermediates were not captured
  6. 2013 High

    Tissue-specific conditional knockouts demonstrated that CD73-derived adenosine attenuates diabetic nephropathy specifically through endothelial A2B receptor signaling, extending the protective axis to chronic metabolic disease.

    Evidence Endothelial vs. tubular-specific Adora2b conditional KO in streptozotocin diabetic mice, soluble nucleotidase rescue

    PMID:24262796

    Open questions at the time
    • Whether podocyte CD73 contributes was not tested
    • Long-term renal outcomes beyond the experimental window were not assessed
  7. 2014 High

    Multiple discoveries in 2014 established post-translational and disease-related control of CD73: (i) an alternatively spliced inactive isoform CD73S promotes proteasomal degradation of canonical CD73L; (ii) disease-causing NT5E mutations (C358Y, S221X, V537fsX7) block plasma membrane trafficking and abolish surface enzymatic activity; and (iii) CD73 deficiency elevates the Pi/PPi ratio causing joint and vascular calcification (ACDC disease).

    Evidence Isoform co-expression and proteasome inhibitor rescue in HepG2 cells; mutant trafficking analysis in COS-7 cells; Nt5e−/− mice with micro-CT and Pi/PPi quantification

    PMID:24887587 PMID:25298403 PMID:25486201

    Open questions at the time
    • Endogenous regulation of CD73S/CD73L isoform ratio in non-hepatic tissues is unknown
    • Whether partial-function NT5E mutations exist with milder calcification phenotypes was not explored
  8. 2014 High

    CD73-generated adenosine was shown to maintain epithelial integrity through A1R–CDC42–N-WASP–ARP2/3 actin polymerization, stabilizing E-cadherin and β-catenin at adherens junctions — a mechanism lost in advanced endometrial carcinoma, linking CD73 loss to tumor invasion.

    Evidence CD73 knockdown/inhibition, adenosine receptor pharmacology, CDC42 and ARP2/3 pathway dissection, in vivo CD73-deficiency model

    PMID:26642367

    Open questions at the time
    • Whether this actin-remodeling mechanism operates in non-epithelial barriers was not tested
    • Direct interaction between adenosine receptor signaling and CDC42 activation was not biochemically reconstituted
  9. 2017 High

    Transcriptional regulation of NT5E was defined: MAPK-driven c-Jun/AP-1 binds an intronic enhancer to activate CD73 transcription in melanoma, linking oncogenic signaling and inflammatory TNFα to immune evasion via CD73 induction.

    Evidence ChIP for c-Jun at NT5E intronic enhancer, MAPK inhibitor treatment, TNFα stimulation, patient biopsy validation under immunotherapy

    PMID:28652246

    Open questions at the time
    • Other transcription factors cooperating with c-Jun at the enhancer were not identified
    • Whether this enhancer is active in non-melanoma tumor types was not established
  10. 2019 High

    Glycosylation-dependent catalytic regulation was elucidated: tumor-selective aberrant N-linked glycosylation at N311 and N333 in the C-terminal domain reduces CD73 enzymatic activity ~3-fold, establishing that specific glycan modifications are required for full catalytic competence.

    Evidence Mass spectrometry glycomics on primary HCC tissue, site-directed mutagenesis of N311/N333 with activity assays

    PMID:31592495

    Open questions at the time
    • Identity of the glycosyltransferases responsible for aberrant glycosylation in tumors is unknown
    • Whether glycosylation changes affect domain rotation dynamics was not structurally assessed
  11. 2019 High

    CD73 was shown to fuel glioblastoma angiogenesis and drug resistance through endothelial A2B receptor signaling that induces MMP-2 for invasion and upregulates multidrug resistance transporters (P-gp, MRP1), and separately to drive microglial neuroinflammation via an A2A receptor feed-forward loop.

    Evidence CD73-FLK transgenic and CD73−/− mouse glioblastoma models with A2B AR pharmacology; CD73 KO/inhibition in microglia and MPTP Parkinson's models with adenosine analogue rescue

    PMID:30689733 PMID:30926752

    Open questions at the time
    • Whether tumor-cell-intrinsic vs. stromal CD73 predominates in human glioblastoma adenosine production is unresolved
    • Structural basis for selective A2B vs. A2A engagement in different cell types is not defined
  12. 2022 Medium

    An epigenetic regulatory circuit was identified: AHR binds the TET2 promoter to induce TET2, which demethylates the NT5E promoter to enable CD73 expression in regulatory T cells — a pathway impaired in systemic lupus erythematosus Tregs.

    Evidence ChIP-PCR for AHR at TET2 promoter, NT5E promoter methylation analysis, kynurenine stimulation, Treg functional assays

    PMID:36314527

    Open questions at the time
    • Whether TET2-mediated NT5E demethylation operates in non-Treg immune cells is unknown
    • Direct TET2 binding to the NT5E promoter was not demonstrated by ChIP
  13. 2023 High

    TRIM21 was identified as the E3 ubiquitin ligase governing CD73 proteolysis, polyubiquitylating CD73 at K133/K208/K262/K321; loss of TRIM21 stabilizes CD73, boosts adenosine, and suppresses antitumor CD8+ T cell immunity.

    Evidence E3 ligase screen, co-IP, K→R mutagenesis, ubiquitylation assays, tumor growth and T cell function assays in vivo

    PMID:36608132

    Open questions at the time
    • Whether TRIM21 ubiquitylates CD73 at the plasma membrane or during biosynthesis is not resolved
    • Other deubiquitinases that may oppose TRIM21 action on CD73 are unknown
  14. 2023 High

    A cell-intrinsic metabolic role was uncovered: CD73 promotes tumor mitochondrial oxidative phosphorylation and aspartate biosynthesis independently of immunosuppression, with aspartate supplementation rescuing proliferation of CD73-deficient tumors even in immunodeficient hosts.

    Evidence Metabolomics, Seahorse metabolic flux analysis, CD73 KO in immunodeficient mice, aspartate rescue

    PMID:37261423

    Open questions at the time
    • Whether the metabolic role requires enzymatic activity or is a non-catalytic function is not resolved
    • The mechanism linking extracellular adenosine to mitochondrial OXPHOS and aspartate synthesis is not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of the non-enzymatic T cell costimulatory function, the mechanism by which extracellular adenosine regulates intracellular mitochondrial metabolism and aspartate biosynthesis, whether TRIM21-mediated ubiquitylation occurs at the plasma membrane or intracellularly, and how isoform switching between CD73L and CD73S is regulated in different tissues.
  • Non-enzymatic signaling mechanism is undefined
  • Metabolic coupling mechanism between extracellular adenosine and mitochondrial function is unknown
  • In vivo regulation of CD73S/CD73L splicing ratio across tissues has not been characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 5 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 5 R-HSA-1643685 Disease 4 R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 3
Partners
ADORA1ADORA2AADORA2BAURKACANXTRIM21

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 Crystal structures of dimeric human CD73 (ecto-5'-nucleotidase) reveal an extensive 114° conformational switch between open and closed forms of the enzyme. The dimerization interface is formed by C-terminal domains. Complex structures with adenosine and AMPCP indicate that structural control of the domain movement determines selectivity for monophosphate nucleotides. An additional binding pocket (~210 ų) in the C-terminal domain in the open form was identified for inhibitor design. X-ray crystallography of human CD73 in apo, adenosine-bound, and AMPCP-bound forms Structure High 23142347
1997 CD73 (ecto-5'-nucleotidase) is a GPI-anchored enzyme that catalyzes dephosphorylation of nucleoside monophosphates to nucleosides, and functions as a costimulatory molecule for T cell activation. Neither enzymatic activity nor the GPI anchor is required for T cell activation via CD73 in vitro, whereas expression of p56lck, CD45, and the T cell receptor are required. Transfection of CD73 cDNA into Jurkat T cells; enzymatic activity and GPI anchor mutants tested for T cell activation Cellular signalling Medium 9113412
1997 CD73 is expressed on the apical surface of human intestinal epithelial cells (T84 monolayers and natural epithelia), anchored via a GPI anchor (released by PI-PLC), and is concentrated in detergent-insoluble glycosphingolipid-rich membrane domains (DIGs/caveolae) containing caveolin. CD73-mediated conversion of PMN-derived 5'-AMP to adenosine activates apical A2b adenosine receptors to drive epithelial Cl⁻ secretion; inhibition of CD73 with AOPCP blocked 5'-AMP-induced but not adenosine-induced Cl⁻ secretion. Confocal immunofluorescence, selective cell-surface biotinylation, PI-PLC release assay, Triton X-100 fractionation on sucrose gradients, pharmacological inhibition with AOPCP The Journal of clinical investigation High 9169488
2007 CD73-dependent adenosine generation is required for cardioprotection by ischemic preconditioning. Genetic deletion or pharmacological inhibition of CD73 abolished infarct size-limiting effects of preconditioning, whereas exogenous 5'-nucleotidase treatment reconstituted cd73−/− mice. The cardioprotective signal is transduced through A2B adenosine receptors, which are selectively induced by ischemic preconditioning. Targeted gene deletion (cd73−/−), pharmacological inhibition, exogenous enzyme reconstitution, A2B AR knockout mice, infarct size measurement Circulation High 17353435
2006 Vascular CD73 limits endothelial activation and monocyte recruitment by generating adenosine that acts through the A2A adenosine receptor. CD73-deficient endothelial cells show increased VCAM-1 expression via elevated NF-κB activity, increased monocyte arrest under flow (mediated by α4β1 integrin), and increased neointimal plaque after wire injury. A2A receptor agonist treatment reversed VCAM-1 upregulation and prevented neointima formation in CD73−/− mice. CD73−/− mice, wire injury model, ex vivo flow adhesion assay, ChIP/p65 binding assay, A2A agonist treatment, bone marrow reconstitution Circulation High 16636171
2010 NT5E/CD73 is located on peptidergic and nonpeptidergic nociceptive neurons in dorsal root ganglia and on axon terminals in spinal cord lamina II. NT5E hydrolyzes extracellular AMP to adenosine in nociceptive circuits; Nt5e−/− mice show reduced AMP hydrolytic activity in DRG and spinal cord, reduced antinociceptive effects of AMP (by ~50%, eliminated in A1R KO), and enhanced sensitivity to thermal, inflammatory, and neuropathic pain stimuli. Nt5e−/− mice, AMP histochemistry, enzyme activity assays, behavioral pain tests (tail immersion, CFA, spared nerve injury), A1R KO epistasis The Journal of neuroscience High 20147550
2011 PAP and NT5E (CD73) are the principal ectonucleotidases generating adenosine in spinal nociceptive circuits. AMP hydrolysis is nearly abolished in DRG and lamina II of Pap/Nt5e double KO mice. Fast-scan cyclic voltammetry showed adenosine is maximally produced within seconds from AMP in wild-type but reduced >50% in dKO mice. CD73-generated adenosine acts via A1 receptor to inhibit excitatory neurotransmission. Spontaneous adenosine transients in lamina II were reduced >60% in Pap−/−, Nt5e−/−, and dKO mice. Pap/Nt5e double KO mice, AMP histochemistry, fast-scan cyclic voltammetry, field potential recordings, behavioral assays Molecular pain High 22011440
2014 CD73-generated adenosine promotes epithelial integrity in endometrial carcinoma via A1 receptor-induced CDC42-dependent conformational change of the ARP2/3 complex member N-WASP, driving cortical actin polymerization. This elevates membrane E-cadherin, β-catenin, and Na+K+ ATPase. Loss of CD73 in advanced endometrial carcinoma leads to loss of epithelial barrier function and increased migration/invasion. CD73 inhibition/knockdown, murine CD73-deficiency model, in vitro migration/invasion assays, adenosine receptor pharmacology, Rho GTPase/ARP2/3 pathway analysis, immunofluorescence for actin and adhesion molecules The Journal of clinical investigation High 26642367
2014 NT5E encodes a novel splice variant (CD73S) that is upregulated in cirrhosis and hepatocellular carcinoma. CD73S lacks 50 amino acids, is glycosylated but catalytically inactive, unable to dimerize, retained in the ER via complex with the chaperone calnexin, and promotes proteasome-dependent degradation of canonical CD73L when the two isoforms are co-expressed. Genomic database analysis, isoform-specific antibody detection, HCC tissue analysis, transfection of CD73S and CD73L in HepG2 cells, co-immunoprecipitation with calnexin, enzyme activity assay, proteasome inhibitor rescue Molecular biology of the cell High 25298403
2014 CD73-deficient mice exhibit joint-capsule and ligament mineralization with significantly increased serum Pi and significantly reduced plasma PPi, resulting in a markedly increased Pi/PPi ratio that creates a pro-mineralization environment. Loss-of-function NT5E mutations in humans cause arterial calcification due to CD73 deficiency (ACDC). Nt5e−/− knockout mice, micro-CT, serum/plasma Pi and PPi measurement Cell cycle High 25486201
2014 Disease-causing missense (C358Y) and nonsense (S221X, V537fsX7) NT5E mutations result in mistrafficking of NT5E protein: all three mutant proteins show significantly reduced trafficking to the plasma membrane, reduced ER retention, accumulate in vesicles in the cell synthetic apparatus, and display absent NT5E enzymatic activity at the cell surface. DsRed-tagged NT5E wild-type and mutant transfection in COS-7 cells, enzyme histochemistry, Malachite green AMP hydrolysis assay, confocal microscopy, Western blot of fractionated cell constituents PloS one High 24887587
2019 CD73-derived adenosine activates A2A receptor (A2AR) in a feed-forward manner to modulate microglial immunoresponses. CD73 inactivation attenuated LPS-induced pro-inflammatory responses in microglia, enhanced microglial process extension and morphological transformation, suppressed A2AR induction, and improved dopaminergic neuron viability in MPTP Parkinson's disease models. Adenosine analogue replenishment restored CD73 knockdown effects, confirming the mechanistic link. CD73 knockout/inhibition in microglia and mouse MPTP models, laser injury live imaging, adenosine analogue rescue, A2AR pathway analysis Brain High 30689733
2019 CD73 undergoes tumor-selective aberrant N-linked glycosylation in human hepatocellular carcinoma, specifically at residues N311 and N333 in the C-terminal catalytic domain, resulting in a 3-fold decrease in 5'-nucleotidase activity. Site-directed mutagenesis of N311/N333 recapitulated the activity decrease in vitro, establishing glycosylation at these sites as required for full catalytic function. Mass spectrometry glycomics, 5'-nucleotidase activity assays on primary HCC tissue, site-directed mutagenesis of N311/N333, RNAseq, immunofluorescence for Golgi colocalization Hepatology communications High 31592495
2023 TRIM21 is an E3 ubiquitin ligase that governs CD73 proteolysis. TRIM21 polyubiquitylates CD73 at lysine residues K133, K208, K262, and K321; substitution of these residues with arginine attenuated CD73 ubiquitylation and degradation. TRIM21 disruption stabilizes CD73, enhances CD73-catalyzed adenosine production, and suppresses CD8+ T cell function and antitumor immunity. E3 ligase identification, co-IP, site-directed mutagenesis (K→R substitutions), ubiquitylation assays, tumor growth and T cell function assays in vivo Science advances High 36608132
2023 CD73 promotes tumor cell mitochondrial respiration and aspartate biosynthesis independently of its immunosuppressive function. CD73 deficiency decreases oxidative phosphorylation and glycolytic reserve (Seahorse analysis), increases genomic instability, and suppresses PARP activity. Rescuing aspartate biosynthesis restored proliferation of CD73-deficient tumors in immune-deficient mice. Metabolomics, Seahorse metabolic flux analysis in mouse and human tumor cell lines, CD73 KO in immunodeficient mice, aspartate rescue experiments eLife High 37261423
2023 CD73 directly interacts with Aurora kinase A (AURKA) in hepatic stellate cells, as confirmed by co-immunoprecipitation and molecular docking. CD73 overexpression inhibits AURKA ubiquitination and downregulates p53 signaling, regulating hepatic stellate cell senescence and activation, thereby promoting alcohol-related liver fibrosis. Co-immunoprecipitation, molecular docking, ubiquitination assay, KEGG pathway analysis, CD73 overexpression/knockdown in hepatic stellate cells, mouse alcohol-related fibrosis models International journal of biological sciences Medium 36778123
2019 CD73 on endothelial cells promotes glioblastoma angiogenesis and invasiveness via A2B adenosine receptor (A2B AR) signaling. A2B AR is upregulated 20-fold on glioblastoma versus sham. A2B AR activation induces matrix metalloproteinase-2, enhancing tumor invasiveness. Inhibition of A2B AR signaling decreases multidrug resistance transporter expression (P-gp and MRP1) and potentiates temozolomide-induced tumor cell death. Unique CD73-FLK transgenic mouse model, CD73−/− mouse comparisons, A2B AR inhibition, MMP-2 and MDR protein expression assays, temozolomide cytotoxicity assay The Journal of neuroscience High 30926752
2017 CD73 induction in melanoma is linked to a mesenchymal-like phenotype switch. MAPK signaling (activating mutations) and growth factors drive CD73 expression. Proinflammatory TNFα cooperates with MAPK signaling through c-Jun/AP-1 transcription factor complex to activate CD73 transcription by binding to an intronic enhancer. MAPK inhibitors, TNFα stimulation, ChIP assay for c-Jun binding to CD73 intronic enhancer, melanoma mouse T-cell immunotherapy model, patient biopsy analysis under immunotherapy Cancer research High 28652246
2013 CD73-dependent generation of extracellular adenosine and endothelial A2B receptor (Adora2b) signaling attenuates diabetic nephropathy. CD73 transcripts and protein are elevated in diabetic kidneys. Genetic deletion of CD73 worsens nephropathy, soluble nucleotidase treatment is therapeutic, and tissue-specific deletion of Adora2b from vascular endothelium (but not tubular epithelium) exacerbates nephropathy. CD73−/− mice, streptozotocin diabetes model, tissue-specific Adora2b conditional KO, Adora2b transgenic reporter, Adora2b agonist treatment Journal of the American Society of Nephrology High 24262796
2017 CD73 regulates anti-inflammatory signaling between apoptotic cells and endotoxin-conditioned macrophages. CD73 (AMP→adenosine), but not CD39, is required on macrophages for apoptotic cell-driven suppression of TNF. Ectopic co-expression of both A2a receptor and CD73 in RAW264.7 cells is required for TNF suppression by apoptotic cells. CD73 is required to limit neutrophil influx in a peritonitis model in vivo. CD73−/− macrophages, adenosine depletion, A2a receptor inhibition, ectopic expression in RAW264.7, peritonitis in vivo model Cell death and differentiation High 28060378
2014 CD73 inhibition by CD73KO or APCP reduces in vivo rat glioblastoma tumor size by 40–45%, accompanied by 95% reduction of adenosine levels in cerebrospinal fluid, demonstrating that extracellular adenosine derived from CD73 activity drives in vivo glioma growth. CD73 knockdown decreased glioma migration and invasion by reducing MMP-2 and vimentin, and reduced proliferation via Akt/NF-κB pathways. siRNA-CD73 knockdown, APCP enzyme inhibitor, in vivo rat glioblastoma model, CSF adenosine measurement, MMP-2 and vimentin expression, Akt/NF-κB pathway analysis Molecular neurobiology Medium 30117104
2014 CD73-generated adenosine suppresses TNAP (tissue nonspecific alkaline phosphatase) activity in cardiomyocytes. Phenylephrine reduces CD73 gene/protein expression and activity while increasing TNAP expression/activity, inducing hypertrophy and calcification. CD73 inhibition alone (without phenylephrine) induces hypertrophy and calcification, and these effects are abrogated by TNAP inhibition, demonstrating a CD73-TNAP crosstalk axis. Neonatal rat cardiomyocyte cultures, CD73 inhibitor (α,β-methylene ADP), TNAP inhibitor (tetramisole), adenosine analogue (2-chloro-adenosine), Alizarin Red S calcification staining, ANP gene expression, CD73/TNAP activity assays Molecular and cellular biochemistry Medium 24894822
2022 AHR promotes TET2 expression by binding to the TET2 promoter (ChIP confirmed), and TET2-mediated demethylation of the NT5E promoter regulates NT5E/CD73 expression in regulatory T cells. Downregulation of the AHR/TET2/NT5E axis in SLE Tregs is associated with reduced NT5E promoter demethylation and impaired Treg immunosuppressive activity via the adenosine-A2AR pathway. ChIP-PCR for AHR binding at TET2 promoter, methylation analysis of NT5E promoter, kynurenine stimulation of AHR, flow cytometry, Treg functional assays Immunology Medium 36314527
2017 CD73 is a novel regulator of carotid body sensory activity; CD73 inhibition with AOPCP in vitro reduces barotid body basal discharge frequency by 76% and attenuates responses to graded hypoxia and mitochondrial inhibition. These effects are mimicked by adenosine receptor antagonism. In vivo, AOPCP infusion decreases the hypoxic ventilatory response and modifies cardiovascular responses to hypoxia. Whole carotid body preparation in vitro, AOPCP pharmacological inhibition, adenosine receptor antagonist (8-SPT), in vivo AOPCP infusion with physiological monitoring The Journal of physiology Medium 28560821
2023 CD73 expression protects pancreatic ductal adenocarcinoma tumor cells against DNA damage by gemcitabine and irradiation. CD73-deficient tumor cells show increased DNA damage associated with activation of the cGAS-STING pathway, and cGAS expression in tumor cells is required for antitumor activity of the CD73 inhibitor AB680 in vivo. CD73 inhibitor AB680 in vivo KPC mouse model, cGAS KO tumor cells, DNA damage assays, pharmacogenomic analysis of human PDAC cell lines Cancer immunology research Medium 36409930

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 CD39 and CD73 in immunity and inflammation. Trends in molecular medicine 985 23601906
2007 Cardioprotection by ecto-5'-nucleotidase (CD73) and A2B adenosine receptors. Circulation 382 17353435
1995 Rescue of the En-1 mutant phenotype by replacement of En-1 with En-2. Science (New York, N.Y.) 352 7624797
2023 CD39/CD73/A2AR pathway and cancer immunotherapy. Molecular cancer 274 36859386
1998 Ecto-enzyme and signaling functions of lymphocyte CD73. Immunological reviews 274 9553767
2018 Chemotherapy induces enrichment of CD47+/CD73+/PDL1+ immune evasive triple-negative breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America 250 29367423
2020 Breast cancer-derived exosomes transmit lncRNA SNHG16 to induce CD73+γδ1 Treg cells. Signal transduction and targeted therapy 211 32345959
2012 Crystal structure of the human ecto-5'-nucleotidase (CD73): insights into the regulation of purinergic signaling. Structure (London, England : 1993) 166 23142347
2014 The roles of CD73 in cancer. BioMed research international 165 25126561
2008 Human equilibrative nucleoside transporter (ENT) family of nucleoside and nucleobase transporter proteins. Xenobiotica; the fate of foreign compounds in biological systems 165 18668437
1997 Surface expression, polarization, and functional significance of CD73 in human intestinal epithelia. The Journal of clinical investigation 147 9169488
2015 CD73 and CD39 ectonucleotidases in T cell differentiation: Beyond immunosuppression. FEBS letters 145 26226423
2020 Targeting CD73 to augment cancer immunotherapy. Current opinion in pharmacology 132 32777746
2017 MAPK Signaling and Inflammation Link Melanoma Phenotype Switching to Induction of CD73 during Immunotherapy. Cancer research 131 28652246
2006 CD73/ecto-5'-nucleotidase protects against vascular inflammation and neointima formation. Circulation 127 16636171
2018 Targeting the CD73-adenosine axis in immuno-oncology. Immunology letters 120 29758241
2018 CD73 as a potential opportunity for cancer immunotherapy. Expert opinion on therapeutic targets 120 30556751
2020 CD73 Blockade Promotes Dendritic Cell Infiltration of Irradiated Tumors and Tumor Rejection. Cancer immunology research 115 32047024
2007 VAP-1 and CD73, endothelial cell surface enzymes in leukocyte extravasation. Arteriosclerosis, thrombosis, and vascular biology 93 17962625
2019 Cell type- and tissue-specific functions of ecto-5'-nucleotidase (CD73). American journal of physiology. Cell physiology 89 31461341
2018 Controlling the Immune Suppressor: Transcription Factors and MicroRNAs Regulating CD73/NT5E. Frontiers in immunology 85 29720980
2012 NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity. British journal of cancer 81 22454080
2019 CD73-derived adenosine controls inflammation and neurodegeneration by modulating dopamine signalling. Brain : a journal of neurology 80 30689733
2018 CD73 Downregulation Decreases In Vitro and In Vivo Glioblastoma Growth. Molecular neurobiology 79 30117104
2016 The SLC28 (CNT) and SLC29 (ENT) nucleoside transporter families: a 30-year collaborative odyssey. Biochemical Society transactions 79 27284054
2010 Ecto-5'-nucleotidase (CD73) inhibits nociception by hydrolyzing AMP to adenosine in nociceptive circuits. The Journal of neuroscience : the official journal of the Society for Neuroscience 77 20147550
2015 Loss of CD73-mediated actin polymerization promotes endometrial tumor progression. The Journal of clinical investigation 74 26642367
2020 Discovery of AB680: A Potent and Selective Inhibitor of CD73. Journal of medicinal chemistry 73 32614585
2019 Targeting the Immunomodulatory CD73/Adenosine System to Improve the Therapeutic Gain of Radiotherapy. Frontiers in immunology 66 31024543
2019 CD73 Promotes Glioblastoma Pathogenesis and Enhances Its Chemoresistance via A2B Adenosine Receptor Signaling. The Journal of neuroscience : the official journal of the Society for Neuroscience 65 30926752
2016 Oridonin, a Promising ent-Kaurane Diterpenoid Lead Compound. International journal of molecular sciences 64 27563888
2019 Structure-Activity Relationship of Purine and Pyrimidine Nucleotides as Ecto-5'-Nucleotidase (CD73) Inhibitors. Journal of medicinal chemistry 56 30895781
2023 CD73 Inhibits cGAS-STING and Cooperates with CD39 to Promote Pancreatic Cancer. Cancer immunology research 55 36409930
2021 The elegant complexity of mammalian ecto-5'-nucleotidase (CD73). Trends in cell biology 54 34116887
2017 CD73 regulates anti-inflammatory signaling between apoptotic cells and endotoxin-conditioned tissue macrophages. Cell death and differentiation 54 28060378
2019 The distinct role of CD73 in the progression of pancreatic cancer. Journal of molecular medicine (Berlin, Germany) 53 30927045
2021 CD73, Tumor Plasticity and Immune Evasion in Solid Cancers. Cancers 52 33430239
1997 T cell signalling through CD73. Cellular signalling 52 9113412
2019 Generation and Function of Non-cell-bound CD73 in Inflammation. Frontiers in immunology 51 31404305
2014 Reducing CD73 expression by IL1β-Programmed Th17 cells improves immunotherapeutic control of tumors. Cancer research 51 25205101
2023 The Clinical Significance of CD73 in Cancer. International journal of molecular sciences 49 37511518
2015 The expression and clinical significance of CD73 molecule in human rectal adenocarcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 49 25677906
2014 High expression of ecto-nucleotidases CD39 and CD73 in human endometrial tumors. Mediators of inflammation 48 24707115
2011 PAP and NT5E inhibit nociceptive neurotransmission by rapidly hydrolyzing nucleotides to adenosine. Molecular pain 48 22011440
2014 Alternative splicing of human NT5E in cirrhosis and hepatocellular carcinoma produces a negative regulator of ecto-5'-nucleotidase (CD73). Molecular biology of the cell 46 25298403
2022 CD4+FoxP3+CD73+ regulatory T cell promotes cardiac healing post-myocardial infarction. Theranostics 44 35401839
2014 Juxta-articular joint-capsule mineralization in CD73 deficient mice: similarities to patients with NT5E mutations. Cell cycle (Georgetown, Tex.) 44 25486201
2019 CD73 (Cluster of Differentiation 73) and the Differences Between Mice and Humans. Arteriosclerosis, thrombosis, and vascular biology 43 30676071
2010 ent-kaurane and ent-pimarane diterpenoids from Siegesbeckia pubescens. Journal of natural products 43 19928884
2021 Regulation of immune responses through CD39 and CD73 in cancer: Novel checkpoints. Life sciences 41 34265363
2020 CD73+ extracellular vesicles inhibit angiogenesis through adenosine A2B receptor signalling. Journal of extracellular vesicles 41 32489531
2013 CD73-dependent generation of adenosine and endothelial Adora2b signaling attenuate diabetic nephropathy. Journal of the American Society of Nephrology : JASN 41 24262796
2004 The pea gene LH encodes ent-kaurene oxidase. Plant physiology 39 14988475
2017 Targeting of NT5E by miR-30b and miR-340 attenuates proliferation, invasion and migration of gallbladder carcinoma. Biochimie 35 29155108
2022 The Multifaceted Actions of CD73 During Development and Suppressive Actions of Regulatory T Cells. Frontiers in immunology 34 35711418
2019 The metabolic milieu in melanoma: Role of immune suppression by CD73/adenosine. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 33 30957676
2022 The regulation of CD73 in non-small cell lung cancer. European journal of cancer (Oxford, England : 1990) 31 35598361
2014 Roles of the adenosine receptor and CD73 in the regulatory effect of γδ T cells. PloS one 31 25268760
2019 CD73 expression in normal and pathological human hepatobiliopancreatic tissues. Cancer immunology, immunotherapy : CII 30 30607549
2024 Neutrophil extracellular traps promote immune escape in hepatocellular carcinoma by up-regulating CD73 through Notch2. Cancer letters 29 38969159
2014 Intestinal immunopathology is associated with decreased CD73-generated adenosine during lethal infection. Mucosal immunology 29 25389034
2022 CD73+ Epithelial Progenitor Cells That Contribute to Homeostasis and Renewal Are Depleted in Eosinophilic Esophagitis. Cellular and molecular gastroenterology and hepatology 28 35108658
2021 Discovery of Potent and Selective Methylenephosphonic Acid CD73 Inhibitors. Journal of medicinal chemistry 28 33399453
2020 PCBP2 Posttranscriptional Modifications Induce Breast Cancer Progression via Upregulation of UFD1 and NT5E. Molecular cancer research : MCR 28 33037085
2020 CD73 Overexpression Promotes Progression and Recurrence of Papillary Thyroid Carcinoma. Cancers 28 33086655
2019 Downregulation of CD73 associates with T cell exhaustion in AML patients. Journal of hematology & oncology 28 31014364
2019 Tumor-Selective Altered Glycosylation and Functional Attenuation of CD73 in Human Hepatocellular Carcinoma. Hepatology communications 28 31592495
2023 Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity. Science advances 27 36608132
2015 A Systems Oncology Approach Identifies NT5E as a Key Metabolic Regulator in Tumor Cells and Modulator of Platinum Sensitivity. Journal of proteome research 27 26629888
2015 Calcification of joints and arteries: second report with novel NT5E mutations and expansion of the phenotype. Journal of human genetics 26 26178434
2022 Reshaping hypoxia and silencing CD73 via biomimetic gelatin nanotherapeutics to boost immunotherapy. Journal of controlled release : official journal of the Controlled Release Society 24 36165836
2019 Perivascular CD73+ cells attenuate inflammation and interstitial fibrosis in the kidney microenvironment. American journal of physiology. Renal physiology 24 31364375
2020 ent-Labdane and ent-kaurane diterpenoids from Chelonopsis odontochila with α-glucosidase inhibitory activity. Bioorganic chemistry 23 31927318
2024 Regulatory role of CD39 and CD73 in tumor immunity. Future oncology (London, England) 21 38652041
2021 CD73 expression defines immune, molecular, and clinicopathological subgroups of lung adenocarcinoma. Cancer immunology, immunotherapy : CII 21 33416944
2019 Ent-abietane and ent-pimarane diterpenoids from Croton mubango (Euphorbiaceae). Phytochemistry 21 31812109
2018 Ecto-5'-nucleotidase (CD73) is a potential target of hepatocellular carcinoma. Journal of cellular physiology 21 30417547
2014 CD73-TNAP crosstalk regulates the hypertrophic response and cardiomyocyte calcification due to α1 adrenoceptor activation. Molecular and cellular biochemistry 21 24894822
2023 Combining High-Z Sensitized Radiotherapy with CD73 Blockade to Boost Tumor Immunotherapy. ACS nano 20 37327456
2017 Ecto-5'-nucleotidase (CD73) regulates peripheral chemoreceptor activity and cardiorespiratory responses to hypoxia. The Journal of physiology 19 28560821
2014 Ecto-5'-nucleotidase (CD73) regulates host inflammatory responses and exacerbates murine salmonellosis. Scientific reports 19 24670982
2018 Extracellular ATP Regulates CD73 and ABCC6 Expression in HepG2 Cells. Frontiers in molecular biosciences 18 30155470
2022 AHR/TET2/NT5E axis downregulation is associated with the risk of systemic lupus erythematosus and its progression. Immunology 17 36314527
2023 The CD73 immune checkpoint promotes tumor cell metabolic fitness. eLife 16 37261423
2021 Transcriptome Profiling Reveals CD73 and Age-Driven Changes in Neutrophil Responses against Streptococcus pneumoniae. Infection and immunity 16 34310891
2024 Regulation of CD73 on NAD metabolism: Unravelling the interplay between tumour immunity and tumour metabolism. Cell communication and signaling : CCS 15 39090604
2023 The hypoxia-regulated ectonucleotidase CD73 is a host determinant of HIV latency. Cell reports 15 37910505
2022 Functional expression of CD73 on human natural killer cells. Cancer immunology, immunotherapy : CII 15 35622118
2006 Synthesis of ent-25-hydroxycholesterol. Steroids 15 16519912
2023 5'-Ectonucleotidase CD73/NT5E supports EGFR-mediated invasion of HPV-negative head and neck carcinoma cells. Journal of biomedical science 14 37620936
2023 CD73/NT5E-mediated ubiquitination of AURKA regulates alcohol-related liver fibrosis via modulating hepatic stellate cell senescence. International journal of biological sciences 13 36778123
2022 Discovery and optimization of betulinic acid derivatives as novel potent CD73 inhibitors. Bioorganic & medicinal chemistry 13 35217359
2017 Identification of CD4+ T-cell-derived CD161+ CD39+ and CD39+CD73+ microparticles as new biomarkers for rheumatoid arthritis. Biomarkers in medicine 13 28111965
2024 Blockade of CD73 potentiates radiotherapy antitumor immunity and abscopal effects via STING pathway. Cell death discovery 12 39285178
2023 Impact of CRISPR/Cas9-Mediated CD73 Knockout in Pancreatic Cancer. Cancers 12 37835536
2022 Tumor Infiltration with CD20+CD73+ B Cells Correlates with Better Outcome in Colorectal Cancer. International journal of molecular sciences 12 35563553
2020 MicroRNA-30a suppresses self-renewal and tumorigenicity of glioma stem cells by blocking the NT5E-dependent Akt signaling pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 12 32067282
2020 Interleukin 13 (IL-13) alters hypoxia-associated genes and upregulates CD73. International forum of allergy & rhinology 12 32673430
2014 NT5E mutations that cause human disease are associated with intracellular mistrafficking of NT5E protein. PloS one 12 24887587
2020 Prospective isolation of human fibroadipogenic progenitors with CD73. Heliyon 11 32728644