Details for: ENTPD1

Gene ID: 953

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: ENTPD1

Ensembl ID: ENSG00000138185

Description: ectonucleoside triphosphate diphosphohydrolase 1

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • CD8-positive, CD28-negative, alpha-beta regulatory T cell CL0000920
    CSI 20.81
    rCSI 41.48%
    PRS 93.23
  • central nervous system macrophage CL0000878
    CSI 13.06
    rCSI 43.27%
    PRS 87.38
  • granulocyte CL0000094
    CSI 8.84
    rCSI 13.51%
    PRS 89.73
  • IgG plasma cell CL0000985
    CSI 8.61
    rCSI 10.31%
    PRS 91.32
  • colon macrophage CL0009038
    CSI 7.28
    rCSI 33.62%
    PRS 93.34
  • intraepithelial lymphocyte CL0002496
    CSI 6.96
    rCSI 18.93%
    PRS 96.01
  • microglial cell CL0000129
    CSI 6.22
    rCSI 25.02%
    PRS 84.18
  • CD14-low, CD16-positive monocyte CL0002396
    CSI 5.73
    rCSI 4.42%
    PRS 86.75
  • Langerhans cell CL0000453
    CSI 5.49
    rCSI 8.39%
    PRS 92.57
  • myeloid dendritic cell CL0000782
    CSI 5.06
    rCSI 7.33%
    PRS 94.04
  • CD4-positive, CD25-positive, alpha-beta regulatory T cell CL0000792
    CSI 4.9
    rCSI 4.81%
    PRS 94.39
  • plasmablast CL0000980
    CSI 4.6
    rCSI 3.62%
    PRS 87.78
  • kidney interstitial alternatively activated macrophage CL1000695
    CSI 4.5
    rCSI 11.72%
    PRS 84.65
  • bronchus fibroblast of lung CL2000093
    CSI 4.42
    rCSI 3.59%
    PRS 83.1
  • hepatic stellate cell CL0000632
    CSI 4.04
    rCSI 15.15%
    PRS 76.71
  • Kupffer cell CL0000091
    CSI 3.98
    rCSI 9.11%
    PRS 84.48
  • interstitial cell of Cajal CL0002088
    CSI 3.86
    rCSI 4.92%
    PRS 88.29
  • CD14-positive monocyte CL0001054
    CSI 3.83
    rCSI 4.76%
    PRS 91.37
  • T-helper 17 cell CL0000899
    CSI 3.71
    rCSI 2.95%
    PRS 96.61
  • CD1c-positive myeloid dendritic cell CL0002399
    CSI 3.7
    rCSI 4.47%
    PRS 90.29
  • blood vessel endothelial cell CL0000071
    CSI 3.52
    rCSI 7.31%
    PRS 80.76
  • IgA plasma cell CL0000987
    CSI 3.35
    rCSI 3.43%
    PRS 89.28
  • contractile cell CL0000183
    CSI 3.18
    rCSI 9.38%
    PRS 82.79
  • promyelocyte CL0000836
    CSI 3.1
    rCSI 4.48%
    PRS 88.14
  • myeloid leukocyte CL0000766
    CSI 3.09
    rCSI 2.85%
    PRS 84.98
  • endothelial cell of vascular tree CL0002139
    CSI 3.01
    rCSI 16.47%
    PRS 80.09
  • alveolar macrophage CL0000583
    CSI 2.92
    rCSI 4.8%
    PRS 87.03
  • early lymphoid progenitor CL0000936
    CSI 2.77
    rCSI 2.44%
    PRS 88.13
  • mature microglial cell CL0002629
    CSI 2.65
    rCSI 11.03%
    PRS 83.74
  • stromal cell CL0000499
    CSI 2.54
    rCSI 7.13%
    PRS 78.94
  • group 3 innate lymphoid cell CL0001071
    CSI 2.42
    rCSI 1.82%
    PRS 88.85
  • elicited macrophage CL0000861
    CSI 2.41
    rCSI 2.21%
    PRS 90.3
  • inflammatory macrophage CL0000863
    CSI 2.4
    rCSI 4.1%
    PRS 95.19
  • astrocyte of the cerebral cortex CL0002605
    CSI 2.35
    rCSI 5.26%
    PRS 67.73
  • pulmonary artery endothelial cell CL1001568
    CSI 2.31
    rCSI 3.15%
    PRS 90.79
  • retinal blood vessel endothelial cell CL0002585
    CSI 2.04
    rCSI 3.25%
    PRS 86.95
  • lung endothelial cell CL1001567
    CSI 1.97
    rCSI 4.58%
    PRS 92.22
  • cerebral cortex endothelial cell CL1001602
    CSI 1.96
    rCSI 3.39%
    PRS 75.94
  • lung macrophage CL1001603
    CSI 1.92
    rCSI 4.3%
    PRS 89.9
  • CD14-positive, CD16-positive monocyte CL0002397
    CSI 1.91
    rCSI 2.51%
    PRS 92.5
  • T follicular helper cell CL0002038
    CSI 1.79
    rCSI 1.34%
    PRS 94.02
  • enteric smooth muscle cell CL0002504
    CSI 1.78
    rCSI 2.54%
    PRS 84.3
  • intermediate monocyte CL0002393
    CSI 1.74
    rCSI 2.62%
    PRS 88.48
  • endothelial cell of uterus CL0009095
    CSI 1.73
    rCSI 12.62%
    PRS 90.13
  • blood vessel smooth muscle cell CL0019018
    CSI 1.71
    rCSI 13.95%
    PRS 78.58
  • mononuclear phagocyte CL0000113
    CSI 1.7
    rCSI 3.74%
    PRS 86.94
  • differentiation-committed oligodendrocyte precursor CL4023059
    CSI 1.7
    rCSI 3.08%
    PRS 75.68
  • endocardial cell CL0002350
    CSI 1.68
    rCSI 8.04%
    PRS 79.76
  • microcirculation associated smooth muscle cell CL0008035
    CSI 1.66
    rCSI 4.82%
    PRS 82.88
  • mature B cell CL0000785
    CSI 1.66
    rCSI 1.44%
    PRS 91.59
  • myeloid dendritic cell, human CL0001057
    CSI 1.59
    rCSI 8.94%
    PRS 93.99
  • conjunctival epithelial cell CL1000432
    CSI 1.55
    rCSI 2.37%
    PRS 83.62
  • cardiac endothelial cell CL0010008
    CSI 1.55
    rCSI 6.24%
    PRS 83.8
  • neutrophil CL0000775
    CSI 1.53
    rCSI 8.56%
    PRS 83.69
  • tracheobronchial smooth muscle cell CL0019019
    CSI 1.49
    rCSI 2.62%
    PRS 88.09
  • promonocyte CL0000559
    CSI 1.37
    rCSI 2.35%
    PRS 88.37
  • renal interstitial pericyte CL1001318
    CSI 1.36
    rCSI 3.75%
    PRS 79.23
  • Hofbauer cell CL3000001
    CSI 1.36
    rCSI 2.57%
    PRS 90.35
  • effector CD4-positive, alpha-beta T cell CL0001044
    CSI 1.29
    rCSI 3.7%
    PRS 96.48
  • common dendritic progenitor CL0001029
    CSI 1.25
    rCSI 1.57%
    PRS 90.77
  • dendritic cell, human CL0001056
    CSI 1.24
    rCSI 1.91%
    PRS 90.76
  • antibody secreting cell CL0000946
    CSI 1.14
    rCSI 5.06%
    PRS 97.07
  • tissue-resident macrophage CL0000864
    CSI 1.1
    rCSI 5.17%
    PRS 92.96
  • endothelial cell of venule CL1000414
    CSI 1.05
    rCSI 9.31%
    PRS 89.81
  • endothelial cell of arteriole CL1000412
    CSI 0.92
    rCSI 5.12%
    PRS 90.94
  • myelocyte CL0002193
    CSI 0.89
    rCSI 5.88%
    PRS 93.92
  • vein endothelial cell of respiratory system CL4033008
    CSI 0.85
    rCSI 5.86%
    PRS 88.93
  • type EC enteroendocrine cell CL0000577
    CSI 0.81
    rCSI 2.86%
    PRS 86.52
  • vasa recta ascending limb cell CL1001131
    CSI 0.79
    rCSI 3.58%
    PRS 89.53
  • retinal ganglion cell CL0000740
    CSI 0.74
    rCSI 1.63%
    PRS 70.31
  • cardiac blood vessel endothelial cell CL0010006
    CSI 0.72
    rCSI 5.09%
    PRS 76.61
  • IgM plasma cell CL0000986
    CSI 0.69
    rCSI 3.1%
    PRS 95.12
  • CD14-positive, CD16-negative classical monocyte CL0002057
    CSI 0.57
    rCSI 3.44%
    PRS 92.4
  • decidual natural killer cell, human CL0002343
    CSI 0.48
    rCSI 4.86%
    PRS 92.94
  • immature innate lymphoid cell CL0001082
    CSI 0.46
    rCSI 14.19%
    PRS 98.36

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Ectonucleoside triphosphate diphosphohydrolase 1 ([ENTPD1](/details-gene/953)), also widely known as CD39, is a cell surface ectoenzyme that plays a pivotal role in regulating extracellular nucleotide concentrations. By sequentially hydrolyzing ATP and ADP to AMP, [ENTPD1](/details-gene/953) is a critical checkpoint in purinergic signaling, thereby modulating processes such as inflammation, immune responses, and thrombosis. Its function as a lymphoid cell activation antigen was first described in early cloning studies ([Link](https://pubmed.ncbi.nlm.nih.gov/7930580/)). The expression profile of [ENTPD1](/details-gene/953) indicates its profound importance in the immune system, with particularly high significance observed in regulatory T cell subsets, including [CD8-positive, CD28-negative, alpha-beta regulatory T cell](/details-cell/CL0000920), and various macrophage populations like [central nervous system macrophage](/details-cell/CL0000878). Clinically, it is associated with disorders of the corticospinal motor neurons ([OMIM: 601752](https://omim.org/entry/601752)). ## Cellular Roles and Expression Landscape The expression landscape of [ENTPD1](/details-gene/953) highlights its specialization in the immune system, where it acts as a key regulator of cellular activation and function. **Overall**, the gene exhibits its highest significance in both innate and adaptive immune cell populations. It is a defining marker for specific regulatory T cell subsets, including [CD8-positive, CD28-negative, alpha-beta regulatory T cell](/details-cell/CL0000920) (CSI: 20.81) and [CD4-positive, CD25-positive, alpha-beta regulatory T cell](/details-cell/CL0000792) (CSI: 4.90), underscoring its role in T cell-mediated immune suppression. Furthermore, [ENTPD1](/details-gene/953) is highly significant across a range of macrophage and myeloid lineages. This includes tissue-resident macrophages such as [central nervous system macrophage](/details-cell/CL0000878) (CSI: 13.06), [microglial cell](/details-cell/CL0000129) (CSI: 6.22), [colon macrophage](/details-cell/CL0009038) (CSI: 7.28), and specialized populations like [kidney interstitial alternatively activated macrophage](/details-cell/CL1000695) (CSI: 4.50). Its prominence in [granulocyte](/details-cell/CL0000094), [CD14-low, CD16-positive monocyte](/details-cell/CL0002396), [Langerhans cell](/details-cell/CL0000453), and [myeloid dendritic cell](/details-cell/CL0000782) further cements its broad role in innate immunity. Beyond these classic immune cells, [ENTPD1](/details-gene/953) is also significantly expressed in antibody-producing cells like [IgG plasma cell](/details-cell/CL0000985) and [plasmablast](/details-cell/CL0000980). The gene's activity is not strictly confined to hematopoietic cells, as evidenced by its significance in stromal cells like [bronchus fibroblast of lung](/details-cell/CL2000093) and [hepatic stellate cell](/details-cell/CL0000632), suggesting a role in tissue homeostasis and remodeling. This expression pattern is consistent with its function as an ectoenzyme that fine-tunes the extracellular environment shared by diverse cell types. ## Pathways and Molecular Function The molecular function of [ENTPD1](/details-gene/953) is centered on its enzymatic activity as a hydrolase acting on phosphate bonds in nucleotides. Gene Ontology annotations confirm its role in multiple catalytic activities, most notably [apyraise activity](/details-go/GO:0004050), [ADP phosphatase activity](/details-go/GO:0043262), and [ribonucleoside triphosphate phosphatase activity](/details-go/GO:0017111). These functions are integral to the biological processes of [blood coagulation](/details-go/GO:0007596) and [platelet aggregation](/details-go/GO:0070527), where the hydrolysis of pro-thrombotic ADP is a key regulatory step ([Link](https://doi.org/10.1016/s0925-5710(98)00080-2)). As an ectoenzyme, [ENTPD1](/details-gene/953) is primarily localized to the [plasma membrane](/details-go/GO:0005886), with specific enrichment in [caveolae](/details-go/GO:0005901), a localization directed by palmitoylation ([Link](https://doi.org/10.1074/jbc.275.3.2057)). This strategic positioning allows it to efficiently control purinergic signaling in the extracellular space. Reactome pathway analysis further contextualizes its function. [ENTPD1](/details-gene/953) is a central component of [metabolism of nucleotides](/details-pathway/R-HSA-15869), specifically [phosphate bond hydrolysis by NTPDase proteins](/details-pathway/R-HSA-8850843). Its high expression on immune cells aligns with its involvement in pathways like [cell recruitment (pro-inflammatory response)](/details-pathway/R-HSA-9664424) and its role in host-pathogen interactions, as highlighted by its inclusion in infectious disease pathways such as [Leishmania infection](/details-pathway/R-HSA-9658195). By converting pro-inflammatory extracellular ATP into AMP, which can be further converted to the immunosuppressive molecule adenosine, [ENTPD1](/details-gene/953) functions as a critical regulator of immune homeostasis. ## Research Directions The well-established role of [ENTPD1](/details-gene/953) as an immune checkpoint and its specific expression pattern provide fertile ground for further investigation, particularly in immunology and oncology. ### Proposed Hypotheses: 1. **Role in T Cell Exhaustion and Suppression:** The exceptionally high significance of [ENTPD1](/details-gene/953) in regulatory T cell subsets, including the [CD8-positive, CD28-negative, alpha-beta regulatory T cell](/details-cell/CL0000920), suggests it is a primary effector molecule for immune suppression. We hypothesize that in chronic inflammatory states and the tumor microenvironment, [ENTPD1](/details-gene/953) activity on Tregs is a dominant mechanism for generating immunosuppressive adenosine, leading to the exhaustion and dysfunction of cytotoxic effector T cells. 2. **Modulation of Macrophage-Mediated Fibrosis:** The notable significance of [ENTPD1](/details-gene/953) in both [kidney interstitial alternatively activated macrophage](/details-cell/CL1000695) and stromal cells like [hepatic stellate cell](/details-cell/CL0000632) points towards a role in tissue repair and fibrosis. We hypothesize that [ENTPD1](/details-gene/953)-mediated purinergic signaling is a key axis of communication between M2-like macrophages and fibroblasts, where the clearance of ATP and generation of adenosine promotes a pro-fibrotic phenotype in response to tissue injury. ### Experimental Approach: To test the first hypothesis regarding T cell suppression, a robust in vitro and in vivo approach is required. One could generate [ENTPD1](/details-gene/953) knockout (KO) regulatory T cells using CRISPR-Cas9 editing of primary human CD4+ T cells followed by differentiation into Tregs. These KO Tregs and wild-type controls would then be co-cultured with autologous CFSE-labeled CD8+ effector T cells. The primary readouts would be effector T cell proliferation (via CFSE dilution by flow cytometry) and cytokine production (e.g., IFN-gamma by ELISA). It would be crucial to also measure ATP, ADP, AMP, and adenosine levels in the culture supernatant using liquid chromatography-mass spectrometry (LC-MS) to directly link changes in T cell function to alterations in purinergic metabolite concentrations. ### Therapeutic Potential: [ENTPD1](/details-gene/953) represents a highly attractive therapeutic target, particularly in oncology. As a cell surface enzyme that initiates an immunosuppressive cascade, its **inhibition** is a promising strategy to restore anti-tumor immunity. By blocking the conversion of ATP to AMP, inhibitors would prevent the subsequent generation of adenosine by CD73, thereby reducing the suppression of T cells and NK cells in the tumor microenvironment. Because it is an extracellular protein, it is highly amenable to targeting with monoclonal antibodies, small molecule inhibitors, or antibody-drug conjugates. This places [ENTPD1](/details-gene/953) among the next generation of immune checkpoint inhibitors being developed for cancer immunotherapy.

Genular Protein ID: 469578330

Symbol: ENTP1_HUMAN

Name: N/A

UniProtKB Accession Codes:

P49961 A9Z1X8 B4DWB9 B4E1X1 B7Z599 G3XAF6 Q5T561 Q5T562 Q86VV3 Q9UQQ9 Q9Y3Q9

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 4 CDD 1 CORUM 1 CPTAC 1 CPTC 1 CTD 1 ChEBI 92 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EC 1 EMBL 15 Ensembl 4 ExpressionAtlas 1 GO 21 Gene3D 2 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyConnect 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 1 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PIR 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 6 RNAct 1 Reactome 2 RefSeq 12 Rhea 36 SABIO-RK 1 SMR 1 STRING 1 SignaLink 1 SwissPalm 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 7930580

Title: The CD39 lymphoid cell activation antigen. Molecular cloning and structural characterization.

PubMed ID: 7930580

PubMed ID: 8955160

Title: Identification and characterization of CD39/vascular ATP diphosphohydrolase.

PubMed ID: 8955160

DOI: 10.1074/jbc.271.51.33116

PubMed ID: 10405171

Title: The cDNA cloning of human placental ecto-ATP diphosphohydrolases I and II.

PubMed ID: 10405171

DOI: 10.1016/s0014-5793(99)00751-6

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15164054

Title: The DNA sequence and comparative analysis of human chromosome 10.

PubMed ID: 15164054

DOI: 10.1038/nature02462

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 8529670

Title: Purification and properties of human placental ATP diphosphohydrolase.

PubMed ID: 8529670

DOI: 10.1111/j.1432-1033.1995.066_c.x

PubMed ID: 9846014

Title: Placental ecto-ATP diphosphohydrolase: its structural feature distinct from CD39, localization and inhibition on shear-induced platelet aggregation.

PubMed ID: 9846014

DOI: 10.1016/s0925-5710(98)00080-2

PubMed ID: 8996251

Title: Loss of ATP diphosphohydrolase activity with endothelial cell activation.

PubMed ID: 8996251

DOI: 10.1084/jem.185.1.153

PubMed ID: 8626624

Title: CD39 is an ecto-(Ca2+,Mg2+)-apyrase.

PubMed ID: 8626624

DOI: 10.1074/jbc.271.17.10391

PubMed ID: 10636909

Title: Palmitoylation targets CD39/endothelial ATP diphosphohydrolase to caveolae.

PubMed ID: 10636909

DOI: 10.1074/jbc.275.3.2057

PubMed ID: 19159218

Title: Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry.

PubMed ID: 19159218

DOI: 10.1021/pr8008012

PubMed ID: 24482476

Title: Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders.

PubMed ID: 24482476

DOI: 10.1126/science.1247363

Sequence Information:

  • Length: 510
  • Mass: 57965
  • Checksum: BAD87D2499649159
  • Sequence:
    • MEDTKESNVK TFCSKNILAI LGFSSIIAVI ALLAVGLTQN KALPENVKYG IVLDAGSSHT 
SLYIYKWPAE KENDTGVVHQ VEECRVKGPG ISKFVQKVNE IGIYLTDCME RAREVIPRSQ 
HQETPVYLGA TAGMRLLRME SEELADRVLD VVERSLSNYP FDFQGARIIT GQEEGAYGWI 
TINYLLGKFS QKTRWFSIVP YETNNQETFG ALDLGGASTQ VTFVPQNQTI ESPDNALQFR 
LYGKDYNVYT HSFLCYGKDQ ALWQKLAKDI QVASNEILRD PCFHPGYKKV VNVSDLYKTP 
CTKRFEMTLP FQQFEIQGIG NYQQCHQSIL ELFNTSYCPY SQCAFNGIFL PPLQGDFGAF 
SAFYFVMKFL NLTSEKVSQE KVTEMMKKFC AQPWEEIKTS YAGVKEKYLS EYCFSGTYIL 
SLLLQGYHFT ADSWEHIHFI GKIQGSDAGW TLGYMLNLTN MIPAEQPLST PLSHSTYVFL 
MVLFSLVLFT VAIIGLLIFH KPSYFWKDMV