Details for: ENPP3

Gene ID: 5169

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: ENPP3

Ensembl ID: ENSG00000154269

Description: ectonucleotide pyrophosphatase/phosphodiesterase 3

Cell Significance Landscape

Associated with

Significant Cells

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

  • secretory cell CL0000151
    CSI 4.15
    rCSI 4.33%
    PRS 99.37
  • duct epithelial cell CL0000068
    CSI 4.08
    rCSI 5.96%
    PRS 99.82
  • epithelial cell CL0000066
    CSI 2.99
    rCSI 4.6%
    PRS 96.82
  • ciliated cell CL0000064
    CSI 2.6
    rCSI 4.21%
    PRS 97.88
  • epithelial cell of proximal tubule CL0002306
    CSI 2.47
    rCSI 6.04%
    PRS 97.95
  • basophil CL0000767
    CSI 2.02
    rCSI 4.27%
    PRS 99.29
  • ciliated columnar cell of tracheobronchial tree CL0002145
    CSI 1.52
    rCSI 3.47%
    PRS 97.83
  • eosinophil CL0000771
    CSI 0.9
    rCSI 5.92%
    PRS 99.5

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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  • Node Color (Target Cell CSI, relative to current network):
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    • 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 [ENPP3](/details-gene/5169) (Ectonucleotide Pyrophosphatase/Phosphodiesterase 3), also widely known as CD203c, is a type II transmembrane glycoprotein that functions as an ectoenzyme. It catalyzes the hydrolysis of extracellular nucleotides, including ATP, contributing to the regulation of purinergic signaling. Its molecular functions include ATP diphosphatase and phosphodiesterase I activities ([GO:0047693](https://www.ebi.ac.uk/QuickGO/term/GO:0047693), [GO:0004528](https://www.ebi.ac.uk/QuickGO/term/GO:0004528)). **Overall**, expression data reveals that [ENPP3](/details-gene/5169) is a highly significant gene in various [secretory](/details-cell/CL0000151) and [epithelial cells](/details-cell/CL0000066), such as those in ducts and the proximal tubule. It is also a well-established and clinically relevant marker for [basophils](/details-cell/CL0000767), where its expression is upregulated upon activation, playing a role in the modulation of allergic and inflammatory responses. Its clinical association is documented in OMIM ([602182](https://omim.org/entry/602182)). ## Cellular Roles and Expression Landscape The expression profile of [ENPP3](/details-gene/5169) highlights its dual role in both epithelial barrier/secretory functions and innate immunity. **Overall**, the gene shows the highest significance in [secretory cells](/details-cell/CL0000151) (CSI: 4.15) and [duct epithelial cells](/details-cell/CL0000068) (CSI: 4.08). Its strong presence is also noted in general [epithelial cells](/details-cell/CL0000066), [ciliated cells](/details-cell/CL0000064), and specialized [epithelial cells of the proximal tubule](/details-cell/CL0002306). This pattern suggests a fundamental role for [ENPP3](/details-gene/5169) in tissues involved in transport and secretion, likely through the modulation of extracellular nucleotide concentrations. In the hematopoietic system, [ENPP3](/details-gene/5169) is a defining marker for [basophils](/details-cell/CL0000767) (CSI: 2.02) and is also expressed in [eosinophils](/details-cell/CL0000771). Its identity as a key basophil activation marker has been confirmed by research showing that the antibody 97A6, which recognizes activated basophils, targets [ENPP3](/details-gene/5169) (also known as CD203c) [Link](https://doi.org/10.1182/blood.v97.10.3303). This specific expression pattern has made it a valuable tool in allergy diagnostics [Link](https://doi.org/10.1159/000077351). ## Pathways and Molecular Function Functionally, [ENPP3](/details-gene/5169) is an ectoenzyme localized to the external side of the plasma membrane ([GO:0009897](https://www.ebi.ac.uk/QuickGO/term/GO:0009897)), positioning it to regulate extracellular signaling molecules. Its primary role involves the catabolism of nucleoside triphosphates ([GO:0009143](https://www.ebi.ac.uk/QuickGO/term/GO:0009143)) and the hydrolysis of pyrophosphate bonds. This enzymatic activity is central to its involvement in ATP metabolic processes ([GO:0046034](https://www.ebi.ac.uk/QuickGO/term/GO:0046034)) and phosphate ion homeostasis ([GO:0055062](https://www.ebi.ac.uk/QuickGO/term/GO:0055062)). The functional annotations point towards a significant immunomodulatory role. [ENPP3](/details-gene/5169) is implicated in the negative regulation of both [basophil](/details-cell/CL0000767) activation ([GO:0002276](https://www.ebi.ac.uk/QuickGO/term/GO:0002276)) and mast cell activation ([GO:0033007](https://www.ebi.ac.uk/QuickGO/term/GO:0033007)). This suggests that by degrading extracellular ATP, a potent pro-inflammatory signal, [ENPP3](/details-gene/5169) acts as a brake on allergic and inflammatory responses. The gene is also annotated in broader metabolic pathways, such as the metabolism of vitamins and cofactors ([R-HSA-196854](https://reactome.org/content/detail/R-HSA-196854)), indicating a wider role in cellular metabolism beyond purinergic signaling. ## Research Directions The dual role of [ENPP3](/details-gene/5169) as an activation marker and a negative regulator of basophil function presents a compelling area for further investigation. Its high expression in diverse epithelial tissues also warrants deeper exploration. ### Proposed Hypotheses 1. **Hypothesis:** The upregulation of [ENPP3](/details-gene/5169) on the surface of activated [basophils](/details-cell/CL0000767) constitutes a negative feedback mechanism. By rapidly hydrolyzing extracellular ATP released during degranulation, it serves to limit the duration and intensity of the local allergic response, preventing excessive inflammation. 2. **Hypothesis:** In secretory and ductal epithelia, [ENPP3](/details-gene/5169) regulates fluid and electrolyte secretion by controlling the availability of ATP for P2Y and P2X purinergic receptors. Its activity may be a key factor in maintaining luminal homeostasis in organs like the kidneys and salivary glands. ### Experimental Approach To test the hypothesis that [ENPP3](/details-gene/5169) acts as a negative feedback regulator in allergic responses, one could utilize primary human [basophils](/details-cell/CL0000767) or a suitable cell line. A CRISPR-Cas9 knockout or siRNA-mediated knockdown of [ENPP3](/details-gene/5169) would be performed. Control and [ENPP3](/details-gene/5169)-deficient cells would then be stimulated with an IgE-crosslinking agent. The functional consequences would be assessed by measuring key markers of activation, such as the rate and extent of degranulation (via histamine or beta-hexosaminidase release assays) and the production of pro-inflammatory cytokines (e.g., IL-4, IL-13) by ELISA or flow cytometry. If the hypothesis is correct, [ENPP3](/details-gene/5169)-deficient [basophils](/details-cell/CL0000767) should exhibit a prolonged and exaggerated response compared to wild-type controls. ### Therapeutic Potential Given its role as an ectoenzyme that negatively regulates basophil and mast cell activation, [ENPP3](/details-gene/5169) presents an interesting therapeutic target for allergic diseases like asthma and atopic dermatitis. Rather than inhibition, a therapeutic strategy could focus on **activation** or potentiation of its enzymatic activity. A small molecule agonist that enhances the ATP-hydrolyzing function of [ENPP3](/details-gene/5169) could potentially serve as a novel anti-allergic agent by dampening the purinergic signaling that drives inflammation. Its cell-surface location makes it highly accessible to such pharmacological intervention.

Genular Protein ID: 3679958556

Symbol: ENPP3_HUMAN

Name: Phosphodiesterase I/nucleotide pyrophosphatase 3

UniProtKB Accession Codes:

O14638 Q5JTL3

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 2 CTD 1 ChEBI 67 ChEMBL 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EC 6 EMBL 6 Ensembl 2 ExpressionAtlas 1 GO 25 Gene3D 3 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 8 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 2 PDBsum 2 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 Reactome 1 RefSeq 1 Rhea 19 SABIO-RK 1 SMART 3 SMR 1 STRING 1 SUPFAM 3 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 9344668

Title: Molecular cloning and chromosomal localization of PD-Ibeta (PDNP3), a new member of the human phosphodiesterase I genes.

PubMed ID: 9344668

DOI: 10.1006/geno.1997.4949

PubMed ID: 17974005

Title: The full-ORF clone resource of the German cDNA consortium.

PubMed ID: 17974005

DOI: 10.1186/1471-2164-8-399

PubMed ID: 14574404

Title: The DNA sequence and analysis of human chromosome 6.

PubMed ID: 14574404

DOI: 10.1038/nature02055

PubMed ID: 11342463

Title: The basophil activation marker defined by antibody 97A6 is identical to the ectonucleotide pyrophosphatase/phosphodiesterase 3.

PubMed ID: 11342463

DOI: 10.1182/blood.v97.10.3303

PubMed ID: 12846830

Title: Hydrolysis of diadenosine polyphosphates by nucleotide pyrophosphatases/phosphodiesterases.

PubMed ID: 12846830

DOI: 10.1046/j.1432-1033.2003.03674.x

PubMed ID: 15072822

Title: Expression and localization of ecto-nucleotide pyrophosphatase/phosphodiesterase I-1 (E-NPP1/PC-1) and -3 (E-NPP3/CD203c/PD-Ibeta/B10/gp130(RB13-6)) in inflammatory and neoplastic bile duct diseases.

PubMed ID: 15072822

DOI: 10.1016/j.canlet.2003.11.002

PubMed ID: 15031605

Title: The basophil-specific ectoenzyme E-NPP3 (CD203c) as a marker for cell activation and allergy diagnosis.

PubMed ID: 15031605

DOI: 10.1159/000077351

PubMed ID: 29717535

Title: Structural basis for nucleotide recognition by the ectoenzyme CD203c.

PubMed ID: 29717535

DOI: 10.1111/febs.14489

Sequence Information:

  • Length: 875
  • Mass: 100124
  • Checksum: 629D2E33B4C45196
  • Sequence:
    • MESTLTLATE QPVKKNTLKK YKIACIVLLA LLVIMSLGLG LGLGLRKLEK QGSCRKKCFD 
ASFRGLENCR CDVACKDRGD CCWDFEDTCV ESTRIWMCNK FRCGETRLEA SLCSCSDDCL 
QRKDCCADYK SVCQGETSWL EENCDTAQQS QCPEGFDLPP VILFSMDGFR AEYLYTWDTL 
MPNINKLKTC GIHSKYMRAM YPTKTFPNHY TIVTGLYPES HGIIDNNMYD VNLNKNFSLS 
SKEQNNPAWW HGQPMWLTAM YQGLKAATYF WPGSEVAING SFPSIYMPYN GSVPFEERIS 
TLLKWLDLPK AERPRFYTMY FEEPDSSGHA GGPVSARVIK ALQVVDHAFG MLMEGLKQRN 
LHNCVNIILL ADHGMDQTYC NKMEYMTDYF PRINFFYMYE GPAPRIRAHN IPHDFFSFNS 
EEIVRNLSCR KPDQHFKPYL TPDLPKRLHY AKNVRIDKVH LFVDQQWLAV RSKSNTNCGG 
GNHGYNNEFR SMEAIFLAHG PSFKEKTEVE PFENIEVYNL MCDLLRIQPA PNNGTHGSLN 
HLLKVPFYEP SHAEEVSKFS VCGFANPLPT ESLDCFCPHL QNSTQLEQVN QMLNLTQEEI 
TATVKVNLPF GRPRVLQKNV DHCLLYHREY VSGFGKAMRM PMWSSYTVPQ LGDTSPLPPT 
VPDCLRADVR VPPSESQKCS FYLADKNITH GFLYPPASNR TSDSQYDALI TSNLVPMYEE 
FRKMWDYFHS VLLIKHATER NGVNVVSGPI FDYNYDGHFD APDEITKHLA NTDVPIPTHY 
FVVLTSCKNK SHTPENCPGW LDVLPFIIPH RPTNVESCPE GKPEALWVEE RFTAHIARVR 
DVELLTGLDF YQDKVQPVSE ILQLKTYLPT FETTI