Disease relevance of ENTPD1

• Ecto-ATP diphosphohydrolase/CD39 is overexpressed in differentiated human melanomas [1].
• Ectonucleotidases of CD39 family modulate vascular inflammation and thrombosis in transplantation [2].
• Administration of soluble CD39 or targeted expression may have future therapeutic application in transplantation-associated and other vascular diseases [2].
• High-tissue mRNA levels of CD39 significantly correlated with better long-term survival after tumor resection in patients with pancreatic cancer [3].
• Our data suggest distinct roles for CD39 and P2-purinergic signaling in both tissue remodeling and fibrogenesis with respect to human pancreatic diseases [3].

High impact information on ENTPD1

• Nucleotides are rapidly converted to adenosine by a family of ecto-nucleotidases including CD39 and CD73 [4].
• An additional thromboregulatory factor, ATP diphosphohydrolase (ATPDase; designated as EC 3.6.1.5) is also expressed by quiescent EC, and has the capacity to degrade the extracellular inflammatory mediators ATP and ADP to AMP, thereby inhibiting platelet activation and modulating vascular thrombosis [5].
• Because platelet activation and aggregation are important components of the hemostatic changes that accompany inflammatory diseases, we suggest that the loss of vascular ATPDase may be crucial for the progression of vascular injury [5].
• We describe here that the antithrombotic effects of the ATPDase, like heparan sulfate and thrombomodulin, are lost after EC activation, both in vitro and in vivo [5].
• CD39, the major vascular nucleoside triphosphate diphosphohydrolase (NTPDase), converts ATP and ADP to AMP, which is further degraded to the antithrombotic and anti-inflammatory mediator adenosine [6].

Chemical compound and disease context of ENTPD1

• This suggests that NTPDase (nucleoside triphosphate diphosphohydrolase) could exert a cardioprotective action by reducing ATP-mediated norepinephrine release, thereby offering a novel therapeutic approach to myocardial ischemia and its consequences [7].
• Total RNA was isolated from cultured glioma C6 cells and the cDNA was analyzed by Real Time-PCR with primers for the NTPDase family [8].

Biological context of ENTPD1

• Database searches with sequences of one group of clones from the selected cDNA library showed strong amino acid homology to the lymphoid cell activation antigen CD39, an ecto-apyrase gene from human and mouse [9].
• The human CD39-like-1 gene (CD39L1) was isolated from a selected cDNA library enriched for transcripts from regions of human Chromosome (Chr) 9q [9].
• However, this hydrolysis ratio is intermediate between that observed for the ecto-ATPases and the CD39 ecto-apyrases (L. Plesner, Int. Rev. Cytol. 158 (1995) 141-214) [10].
• We and others have documented that NTPDase1 (CD39, 78 kd) hydrolyzes both triphosphonucleosides and diphosphonucleosides and thereby terminates platelet aggregation responses to adenosine diphosphate (ADP) [11].
• Upregulation of CD39/NTPDases and P2 receptors in human pancreatic disease [3].

Anatomical context of ENTPD1

• Microarray RNA analysis revealed an increase in CD73 and ecto-apyrase CD39 in hypoxic epithelial cells [12].
• CD39 is localized in caveolae, which are plasma membrane invaginations with distinct lipid composition, similar to dynamic lipid microdomains, called rafts [13].
• Since CD39 is known to regulate homotypic adhesion and, supposedly, affects the disaggregation step, we suggest that overexpression of CD39 may enable tumor cells to reduce contacts with T-lymphocytes and escape from immunological recognition [1].
• By quantitative real-time PCR, we identified Entpd2 (CD39L1) as the dominant Entpd gene expressed by rat hippocampal, cortical and cerebellar astrocytes [14].
• Stage-specific expression of P2Y receptors, ecto-apyrase, and ecto-5'-nucleotidase in myeloid leukocytes [15].

Associations of ENTPD1 with chemical compounds

• CD39 (ecto-nucleoside triphosphate diphosphohydrolase-1; E-NTPDase1) is a plasma membrane ecto-enzyme that regulates purinergic receptor signaling by controlling the levels of extracellular nucleotides [13].
• These data suggest a functional link between the localization of CD39 in cholesterol-rich domains of the membrane and its role in thromboregulation [13].
• Ecto-apyrase activity was modestly increased with differentiation of myeloid progenitors with either phorbol 12-myristate 13-acetate (PMA) or dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) [15].
• The results demonstrate that CD39 is a novel cell surface glycoprotein with unusual structural characteristics [16].
• The nucleotide sequence of human CD39 includes an open reading frame encoding a putative 510 amino acid protein with six potential N-linked glycosylation sites, 11 Cys residues, and two potential transmembrane regions [16].
• Because ectoapyrase (CD39) and ecto-5'-nucleotidase (CD73) are rate limiting for extracellular adenosine generation, we examined their contribution to ALI [17].

Regulatory relationships of ENTPD1

• Therefore, CD39 regulates extracellular ATP concentrations and may be an important modulator of purinergic receptor activity in vascular endothelial cells [18].
• CD39 also decreased the extent of apoptosis triggered by putative type-2X purinergic (P2X7) receptors in response to high concentrations of extracellular ATP in vitro [19].
• We conclude that CD39 associations with RanBPM have the potential to regulate NTPDase catalytic activity [20].

Other interactions of ENTPD1

• Co-localization of P2Y1 receptor and NTPDase1/CD39 within caveolae in human placenta [21].
• Using polarized Madin-Darby canine kidney (MDCK) cells and caveolin-1 gene-disrupted mice, we show that caveolae are not essential either for the enzymatic activity of CD39 or for its targeting to plasma membrane [13].
• Reversal of thrombin-induced deactivation of CD39/ATPDase in endothelial cells by HMG-CoA reductase inhibition: effects on Rho-GTPase and adenosine nucleotide metabolism [22].
• By contrast, only a few antigens increased in density, including CD 39, A96/G8 and SC9, on both cell lines, CD 22 on JOK-1, and CD 21 on Daudi [23].
• Characterization of disulfide bonds in human nucleoside triphosphate diphosphohydrolase 3 (NTPDase3): implications for NTPDase structural modeling [24].

Analytical, diagnostic and therapeutic context of ENTPD1

• DC expressed the ecto-apyrase CD39 and the ecto-5'-nucleotidase CD73 as demonstrated by RT-PCR [25].
• Over-expression of CD39 at sites of vascular injury and inflammation by adenoviral vectors, by transgenesis or by the use of pharmacological modalities with soluble derivatives has been shown to have major potential in several animal models tested to date [26].
• Ecto-nucleotidase biochemical activity of CD39 is lost at sites of acute vascular injury, such as in ischemia reperfusion and immune graft rejection [26].
• These thromboregulatory manifestations in hCD39 transgenic mice suggest important therapeutic potential in clinical vascular disease and in the control of serious thrombotic events that compromise the survival of porcine xenografts in primates [6].
• The CD39 lymphoid cell activation antigen. Molecular cloning and structural characterization [16].

References