Alternative titles; symbols
HGNC Approved Gene Symbol: ENTPD5
Cytogenetic location: 14q24.3 Genomic coordinates (GRCh38): 14:73,955,329-74,019,288 (from NCBI)
Nucleoside triphosphatases (NTPases) are divalent cation-dependent transmembrane glycoproteins that hydrolyze extracellular nucleoside tri- and/or diphosphates. NTPases are characterized by the presence of 4 motifs known as apyrase-conserved regions (ACRs). Chadwick et al. (1998) identified cDNAs encoding a mouse NTPase, which they symbolized MNTPase. By searching an EST database for sequences similar to that of MNTPase, Chadwick and Frischauf (1998) identified cDNAs corresponding to 2 human genes, CD39L2 (603160) and CD39L4. The coding regions of the mouse and human CD39L4 genes share 88% nucleotide sequence identity. The predicted 428-amino acid CD39L4 protein contains all 4 ACRs, a single N-terminal transmembrane segment, and a large extracellular C-terminal domain. Northern blot analysis revealed that CD39L4 was expressed as a 4.8-kb mRNA in all tissues tested. Several smaller bands were also observed in tissues with the strongest CD39L4 expression.
Fang et al. (2010) showed that fluorescence-tagged Entpd5 localized with an endoplasmic reticulum (ER) marker in mouse embryonic fibroblasts (MEFs).
By PCR analysis of cDNA libraries, Mulero et al. (1999) detected CD39L4 only in macrophages. Functional and Western blot analysis determined that the ADPase and nucleotide disphosphatase activity of the secreted 51-kD protein is enhanced by the presence of divalent cations. Glycosidase or tunicamycin treatment (Mulero et al., 2000) reduced the size of the protein to the predicted 46 kD and reduced the amount secreted as well; unlike CD39L3 (603161), however, it did not impair enzymatic activity.
Fang et al. (2010) showed that in vitro-translated ENTPD5 hydrolyzed UDP and GDP, but not other nucleotides. Deletion of Pten (601728) in MEFs results in activation of the PI3 kinase (see 601232)/Akt (see 164730) pathway, which promotes cell growth and survival, with a concomitant increase in protein translation. Fang et al. (2010) showed that Entpd5 expression and ATP hydrolysis were significantly elevated in Pten -/- MEFs. Mass spectrometric analysis identified ENTPD5, UMP/CMP kinase-1 (CMPK1; 191710), and adenylate kinase-1 (AK1; 103000) as components of an ATP hydrolysis cycle in HeLa cells. Within this cycle, ENTPD5 provided the critical UMP or GMP cofactors for hydrolysis of ATP to AMP, and lack of any of the 3 enzymes compromised ATP hydrolysis. Knockdown of Entpd5 in Pten -/- MEFs increased expression of markers of ER stress, reduced protein N-glycosylation, and reduced lactate production. Western blot, immunohistochemical, and microarray analyses showed that upregulation of ENTPD5 correlated with AKT activation in human prostate cancer cell lines and primary prostate tumor samples. Knockdown of ENTPD5 in LNCaP prostate cancer cells reduced tumor growth in nude mice. Fang et al. (2010) concluded that ENTPD5 has a critical role in N-glycosylation and contributes to the Warburg effect, i.e., elevated lactate production under aerobic conditions, in tumor cells.
By fluorescence in situ hybridization and linkage analysis, Chadwick et al. (1998) mapped the MNTPase gene to mouse chromosome 12 in a region showing homology of synteny with human chromosome 14q. By analysis of radiation hybrid and somatic cell hybrid panels, Chadwick and Frischauf (1998) confirmed that CD39L4 is located on human chromosome 14q24. Chadwick and Frischauf (1998) concluded that CD39L4 is the human homolog of MNTPase.
Chadwick, B. P., Frischauf, A.-M. The CD39-like gene family: identification of three new human members (CD39L2, CD39L3, and CD39L4), their murine homologues, and a member of the gene family from Drosophila melanogaster. Genomics 50: 357-367, 1998. [PubMed: 9676430] [Full Text: https://doi.org/10.1006/geno.1998.5317]
Chadwick, B. P., Williamson, J., Sheer, D., Frischauf, A.-M. cDNA cloning and chromosomal mapping of a mouse gene with homology to NTPases. Mammalian Genome 9: 162-164, 1998. [PubMed: 9457681] [Full Text: https://doi.org/10.1007/s003359900710]
Fang, M., Shen, Z., Huang, S., Zhao, L., Chen, S., Mak, T. W., Wang, X. The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway. Cell 143: 711-724, 2010. [PubMed: 21074248] [Full Text: https://doi.org/10.1016/j.cell.2010.10.010]
Mulero, J. J., Yeung, G., Nelken, S. T., Bright, J. M., McGowan, D. W., Ford, J. E. Biochemical characterization of CD39L4. Biochemistry 39: 12924-12928, 2000. [PubMed: 11041857] [Full Text: https://doi.org/10.1021/bi000960y]
Mulero, J. J., Yeung, G., Nelken, S. T., Ford, J. E. CD39-L4 is a secreted human apyrase, specific for the hydrolysis of nucleoside diphosphates. J. Biol. Chem. 274: 20064-20067, 1999. [PubMed: 10400613] [Full Text: https://doi.org/10.1074/jbc.274.29.20064]