CD39-L4 Is a Secreted Human Apyrase, Specific for the Hydrolysis of Nucleoside Diphosphates

Mulero, Julio J.; Yeung, George; Nelken, Sarah T.; Ford, J. E.

doi:10.1074/jbc.274.29.20064

Cited by 106 publications

(107 citation statements)

References 21 publications

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“…Taken together, our findings show that Entpd5 is a previously unappreciated and essential factor for bone formation. Entpd5 encodes a secreted ectonucleoside triphosphate/diphosphohydrolase that preferably hydrolyzes extracellular nucleotide diphosphates (21,22) into nucleotide monophosphates and inorganic phosphate. Circulating extracellular nucleotides are known to be important purinergic signaling molecules that can generate a variety of physiological responses (25,26).…”

Section: Discussionmentioning

confidence: 99%

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Entpd5 is essential for skeletal mineralization and regulates phosphate homeostasis in zebrafish

Huitema

Apschner

Logister

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Bone mineralization is an essential step during the embryonic development of vertebrates, and bone serves vital functions in human physiology. To systematically identify unique gene functions essential for osteogenesis, we performed a forward genetic screen in zebrafish and isolated a mutant, no bone (nob), that does not form any mineralized bone. Positional cloning of nob identified the causative gene to encode ectonucleoside triphosphate/ diphosphohydrolase 5 (entpd5); analysis of its expression pattern demonstrates that entpd5 is specifically expressed in osteoblasts. An additional mutant, dragonfish (dgf), exhibits ectopic mineralization in the craniofacial and axial skeleton and encodes a loss-offunction allele of ectonucleotide pyrophosphatase phosphodiesterase 1 (enpp1). Intriguingly, generation of double-mutant nob/ dgf embryos restored skeletal mineralization in nob mutants, indicating that mechanistically, Entpd5 and Enpp1 act as reciprocal regulators of phosphate/pyrophosphate homeostasis in vivo. Consistent with this, entpd5 mutant embryos can be rescued by high levels of inorganic phosphate, and phosphate-regulating factors, such as fgf23 and npt2a, are significantly affected in entpd5 mutant embryos. Our study demonstrates that Entpd5 represents a previously unappreciated essential player in phosphate homeostasis and skeletal mineralization.

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Section: Discussionmentioning

confidence: 99%

“…Entpd5 and Enpp1 both hydrolyze extracellular nucleotide derivatives (7,10,11,21,22), with Entpd5 generating inorganic phosphate (21,22) and Enpp1 generating pyrophosphate (7). We therefore examined the epistatic relationship of both genes.…”

Section: Sequencing (mentioning

confidence: 99%

Entpd5 is essential for skeletal mineralization and regulates phosphate homeostasis in zebrafish

Huitema

Apschner

Logister

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…7 NTPDases may be either membrane-bound ectoenzymes or soluble enzymes. 5,35 The best-characterized ecto-NTPDase is NTPDase1 (or CD39). NTPDase1 is a vascular ecto-nucleotidase that is a critical regulator of platelet aggregation through hydrolysis of the platelet nucleotide receptor agonist ADP.…”

Section: Discussionmentioning

confidence: 99%

The ecto-nucleoside triphosphate diphosphohydrolase NTPDase2/CD39L1 is expressed in a novel functional compartment within the liver

et al. 2002

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Extracellular nucleotides regulate diverse biological functions and are important in the regulation of liver metabolism, hepatic blood flow, and bile secretion. Ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) hydrolyze extracellular nucleotides and are therefore potential regulators of nucleotide-mediated signaling. To examine this, we have contrasted the structural and functional distributions of the 2 characterized membranebound NTPDases NTPDase1 and NTPDase2 within the rat liver. Hepatic expression of NTPDase2 was determined and contrasted to NTPDase1 using confocal immunofluorescence, immunoelectron microscopy, reverse-transcription polymerase chain reaction, Northern blot analysis, Western blot analysis, and functional assays. NTPDase2 was expressed in the periportal region surrounding intrahepatic bile ducts, whereas NTPDase1 was found in hepatic arteries, portal veins, and hepatic central veins, consistent with its known vascular distribution. Functional and molecular expression of NTPDase2 was shown in portal fibroblasts near basolateral membranes of bile duct epithelia. In conclusion, NTPDase2 is expressed in a novel cellular compartment surrounding intrahepatic bile ducts, namely portal fibroblasts. This distribution may represent a previously unrecognized mechanism for regulation of nucleotide signaling in bile ducts and other epithelia. (HEPATOLOGY 2002;36:1135-1144 B ile duct epithelia, or cholangiocytes, secrete fluid and electrolytes in response to extracellular nucleotides through activation of specific P2Y nucleotide receptors. [1][2][3][4] Cholangiocytes express both apical and basolateral P2Y receptors but basolateral cholangiocyte P2Y receptors are activated only by nonhydrolyzable nucleotide analogues, 4 and there is functional evidence for a distinct pathway for degradation of nucleotides at the basolateral membrane. 3 These observations suggest that nucleotide hydrolysis is a primary means to regulate cholangiocyte P2Y receptor activation at the basolateral membrane.Hydrolysis of extracellular nucleotides may largely occur through proteins belonging to a family of recently identified ecto-nucleoside triphosphate diphosphohydrolases (NTPDases). 5-7 Several of these enzymes have been cloned and characterized at the molecular level. NTPDase1 has been identified as a vascular NTPDase expressed at endothelial and leiomyocyte plasma membranes 8,9 and is a critical regulator of platelet aggregation. 10 NTPDase2 is an NTPDase that is expressed by epithelial organs and cell lines, 11,12 but its specific physiologic function is unknown.Here we show that NTPDase2 is expressed in a newly described cellular population of liver cells, that of portal fibroblasts. By interacting with cholangiocyte nucleotide signaling processes, portal fibroblasts may represent a novel functional compartment of liver cells, thus showing a distinct functional interaction between liver epithelia and stromal cells. Materials and MethodsAnimals and Materials. Male Sprague-Dawley rats (180-250 g) were used for al...

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“…Boldface letters indicate strongly preferred residues. [107]. A soluble ER-located form of NTPDase5 purified from bovine liver (ER-UDPase) has been suggested to promote reglycosylation reactions involved in glycoprotein folding and quality control in the ER [77].…”

Section: General Molecular Propertiesmentioning

confidence: 99%

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

876

922

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Ecto-nucleotidases play a pivotal role in purinergic signal transmission. They hydrolyze extracellular nucleotides and thus can control their availability at purinergic P2 receptors. They generate extracellular nucleosides for cellular reuptake and salvage via nucleoside transporters of the plasma membrane. The extracellular adenosine formed acts as an agonist of purinergic P1 receptors. They also can produce and hydrolyze extracellular inorganic pyrophosphate that is of major relevance in the control of bone mineralization. This review discusses and compares four major groups of ectonucleotidases: the ecto-nucleoside triphosphate diphosphohydrolases, ecto-5′-nucleotidase, ecto-nucleotide pyrophosphatase/phosphodiesterases, and alkaline phosphatases. Only recently and based on crystal structures, detailed information regarding the spatial structures and catalytic mechanisms has become available for members of these four ecto-nucleotidase families. This permits detailed predictions of their catalytic mechanisms and a comparison between the individual enzyme groups. The review focuses on the principal biochemical, cell biological, catalytic, and structural properties of the enzymes and provides brief reference to tissue distribution, and physiological and pathophysiological functions.

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CD39-L4 Is a Secreted Human Apyrase, Specific for the Hydrolysis of Nucleoside Diphosphates

Cited by 106 publications

References 21 publications

Entpd5 is essential for skeletal mineralization and regulates phosphate homeostasis in zebrafish

Entpd5 is essential for skeletal mineralization and regulates phosphate homeostasis in zebrafish

The ecto-nucleoside triphosphate diphosphohydrolase NTPDase2/CD39L1 is expressed in a novel functional compartment within the liver

Cellular function and molecular structure of ecto-nucleotidases

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