Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity

Wu, Jun; Nilsson, Åke; Jönsson, Bo; Stenstad, Hanna; Agace, William W.; Cheng, Yajun; Duan, Rui‐Dong

doi:10.1042/bj20051121

Cited by 47 publications

(57 citation statements)

References 45 publications

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“…Because the WPG loop is present in all other E-NPPs, a different mode for lysophosphatidyl and sphingosyl binding must exist in NPP6 and NPP7. Compared to the lysophospholipase D activity of NPP2, these enzymes exhibit lysophospholipase C activity [388,391]. In addition, NPP6 shows high specificity for choline head groups.…”

Section: Phylogenetic Relationshipmentioning

confidence: 99%

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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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Section: Phylogenetic Relationshipmentioning

confidence: 99%

“…Interestingly, its catalytic activity is inhibited by ATP but not by ADP or AMP. In addition, NPP7 was found to cleave the phosphocholine head group and thus to inactivate platelet-activating factor, a pro-inflammatory phospholipid involved in the pathogenesis of inflammatory bowel disease [391].…”

Section: General Properties and Functional Rolementioning

confidence: 99%

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

876

922

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“…Cloning studies reveal that alk-SMase shares no structural similarities with other SMases, but belongs to the nucleotide pyrophosphatase phosphodiesterase (NPP) family and is now also called NPP7 (11,13,14). However, NPP7 is inactive toward nucleotide phosphate esters but has specific activities against phospholipids containing a phosphocholine moiety, including sphingomyelin, platelet-activating factor (PAF), and lysophosphatidylcholine (13,15). Hydrolyses of these substrates result in the increased ceramide formation, inhibited proinflammatory effects of PAF, and reduced formation of lysophosphatidic acid.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Colonic Tumorigenesis in Alkaline Sphingomyelinase (NPP7) Knockout Mice

Chen

Zhang

et al. 2015

Molecular Cancer Therapeutics

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Intestinal alkaline sphingomyelinase (alk-SMase) generates ceramide and inactivates platelet-activating factor (PAF) and was previously suggested to have anticancer properties. The direct evidence is still lacking. We studied colonic tumorigenesis in alk-SMase knockout (KO) mice. Formation of aberrant crypt foci (ACF) was examined after azoxymethane (AOM) injection. Tumor was induced by AOM alone, a conventional AOM/dextran sulfate sodium (DSS) treatment, and an enhanced AOM/DSS method. b-Catenin was determined by immunohistochemistry, PAF levels by ELISA, and sphingomyelin metabolites by mass spectrometry. Without treatment, spontaneous tumorigenesis was not identified but the intestinal mucosa appeared thicker in KO than in wild-type (WT) littermates. AOM alone induced more ACF in KO mice but no tumors 28 weeks after injection. However, combination of AOM/DSS treatments induced colonic tumors and the incidence was significantly higher in KO than in WT mice. By the enhanced AOM/DSS method, tumor number per mouse increased 4.5 times and tumor size 1.8 times in KO compared with WT mice. Although all tumors were adenomas in WT mice, 32% were adenocarcinomas in KO mice. Compared with WT mice, cytosol expression of b-catenin was significantly increased and nuclear translocation in tumors was more pronounced in KO mice. Lipid analysis showed decreased ceramide in small intestine and increased sphingosine-1-phosphate (S1P) in both small intestine and colon in nontreated KO mice. PAF levels in feces were significantly higher in the KO mice after AOM/DSS treatment. In conclusion, lack of alk-SMase markedly increases AOM/DSS-induced colonic tumorigenesis associated with decreased ceramide and increased S1P and PAF levels.

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“…Second, it hydrolyses and inactivates platelet-activating factor, a potent proinflammatory and proliferative molecule in the intestinal tract . Finally, it degrades lysophosphatidylcholine by a phospholipase C activity, thus reducing the formation of lysophosphatidic acid, a potent factor that stimulates cell migration and angiogenesis (Duan, 2006;Wu et al, 2006). We previously found that alk-SMase activity was decreased in colonic adenomas and carcinomas, in familial adenomatous polyposis and in longstanding ulcerative colitis (Hertervig et al, 1997(Hertervig et al, , 1999Sjöqvist et al, 2002).…”

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confidence: 99%

Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis

Cheng

Wu²,

Hertervig

et al. 2007

Br J Cancer

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Alkaline sphingomyelinase (alk-SMase) is expressed in the intestine and human liver. It may inhibit colonic tumorigenesis, and loss of function mutations have been identified in human colon cancer. The present study investigates its expression in human liver cancer. In HepG2 liver cancer cells, RT -PCR identified three transcripts with 1.4, 1.2 and 0.4 kb, respectively. The 1.4 kb form is the wild-type cDNA with five translated exons, the 1.2 kb product lacks exon 4 and the 0.4 kb form is a combination of exons 1 and 5. Genomic sequence showed that these aberrant transcripts were products of alternative splicing. Transient expression of the 1.2 kb form showed no alk-SMase activity. In HepG2 cells, the alk-SMase activity is low in monolayer condition and increased with cell polarisation. Coexistence of 1.4 and 1.2 kb forms was also identified in one hepatoma biopsy. GenBank search identified a cDNA clone from human liver tumour, which codes a protein containing full length of alk-SMase plus a 73-amino-acid tag at the N terminus. The aberrant form was translated by an alternative starting codon upstream of the wild-type mRNA. Expression study showed that linking the tag markedly reduced the enzyme activity. We also analysed human liver biopsy samples and found relatively low alkSMase activity in diseases with increased risk of liver tumorigenesis. In conclusion, expression of alk-SMase is changed in hepatic tumorigenesis, resulting in loss or marked reduction of the enzyme function.

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Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity

Cited by 47 publications

References 45 publications

Cellular function and molecular structure of ecto-nucleotidases

Cellular function and molecular structure of ecto-nucleotidases

Enhanced Colonic Tumorigenesis in Alkaline Sphingomyelinase (NPP7) Knockout Mice

Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis

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