cDNA Cloning and Expression of a Novel UDP-N-acetyl-d-galactosamine:PolypeptideN-Acetylgalactosaminyltransferase

Hagen, Fred K.; Hagen, Karl S.; Beres, Thomas M.; Balys, Marlene; VanWuyckhuyse, B.C.; Tabak, Lawrence A.

doi:10.1074/jbc.272.21.13843

Cited by 125 publications

(140 citation statements)

References 18 publications

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“…1, panel L). Since GalNAc-T1 transfers GalNAc to Thr 1 , Thr 9 , and Ser 20 in isolated experiments (Fig. 1, panel H), it is concluded that GalNAc-T4 transfers to Ser 10 in -VTSAand Thr 14 in -PDTR-.…”

Section: Galnac-t4 Transfer To At Least Three Sites In the Muc1mentioning

confidence: 86%

The Lectin Domain of UDP-N-acetyl-d-galactosamine:PolypeptideN-acetylgalactosaminyltransferase-T4 Directs Its Glycopeptide Specificities

Hassan¹,

Reis

Bennett³

et al. 2000

Journal of Biological Chemistry

153

137

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The initiation step of mucin-type O-glycosylation is controlled by a large family of homologous UDP-GalNAc: polypeptide N-acetylgalactosaminyltransferases (GalNAc-transferases). Differences in kinetic properties, substrate specificities, and expression patterns of these isoenzymes provide for differential regulation of O-glycan attachment sites and density. Recently, it has emerged that some GalNAc-transferase isoforms in vitro selectively function with partially GalNAc O-glycosylated acceptor peptides rather than with the corresponding unglycosylated peptides. O-Glycan attachment to selected sites, most notably two sites in the MUC1 tandem repeat, is entirely dependent on the glycosylation-dependent function of GalNAc-T4. Here we present data that a putative lectin domain found in the C terminus of GalNAc-T4 functions as a GalNAc lectin and confers its glycopeptide specificity. A single amino acid substitution in the lectin domain of a secreted form of GalNAc-T4 selectively blocked GalNAc-glycopeptide activity, while the general activity to peptides exerted by this enzyme was unaffected. Furthermore, the GalNAc-glycopeptide activity of wild-type secreted GalNAc-T4 was selectively inhibited by free GalNAc, while the activity with peptides was unaffected.

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Section: Galnac-t4 Transfer To At Least Three Sites In the Muc1mentioning

confidence: 86%

The Lectin Domain of UDP-N-acetyl-d-galactosamine:PolypeptideN-acetylgalactosaminyltransferase-T4 Directs Its Glycopeptide Specificities

Hassan¹,

Reis

Bennett³

et al. 2000

Journal of Biological Chemistry

153

137

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“…The finding that GalNAc-T3 expression was retained more frequently in nonsquamous cell carcinomas (most of which were adenocarcinomas) than in squamous cell carcinomas may reflect tissue specific expression of GalNAc-T3 in organs that contain secretory epithelial glands (Hagen et al, 1993; Homa et al, GalNAc-T3 expression in NSCLCs H Dosaka-Akita et al 1993; White et al, 1995;Bennett et al, 1996). Moreover, in nonsquamous cell carcinomas, decreased expression of GalNAc-T3 was associated with unfavourable prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…Each oligosaccharide is synthesised by a specific glycosyltransferase (Varki, 1993). The initial glycosylation of mucin-type O-linked proteins is catalysed by one of the UDP-N-acetyl-a-D-Galactosamine: polypeptide Nacetylgalactosaminyl transferases (GalNAc-transferase family of enzymes) (Hagen et al, 1993;Homa et al, 1993;Wandall et al, 1997;). Three distinct human GalNAc-transferases, GalNAc-T1, GalNAc-T2, and GalNAc-T3, have been characterised (White et al, 1995;Bennett et al, 1996;Wandall et al, 1997).…”

mentioning

confidence: 99%

“…Compared with the expression of GalNAc-T1 and GalNAc-T2, the expression of GalNAc-T3 is highly tissue specific. GalNAc-T3 mRNA has been detected in organs that contain secretory epithelial glands (Hagen et al, 1993;Homa et al, 1993;White et al, 1995;Bennett et al, 1996). It is hypothesised that the differential expression of GalNAc-T3 may affect the specialised functions of glycoproteins produced by normal and malignant cells, and that it is also associated with biological properties of normal and malignant cells (Sutherlin et al, 1997).…”

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confidence: 99%

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N-acetylgalactosaminyl transferase-3 is a potential new marker for non-small cell lung cancers

et al. 2002

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N-acetylgalactosaminyl transferase-3 (GalNAc-T3) is an enzyme involved in the initial glycosylation of mucin-type O-linked proteins. In the present study, we used immunohistochemistry to examine GalNAc-T3 expression in 215 surgically resected non-small cell lung cancers. We analysed the biological and clinical importance of GalNAc-T3 expression, especially with regard to its potential as a prognostic factor. We found that normal bronchial epithelial cells, bronchial gland cells, and alveolar pneumocytes showed cytoplasmic immunostaining for GalNAc-T3. Low expression of GalNAc-T3, observed in 93 of 215 tumours (43.4%), was found more frequently in tumours from smokers than those from nonsmokers (P=0.001), in squamous cell carcinomas than nonsquamous cell carcinomas (P50.0001), and in moderately and poorly differentiated tumours than well differentiated tumours (P=0.0002). Multivariate logistic regression analysis showed that an association of low GalNAc-T3 expression with squamous cell carcinomas was the only one significant relationship of GalNAc-T3 expression with various factors (P50.0001). Moreover, tumours losing GalNAc-T3 expression had a significantly higher Ki-67 labelling index than tumours retaining GalNAc-T3 expression (P=0.0003). Patients with low GalNAc-T3 expression survived a significantly shorter time than patients with high GalNAc-T3 expression in 103 pStage I non-small cell lung cancers (5-year survival rates, 58% and 78%, respectively; P=0.02 by log-rank test) as well as in 61 pStage I nonsquamous cell carcinomas (5-year survival rates, 63% and 85%, respectively; P=0.03). Low GalNAc-T3 expression was an unfavourable prognostic factor in pStage I non-small cell lung cancers (hazards ratio, 2.04; P=0.03), and in pStage I nonsquamous cell carcinomas (hazards ratio, 2.70; P=0.03). These results suggest that GalNAc-T3 is a new marker of non-small cell lung cancers with specificity for histology and prognosis.

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“…Reactions were carried out at 378C in 25-ml mixture containing 500 mM gp 120 or EA2 peptides and 51 mM UDP-[ 14 C]GalNAc (7.8 mCi/mmol, PerkinElmer Life Sciences, Waltham, MA, USA) in 10 mM MnCl 2 , 40 mM sodium cacodylate (pH 6.6), 40 mM b-mercaptoethanol, and 0.1% Triton X-100 as described. (24) The reactions were initiated by adding 12.5 mg total cell extract protein for each sample. Reactions with cell extracts were carried out in the presence of 20 mM CDPcholine to inhibit endogenous non-ppGalNAcT-mediated hydrolysis activity.…”

Section: Cytoimmunochemistry and Laser Confocal Microscopymentioning

confidence: 99%

Mechanism of FGF23 processing in fibrous dysplasia

Bhattacharyya

Wiench

Dumitrescu

et al. 2012

Journal of Bone and Mineral Research

108

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Fibroblast growth factor-23 (FGF23) is a phosphate-and vitamin D-regulating hormone derived from osteoblasts/osteocytes that circulates in both active (intact, iFGF23) and inactive (C-terminal, cFGF23) forms. O-glycosylation by O-glycosyl transferase Nacetylgalactosaminyltransferase 3 (ppGalNAcT3) and differential cleavage by furin have been shown to be involved in regulating the ratio of active to inactive FGF23. Elevated iFGF23 levels are observed in a number of hypophosphatemic disorders, such as X-linked, autosomal recessive, and autosomal dominant hypophosphatemic rickets, whereas low iFGF23 levels are found in the hyperphosphatemic disorder familial tumoral calcinosis/hyperphosphatemic hyperostosis syndrome. Fibrous dysplasia of bone (FD) is associated with increased total FGF23 levels (cFGF23 þ iFGF23); however, classic hypophosphatemic rickets is uncommon. Our results suggest that it can be explained by increased FGF23 cleavage leading to an increase in inactive cFGF23 relative to active iFGF23. Given the fact that FD is caused by activating mutations in the small G-protein G s a that results in increased cyclic adenosine monophosphate (cAMP) levels, we postulated that there may be altered FGF23 cleavage in FD and that the mechanism may involve alterations in cAMP levels and ppGalNacT3 and furin activities. Analysis of blood specimens from patients with FD confirmed that the elevated total FGF23 levels are the result of proportionally increased cFGF23 levels, consistent with less glycosylation and enhanced cleavage by furin. Analysis of primary cell lines of normal and mutation-harboring bone marrow stromal cells (BMSCs) from patients with FD demonstrated that BMSCs harboring the causative G s a mutation had higher cAMP levels, lower ppGalNAcT3, and higher furin activity. These data support the model wherein glycosylation by ppGalNAcT3 inhibits FGF23 cleavage by furin and suggest that FGF23 processing is a regulated process that controls overall FGF23 activity in FD patients. ß

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cDNA Cloning and Expression of a Novel UDP-N-acetyl-d-galactosamine:PolypeptideN-Acetylgalactosaminyltransferase

Cited by 125 publications

References 18 publications

The Lectin Domain of UDP-N-acetyl-d-galactosamine:PolypeptideN-acetylgalactosaminyltransferase-T4 Directs Its Glycopeptide Specificities

The Lectin Domain of UDP-N-acetyl-d-galactosamine:PolypeptideN-acetylgalactosaminyltransferase-T4 Directs Its Glycopeptide Specificities

N-acetylgalactosaminyl transferase-3 is a potential new marker for non-small cell lung cancers

Mechanism of FGF23 processing in fibrous dysplasia

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