Isoform-specific O-Glycosylation of Osteopontin and Bone Sialoprotein by Polypeptide N-Acetylgalactosaminyltransferase-1

Miwa, Hazuki E.; Gerken, Thomas A.; Jamison, Oliver; Tabak, Lawrence A.

doi:10.1074/jbc.m109.035436

Cited by 38 publications

(30 citation statements)

References 51 publications

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“…Protein-sugar linkage between N-acetylgalactosamine (GalNAc) and Thr or Ser residues is catalyzed by members of the UDP-GalNAc polypeptide: N-acetylgalactosaminyltransferase (GALNT) family (28,29). Most of the GALNT isoforms show both unique and overlapping substrate specificities (30). Carbohydrate chip analysis showed a putative oligosaccharide for the glycosylated Integrin a3 recognized by BCMab1.…”

Section: Discussionmentioning

confidence: 99%

BCMab1, A Monoclonal Antibody against Aberrantly Glycosylated Integrin α3β1, Has Potent Antitumor Activity of Bladder Cancer In Vivo

Yang

et al. 2014

Clinical Cancer Research

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Purpose: To identify a novel biomarker for bladder cancer targeting therapy. Experimental Design: The human bladder cancer cell line T24 cells were used as immunogen to generate mouse monoclonal antibodies. We screened and identified a specific antibody BCMab1 against bladder cancer. We examined BCMab1 antigen expression in the patients with bladder cancer through immunohistochemical staining and investigated the BCMab1 antigen association with clinical severity. We detected the antitumor activity of BCMab1 antibody and investigated its therapeutic efficacy by subcutaneous and orthotopic bladder cancer models.Results: We developed a new monoclonal antibody BCMab1 against bladder cancer that specifically recognized the aberrantly glycosylated Integrin a3b1 epitope on bladder cancer cells. Expression of the BCMab1 antigen was consistent with clinical severity and prognosis of bladder cancer. The glycosyltransferase GALNT1 could contribute to aberrant glycosylation of Integrin a3. The aberrant glycosylation of integrin a3-activated integrin signaling to initiate FAK activation. BCMab1 could block Integrin engagement to inhibit its signaling leading to cell-cycle arrest. In addition, BCMab1 enhanced FcgR-dependent antitumor activity in vivo.Conclusions: BCMab1 antigen is a new biomarker for bladder cancer. BCMab1 antibody exhibited potent antitumor activity against bladder cancer in vivo. Clin Cancer Res; 20(15); 4001-13. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

BCMab1, A Monoclonal Antibody against Aberrantly Glycosylated Integrin α3β1, Has Potent Antitumor Activity of Bladder Cancer In Vivo

Yang

et al. 2014

Clinical Cancer Research

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“…A similar analysis has been performed on a series of murine osteopontin and bone sialoprotein model peptides recently characterized against ppGalNAc T1, T2, and T3 (63). In this work, the initial rates of glycosylation for all three transferases were obtained and the sites of glycosylation determined for ppGalNAc T1 and T2 (63).…”

Section: Correlation Of Charged Residue Enhancement Values With Transmentioning

confidence: 99%

“…We would like to further extend this analysis to include ppGalNAc T3, T5, and T12 10 while presenting additional examples for ppGalNAc T1 and T2 that further demonstrate the modulating effect of peptide charge. There are several reports comparing the activity of ppGalNAc T3 and other transferases (usually ppGalNAc T1 and T2) against a range of substrates (8,(63)(64)(65) but only one report each for ppGalNAc T5 and T12 (66,67). Unfortunately, in most of the studies the actual site(s) of glycosylation have typically not been determined, and hence, we can only compare the reported relative activities to our enhancement factor products.…”

Section: Correlation Of Charged Residue Enhancement Values With Transmentioning

confidence: 99%

“…In this work, the initial rates of glycosylation for all three transferases were obtained and the sites of glycosylation determined for ppGalNAc T1 and T2 (63). These data and our enhancement products are given in supplemental Table S2 and are summarized in Fig.…”

Section: Correlation Of Charged Residue Enhancement Values With Transmentioning

confidence: 99%

“…Enhancement Factor Products-We have previously suggested that the product of the enhancement factors flanking a potential site of glycosylation (positions Ϫ3 to ϩ3) can roughly predict glycosylation sites and/or relative rates of glycosylation for ppGalNAc T1 and T2 for a number of selected peptides substrates (47,63). We would like to further extend this analysis to include ppGalNAc T3, T5, and T12 10 while presenting additional examples for ppGalNAc T1 and T2 that further demonstrate the modulating effect of peptide charge.…”

Section: Correlation Of Charged Residue Enhancement Values With Transmentioning

confidence: 99%

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Emerging Paradigms for the Initiation of Mucin-type Protein O-Glycosylation by the Polypeptide GalNAc Transferase Family of Glycosyltransferases

Gerken¹,

Jamison²,

Perrine³

et al. 2011

Journal of Biological Chemistry

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143

160

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Mammalian mucin-type O-glycosylation is initiated by a large family of ϳ20 UDP-GalNAc:polypeptide ␣-N-acetylgalactosaminyltransferases (ppGalNAc Ts) that transfer ␣-GalNAc from UDP-GalNAc to Ser and Thr residues of polypeptide acceptors. Characterizing the peptide substrate specificity of each isoform is critical to understanding their properties, biological roles, and significance. Presently, only the specificities of ppGalNAc T1, T2, and T10 and the fly orthologues of T1 and T2 have been systematically characterized utilizing random peptide substrates. We now extend these studies to ppGalNAc T3, T5, and T12, transferases variously associated with human disease. Our results reveal several common features; the most striking is the similar pattern of enhancements for the three residues C-terminal to the site of glycosylation for those transferases that contain a common conserved Trp. In contrast, residues N-terminal to the site of glycosylation show a wide range of isoform-specific enhancements, with elevated preferences for Pro, Val, and Tyr being the most common at the ؊1 position. Further analysis reveals that the ratio of positive (Arg, Lys, and His) to negative (Asp and Glu) charged residue enhancements varied among transferases, thus further modulating substrate preference in an isoform-specific manner. By utilizing the obtained transferase-specific preferences, the glycosylation patterns of the ppGalNAc Ts against a series of peptide substrates could roughly be reproduced, demonstrating the potential for predicting isoform-specific glycosylation. We conclude that each ppGalNAc T isoform may be uniquely sensitive to peptide sequence and overall charge, which together dictates the substrate sites that will be glycosylated.Mucin-type O-glycosylation is one of the most common post-translational modifications of secreted and membrane-associated proteins. Glycoproteins containing O-glycosylated mucin domains serve many important biological roles chiefly because of their unique biophysical and structural properties that include an extended peptide conformation and robust resistance to proteases. Consequently, glycoproteins containing O-glycosylated mucin domains function in the protection of the cell surface, the modulation of cell-cell interactions, in the inflammatory and immune response, in metastasis and tumorigenesis, and in protein sorting, targeting, and turnover (for examples see Refs.

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Das Tn‐Antigen – strukturell einfach und biologisch komplex

Otto

Cummings

2011

Angewandte Chemie

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Die Glycoproteine tierischer Zellen enthalten vielfältige Glycanstrukturen, die co‐ und/oder posttranslational an die Proteine angeheftet werden. Mehr als zwanzig verschiedene Bindungsarten von Glycanen an Proteine sind bekannt, doch sind N‐Glycane (gebunden an Asn) und O‐Glycane (gebunden an Ser/Thr) die häufigsten. Ein abnormes O‐Glycan, das bei Krebs und anderen menschlichen Erkrankungen auftritt, ist das Tn‐Antigen. Es hat eine einfache Struktur, bestehend aus einem N‐Acetyl‐D‐galactosamin, das α‐glycosidisch an einen Serin‐ oder Threoninrest gebunden ist. Das Tn‐Antigen war eines der ersten Glycokonjugate, die chemisch synthetisiert wurden. Es wird normalerweise von einer spezifischen Galactosyltransferase, der T‐Synthase, im Golgi‐Apparat modifiziert. Die Expression aktiver T‐Synthase hängt vom molekularen Chaperon Cosmc ab, dessen Gen auf dem X‐Chromosom liegt. Genmutationen, die die Funktion von T‐Synthase, Cosmc oder anderen an der O‐Glycosylierung beteiligten Faktoren beeinträchtigen, können zur Expression des Tn‐Antigens führen. Da dieses bei einer Reihe von Krankheiten auftritt, besteht großes Interesse, es für die Entwicklung von Impfstoffen und anderen therapeutischen Ansätzen zu nutzen.

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Isoform-specific O-Glycosylation of Osteopontin and Bone Sialoprotein by Polypeptide N-Acetylgalactosaminyltransferase-1

Cited by 38 publications

References 51 publications

BCMab1, A Monoclonal Antibody against Aberrantly Glycosylated Integrin α3β1, Has Potent Antitumor Activity of Bladder Cancer In Vivo

BCMab1, A Monoclonal Antibody against Aberrantly Glycosylated Integrin α3β1, Has Potent Antitumor Activity of Bladder Cancer In Vivo

Emerging Paradigms for the Initiation of Mucin-type Protein O-Glycosylation by the Polypeptide GalNAc Transferase Family of Glycosyltransferases

Das Tn‐Antigen – strukturell einfach und biologisch komplex

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