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Published in final edited form as: Semin Cell Dev Biol. 2010 Feb 6;21(6):616–621. doi: 10.1016/j.semcdb.2010.02.001

The Role of Mucin-type O-glycans in Eukaryotic Development

Lawrence A Tabak 1
PMCID: PMC2902666  NIHMSID: NIHMS184603  PMID: 20144722

Abstract

Newly emerging genetic studies have revealed that a subset of the family of glycosyltransferases responsible for the formation of mucin-type O glycans is essential for normal development. As additional genetic, biochemical and physical tools are developed to interrogate the complex structure and surface location of this under-studied class of carbohydrate, no doubt additional roles will be elucidated.

1. Introduction: “The sweet husk”

Almost 50 years ago, H. Stanley Bennett, speaking before the Mexican Anatomical Society, proposed that all cell surfaces were enveloped in a sugar coat, that he termed the “glycocalyx” or sweet husk. While early studies (1,2) emphasized the filtration, barrier and supportive functions of this sugar structure, over time, compelling evidence that cell surface carbohydrates mediate specific cell adhesions to either each other or to the underlying extracellular matrix accumulated (reviewed in 3–6). In particular, the ability of surface carbohydrates to form a “polyvalent array” of low affinity binding sites affords a mechanism whereby cells may sample each other and their environment before entering into specific, long-term relationships via high affinity interactions with either carbohydrates and/or proteins.

Mucin-type glycoproteins (mucins) are heavily decorated with carbohydrate side-chains, termed O-glycans, which are linked (via an O-glycosidic bond) to serine (Ser) or threonine (Thr) residues of the protein backbone. One unique feature of O-glycans is that they often cluster within repeating amino acids sequences of the protein, termed tandem repeats, which are enriched in Ser/Thr residues (7–9). Many glycoproteins contain one or more mucin-like domain, typically enriched in Pro, Ser and Thr residues, yielding a discrete region(s) within the overall molecule that are heavily decorated with O-glycans (10).

Mucins or proteins containing mucin-like domains, are expressed in two flavors – membrane bound molecules that contribute directly to the composition of the cellular glycocalyx (5, 10–12) and secreted forms that contribute either to the formation of the extracellular matrix (13,14) or to the gel-like mucus coat that envelopes mucosal surfaces of the body thereby forming the most exterior face of the innate immune system (7,15). In terms of location therefore, both surface bound mucins within in the glycocalyx and secreted mucins contributing to the formation of the extracellular matrix are well positioned to influence development.

2. Biosynthesis and structure of mucin-type O-glycans: Advances and challenges

The step-wise synthesis of O-glycans begins with the transfer of Nacetylgalactosamine (GalNAc) from the sugar donor, UDP-GalNAc, to selected Ser/Thr residues of the protein backbone yielding Tn antigen (GalNAc-α-1-O-Ser/Thr) (8,9, 16–18). This key first step is catalyzed by a multi-gene family of enzymes (E.C. 2.4.1.41) termed UDP- GalNAc:polypeptide α-N-acetylgalactosaminyltransferases (ppGalNAcTs) (19). Most recent data indicates that there are 20 human and 18 mouse genes (galnts) with evidence for additional diversity in the form of splicing variants (20) and as many as 12 genes in Drosophila (pgants) (21).

Why nature requires so many ppGalNAcTs to perform a seemingly simple reaction has been the subject of intense investigation. Transcripts encoding individual ppGalNAcTs display unique temporal and spatial patterns of expression during development (21–23) and so part of the need for the large number of isoforms relates to which isoform is expressed when and where. Moreover, unique substrate preferences have been demonstrated for some ppGalNAcTs (17,19 and references cited therein) using in vitro assays and recently we have demonstrated isoform-specific O-glycosylation of two bone proteins in vivo (24).

Although many studies have probed the question, no consensus amino acid sequence has emerged that is both necessary and sufficient for mucin-type O-glycosylation (ppGalNAcT review). However two classes of ppGalNAcTs have been identified. One class of ppGalNAcTs glycosylates peptides (“naked” or unglycosylated peptide). The other type of ppGalNAcT will only act on glycopeptide substrates (peptides previously decorated with GalNAc residues). This strongly implies that there is a hierarchical acquisition of GalNAc by specific Ser/Thr residues among clusters of hydroxyamino acids found in the tandem repeats (17,19,25–28). Despite the large number of genes that encode ppGalNAcTs, there is remarkable conservation of functional specificity across phyla (29), suggesting an evolutionary requirement to decorate proteins with this class of glycans in a highly specific manner. Collectively, the available evidence strongly supports the view that it does matter which Ser or Thr is, or is not, glycosylated in vivo.

Subsequent elongation of the Tn structure yields an array of 8 distinct “Core” structures that in turn may be further modified by many of the glycosyltransferases resident in the Golgi yielding an extraordinary array of O-glycan structures (9,16–18, 30). The most common structure, Core 1 or “T-antigen” (Galβ1,3GalNAc α1-O-Ser/Thr) is formed by addition of galactose (Gal) under the direction of the Core β1,3 galactosyltransferase. In turn, the transfer of an N-acetylglucosamine (GlcNAc) onto the Core 1 structure, catalyzed by Core 2 β1,6-N acetylglucosaminlytransferase, results in the formation of the Core 2 structure (Galβ1,3[GlcNAcβ1,6] α1-O- GalNAc-Ser/Thr). Additional peripheral sugars can be assembled into unique structures that may impart biological specificity including those observed for the blood group antigens (31), selectin-ligands involved in cell trafficking (32,33) and counter receptors for microbial adhesins (34,35).

Structurally, the presence of O-glycans leads to local stiffening of the protein backbone, an effect potentiated by the presence of repeating clusters of sugar afforded by the tandem repeat motif. The result is a less flexible “rod-like” configuration (36) which can “telescope” the business end of a membrane receptor away from the cell surface. Counter to intuition, longer and/or more complex O-glycan structures do not impact the shape of the mucin greater than simple carbohydrate side chains; rather, considerable expansion occurs with just the core GalNAc present with maximum expansion occurring with only a disaccharide structure (36). When multiple O-glycans are more evenly distributed about the peptide backbone, the resultant structure tends to resist proteolysis and assume an expanded and highly hydrated “jello-like”, form (7–9, 11,15, 36).

3. Implications of multivalency and the glycoside cluster effect for the role of mucin-type O-glycans in eukaryotic development

Affinities for carbohydrates are usually weak – with μM-mM affinity constants being typical (37). However as the density of target carbohydrate is increased, the affinity can increase dramatically. For example, the carbohydrate binding protein soy bean agglutinin binds to a single chain of Tn antigen with an affinity of ~ 170μM; in contrast, a fragment of porcine mucin containing ~2300 O-glycans, binds to this same carbohydrate binding protein with an approximately 100 fold increase in affinity (38). Therefore, the densities of sugars that make up either the glycocalyx or the extracellular matrix could have profound functional importance during development. Since the collective action of ppGalNAcTs regulate the density pattern of O-glycan acquisition, the substrate specificity and expression of specific ppGalNAcTs may underlie a here-to-for unrecognized regulatory system. As will be outlined subsequently, a new generation of reagents will be required to facilitate detection of changes in glycan composition, structure and density in real time.

4. Current approaches to studying glycan function in development

Unlike proteins, carbohydrates cannot be “mutated” directly using genetic approaches. Therefore, one strategy to ascertain function has been to alter the carbohydrate using either chemical and/or enzymatic treatment (39). Antibodies (40) and carbohydrate-binding proteins (lectins) (41,42) have also been used to bind and “block” carbohydrate function and inhibition assays employing excess concentrations of glycans have also been performed (43). Small molecule inhibitors of biosynthetic intermediates have also been used widely (44–46) although the complexities of delivering perturbants with precision, at the appropriate temporal moment and spatial location, and in sufficient quantities to yield an effect, have rendered these approaches as most useful for in vitro studies.

The general in vivo strategy to study glycan function has been to either alter or ablate the expression and/or activity of the relevant proteins responsible for the assembly of the carbohydrate side-chain genetically. Targets include both the glycosyltransferases (47) and the protein transporters that are required to form the various sugar donors (48). Given the large number of genes that encode the family of ppGalNAcTs, and the overlap of expression patterns observed, this approach has limitations that must be addressed. These include difficulties in identifying subtle phenotypes and partial penetrance of phenotypes.

Adding to the experimental genetics approach is the phenotypic characterization of patients with congenital disorders of glycosylation that have increased our understanding of the functional roles played by glycans (49 and see article by _______in this issue).

5. Mucin-type O-glycans matter in eukaryotic development

Recent studies in model organisms provide the clearest and most compelling evidence for the importance of mucin type O-glycans in development. A gene encoding a member of the Drosophila pgant family (50), pgant 35A, is recessive lethal (51,52). Subsequently it was determined that the underlying developmental defect was aberrant tracheal tube formation leading to a respiratory system that lacked an intact diffusion barrier (53). The loss of pgant 35A leads to a marked diminution in the level of apical and luminal O-glycans and specifically the apical protein Crbs, known to play a role in formation of cell shape and polarity, suggesting that pgant 35A mediated O-glycosylation is required for the proper sorting of apical proteins in the developing Drosophila tracheal system (53). Ablation of the enzyme (C1GalTA) that catalyzes the addition of Gal to the GalNAc to yield the core 1 T antigen is lethal in flies – presumably due to aberration in CNS morphogenesis (54) by an as yet unknown mechanism.

Parallel observations have been made in mice. Ablation of the single mammalian gene (C1galt1) that encodes T-synthase leads to embryonic hemorrhage and death. In particular developing embryos display aberrant microvasculature in the brain, pointing to an essential role for the mucin-type O-glycans in angiogenesis (55). Partial inactivation of T-synthase (via an N-ethyl-N-nitrosourea mediated mutagenesis of C1galt1) allows animals to reach adulthood. These animals develop both thrombocytopenia and kidney pathology; the kidneys displayed glomerular lesions and fatty degeneration of corresponding proximal tubules (56). The authors suggest podocalyxin as the affected substrate and hypothesize that proper negatively charged O-glycans are responsible for proper formation of filtration slits in kidney. Targeted deletion of C1galt1 from only endothelial and hematopoietic cells results in abnormal connections between the circulatory and lymphatic systems (57). Using antibody probes to detect glycoproteins involved in angiogenesis, it was ascertained that podoplanin fails to acquire the requisite complement of O-glycans in these mice. Further, podoplanin nulls (Pdpn −/−) phenocopy aspects of the C1galt1 nulls suggesting that this O-glycosylated protein plays a role in keeping blood vessels separate from the lymphatic system (57).

Drosophila pgant3 has been demonstrated to be required for proper integrin-mediated cell-cell adhesion in the developing fly wing (58; personal communication, Kelly Ten Hagen). A decrease in O-glycans was observed along the basal surfaces of columnar epithelial cells in wing discs derived from pgant3 homozygous mutant flies. It is the basal surface of the epithelium that forms the contact interface in wing formation. Using a combination of bioinformatics and proteomic approaches, candidate substrates within the wing epithelium were identified and challenged for their ability to act as acceptor molecules. The extracellular matrix protein tiggrin was shown to be a PGANT3-specific target that fails to acquire O-glycans in a pgant3 null background. Genetic interaction experiments with pgant3 and tiggrin mutant flies demonstrated that these genes act to exacerbate the same phenotype (58). This work is a major step forward in that it is the first to experimentally deduce the substrate implicated in an O-glycan-dependent phenotype.

Gain and loss of function experiments in Xenopus, demonstrate that a frog homologue for mammalian ppGalNAc-“like”T-1 (Galntl1) negatively regulates TGF⍰-signaling and is required for proper formation of both the neural crest and the neural tube (59) underscoring that mucin-type O-glycans have both structural and signaling roles during development.

To date ablation of ppGalNAcTs in mice (ppGalNAcT-1 [33], T-3 [60], T-4[19], T-5[19], T-10 [61], T-13[62] and T-4/T-5 [Ten Hagen and Tabak, unpublished]) does not result in lethality, although several interesting phenotypes have been described (33). Recent work from our group has shown variable occurrence of cardiac abnormalities in the Galnt1-null mice (submitted); both heart valve thickening and ventricular septal defects are observed suggesting primary defects in valvulogenesis. The incomplete penetrance may result from compensatory effects of other ppGalNAcT-1 family members and underscores the difficulties of working with this complex gene family in mice.

6. Congenital disorders of mucin-type O-glycosylation

A number of diseases are now known to be the result of aberrant O-glycosylation (described below) although no fatal congenital disorders of mucin-type O-glycosylation have been identified in mammals to date. This may indicate that this class of O-glycan is not essential for mammalian development or that, in contrast to Drosophila, there is sufficient functional redundancy built into mammalian systems to ensure that mutation of multiple glycosyltransferases must occur before a lethal effect is observed. It may also be possible that lethality occurs at the very earliest stages of development and the underlying event has not yet been recognized.

Several congenital hematological conditions are associated with defects in mucin-type O-glycan biosynthesis. Tn syndrome is a rare autoimmune disorder characterized by a failure to biosynthetically extend the Tn antigen on the surface of blood cells into the T antigen. The typical clinical presentation is hemolysis or thrombocytopenia (63). The underlying defect is not with the T-synthase (C1galt1) per se, but rather with the molecular chaperone of T-synthase, Cosmc, that is required for enzymatic activity of the glycosyltransferase (64).

Under galactosylation of O-glycans is observed in IgA1 mediated nephropathy (65). IgA is among the few serum proteins to be decorated with varying forms of mucin-type O-glycans within its “hinge region” (66). The heritability of the galactose-deficient form of IgA has been estimated at 0.54 using a lectin-based enzyme-linked immunoadsorbent assay suggesting that abnormally glycosylated IgA is an inherited rather than acquired condition (67,68). It is speculated that the under galactosylated form of IgA is recognized by antibodies that had previously been formed against microbial flora (69). While a recent case control association study has implicated genetic variants of the C1GalT1 gene to be associated with some cases of IgA nephropathy (70), the specific genetic defect responsible for this disease has not yet been identified.

Hyperphosphatemic familial tumoral calcinosis is characterized by ectopic skin and subcutaneous calcifications and hyperphosphatemia resulting from mutations in one of three genes - Galnt3, which encodes ppGalNAc-T3, fgf23, which encodes fibroblast growth factor 23 (FGF23) and KL, encoding Klotho, the co-receptor for FGF23 (71). FGF23 is known to regulate blood phosphate levels and is inactivated by proteolytic cleavage. The acquisition of O-glycans (suggested to be mediated by ppGalNAcT-3, [72]) protects FGF23 from subtilisin-like proprotein convertase mediated proteolysis and thus is thought to maintain an active pool of FGF23. In humans, inactivating Galnt3 result in increased proteolysis of FGF23 and increased levels of blood phosphate, leading to the suggestion that O-glycans added to FGF23 by Galnt3 offer protection from proteolysis. Galnt3 null mice also display hyperphosphatemia (60).

Several single nucleotide polymorphisms (SNPS) in Galnts have been demonstrated to be associated with several diseases and conditions. For example, galnt1 shows association with ovarian cancer (73). Polymorphism in galnt4 has been shown to associate with acute coronary syndrome (74). Recently inactivating germ-line and somatic mutations in galnt12 have been demonstrated in individuals with colon cancer (75). Genetic ablation of Muc2 in mice increases their susceptibility to colonic tumor formation (76), and mice lacking core 3 mucin-type O-glycans display increased susceptibility to colitis and colorectal tumors (77), supporting the view that dysregulation of mucin-type biosynthesis is associated with pathogenesis of gastrointestinal disease.

7. Where do we go from here?

7.1 Defining the mucin-type O-glycome

While advances in analytical methods (notably mass spectrometry) are making it easier to identify proteins are O-glycosylated (e.g. 78), we still are unable to predict with 100% certainty which proteins will become O-glycosylated by the family of ppGalNAcTs, although continued refinement of predictive algorithms continues (79, NetOGlyc [http://www.cbs.dtu.dk/services/NetOGlyc/], OGPET [http://ogpet.utep.edu/OGPET/index.php] and see 80–82). This highlights the need for a better understanding of the activity and site preferences of each individual transferase family member. These efforts are greatly informed by systematic in vitro analysis of ppGalNAcT substrate preferences using oriented random peptide (83) and glycopeptides libraries (28,84). Ultimately a model incorporating all of these preferences will need to be integrated and tested experimentally. Efforts would be greatly enhanced by the availability of a high-throughput, unbiased approach to screen all possible substrates with all possible ppGalNAcTs. Attempts to use yeast-two hybrid have not been informative (Ten Hagen and Tabak, unpublished results), likely do the relatively low affinity of the ppGalNAcTs for their substrates and/or the less than optimal conditions in the yeast nucleus for a Golgi reaction event. A system is currently in development to redress the later limitation (Dube & Kohler, D. Dube, personal communication, 2009).

Current in vivo experimental approaches to define ppGalNAcT substrates are laborious since we lack specific inhibitors of ppGalNAcTs that are stable under a broad range of physiological conditions. The availability of crystal structures for both peptide (85,86) and glycopeptide (87) ppGalNAcTs, together with new approaches to high through put screening (88) should facilitate identification for small molecule inhibitors for the ppGalNAcT family and individual isoforms.

Perturbation of ppGalNAcT activity in vivo is currently limited to either targeted gene ablation or RNAi mediated reduction. The expression of glycoproteins in the experimental background is compared to that observed for wild type to determine if there is any change (e.g. 24, 58).

7.2 Mapping the location of mucin-type O-glycans

Since the density of O-glycans can play an a potentially important role in setting the affinity for carbohydrate binding proteins, it is insufficient to simply know if a protein is decorated with mucin-type O-glycans. Experimental mapping of O-glycans remains technically challenging with relatively few mucin-type O-glycans unambiguously assigned to specific Ser/Thr (89–91). While site directed mutagenesis could be employed to localize specific O-glycans this is not a practical approach for most mucin-type glycoproteins given the large number and clustered arrangement of O-glycans that decorate the protein backbone.

Solid-phase Edman degradation remains the most robust approach to site mapping for mucin-type O-glycans but unfortunately this method currently requires relatively large quantities of purified sample and requires highly specialized equipment (90,91). To add further complexity, mucin-type O-glycosylation sites may vary both in the degree that they are occupied by glycans (91) and in the “completeness” of the structure that is attached (e.g. 66,91). Collectively, this variation has been termed “microheterogeneity”. As analytical methods become more robust, we will be able to perform high-throughput analysis of mucin-type glycoproteins at the site-specific level (90,91).

7.3 Dynamic analysis of mucin-type O-glycans in vivo

Present analysis of glycans is largely static in nature; by interrogating a system at different time points, iterative assessment of the system dynamics can be inferred. However, in the future, it will become increasingly important to conduct real-time measurements of the specific glycans on the cell surfaces. This will be particularly important as more attention is played to the increasing number of mucin-type glycoproteins that are being identified that function as part of signaling pathways (59, 92–95).

Once substrate-ppGalNAcT isoform pairs are identified, one could envision engineering mice that express, either conditionally or with on/off promoters, fluorescent reporter molecules (e.g. 96) that would be engineered to act as sentinels for the appearance (or disappearance) of key glycans (that are labeled, e.g. 97) in real time using principles of Fluorescence Resonance Energy Transfer. It may also be possible to employ NMR spectroscopy to monitor glycosylation changes as has recently been done for the intracellular O-N-Acetylglucosamine (98).

8. Concluding remarks

Despite the ubiquitous nature of mucin-type O-glycosylation, the limited number of tools to facilitate their in vivo study and a muted appreciation for glycobiology by the broad scientific research community (99) has made for slow progress in defining the precise roles played by O-glycans in development. Recent advances that have been made by exploiting model organisms have highlighted the significance of mucin-type O-glycans (100). This, coupled with advances in analytical methods has enabled remarkable progress to be made in a relatively short period of time. With this progress will no doubt come a wider appreciation of this molecular class, which in turn will lead to larger numbers of investigations. The future does indeed appear to be “sweet”!

Acknowledgements

Original research from my laboratory is supported by funds of the intramural program of NIDDK, NIH. The helpful comments of Dr. Kelly Ten Hagen and the members of my laboratory are greatly appreciated.

Footnotes

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References

  • 1.Bennett HS. Morphological aspects of extracellular polysaccharides. J Histochem Cytochem. 1963;11:14–23. [Google Scholar]
  • 2.Martinez-Palomo A. The surface coats of animal cells. Intl Rev Cytol. 1970;29:29–75. [Google Scholar]
  • 3.Bourrillon R, Aubery M. Cell surface glycoproteins in embryonic development. Intl Rev Cytol. 1989;116:257–338. doi: 10.1016/s0074-7696(08)60642-7. [DOI] [PubMed] [Google Scholar]
  • 4.Roseman S. Reflections on glycobiology. J Biol Chem. 2001;276:41527–41542. doi: 10.1074/jbc.R100053200. [DOI] [PubMed] [Google Scholar]
  • 5.Hakomori S. The glycosynapse. Proc Natl Acad Sci. 2002;99:225–232. doi: 10.1073/pnas.012540899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Bucior I, Burger MM. Carbohydrate-carbohydrate interactions in cell recognition. 2004;14:631–637. doi: 10.1016/j.sbi.2004.08.006. [DOI] [PubMed] [Google Scholar]
  • 7.Tabak LA, Levine MJ, Mandel ID, Ellison SA. Role of salivary mucins in the protection of the oral cavity. J Oral Path. 1982;11:1–17. doi: 10.1111/j.1600-0714.1982.tb00138.x. [DOI] [PubMed] [Google Scholar]
  • 8.Tabak LA. In defense of the oral cavity: Structure, biosynthesis and function of salivary mucins. Annu Rev Physiol. 1995;57:547–564. doi: 10.1146/annurev.ph.57.030195.002555. [DOI] [PubMed] [Google Scholar]
  • 9.Rose MC, Voynow JA. Respiratory tract mucin genes and mucin glycoproteins in health disease. Physiol Rev. 2006;86:245–278. doi: 10.1152/physrev.00010.2005. [DOI] [PubMed] [Google Scholar]
  • 10.Lang T, Hansson GC, Samuelsson T. Gel-forming mucins appeared early in metazoan development. Proc Natl Acad Sci. 2007;104:16209–16214. doi: 10.1073/pnas.0705984104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Hollingsworth MA, Swanson BJ. Mucins in cancer: Protection and control of the cell surface. Nature Rev Cancer. 2004;4:45–60. doi: 10.1038/nrc1251. [DOI] [PubMed] [Google Scholar]
  • 12.Desseyn J-L, Tetaert D, Gouyer V. Architecture of the large membrane-bound mucins. Gene. 2008;410:215–222. doi: 10.1016/j.gene.2007.12.014. [DOI] [PubMed] [Google Scholar]
  • 13.Daley WP, Peters SB, Larsen M. Extracellular matrix dynamics in development and regenerative medicine. J Cell Sci. 2008;121:25–264. doi: 10.1242/jcs.006064. [DOI] [PubMed] [Google Scholar]
  • 14.Rozario T, DeSimone DW. The extracellular matrix in development and morphogenesis: A dynamic view. Devel Biol. 2009 doi: 10.1016/j.ydbio.2009.10.026. In press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Dharmani P, Srivastava V, Kissoon-Singh V, Chadee K. Role of intestinal mucins in innate host defense mechanisms against pathogens. 2009;1:123–135. doi: 10.1159/000163037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Hang HC, Bertozzi CR. The chemistry and biology of mucin-type O-linked glycosylation. Bioorg & Med Chem. 2005;13:5021–5034. doi: 10.1016/j.bmc.2005.04.085. [DOI] [PubMed] [Google Scholar]
  • 17.Tarp MA, Clausen H. Mucin-type O-glycosylation and its potential use in drug and vaccine development. Biochim Biophys Acta. 2008;1780:546–563. doi: 10.1016/j.bbagen.2007.09.010. [DOI] [PubMed] [Google Scholar]
  • 18.Tian E, Ten Hagen KG. Recent insights into the biological roles of mucin-type O-glycosylation. Glycoconj J. 2009;26:325–334. doi: 10.1007/s10719-008-9162-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Ten Hagen KG, Fritz TA, Tabak LA. All in the Family: the UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases. Glycobiol. 2003;13:1R–16R. doi: 10.1093/glycob/cwg007. [DOI] [PubMed] [Google Scholar]
  • 20.Jaya's paper – submitted
  • 21.Tian E, Ten Hagen KG. Expression of UPD-GalNAc:polypeptide N-acetylgalactosaminyltransferase family is spatially and temporally regulated during Drosophila development. Glycobiol. 2006;16:83–95. doi: 10.1093/glycob/cwj051. [DOI] [PubMed] [Google Scholar]
  • 22.Kingsley PD, Ten Hagen KG, Maltby KM, Zara J, Tabak LA. Diverse spatial expression patterns of UPD-GalNAc:polypeptide N-acetylgalactosaminyltransferase family member mRNAs during mouse development. Glycobiol. 2000;10:1317–1323. doi: 10.1093/glycob/10.12.1317. [DOI] [PubMed] [Google Scholar]
  • 23.Hagen F, Layden M, Nehrke K, Gentile K, Berbach K, Tsao CC, Forsythe M. Trends in Glycosci and Glycotech. 2001;13:463–479. [Google Scholar]
  • 24.Miwa HE, Gerkin TA, Jamison O, Tabak LA. Isoform-specific O-glycosylation of osteopontin and bone sialoprotein by polypeptide N-acetylgalactosaminyltransferase-1. J Biol Chem. 2010;285:1208–1219. doi: 10.1074/jbc.M109.035436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Ten Hagen KG, Tetaert D, Hagen FK, Richet C, Beres TM, Gagnon J, Balys MM, VanWuyckhuyse B, Bedi GS, Degand P, Tabak LA. Characterization of a UDP-GalNAc:polypeptide N-acetylgalactosaminyl- transferase that displays glycopeptide N-acetylgalactosaminyltransferase activity. J Biol Chem. 1999;274:27867–27874. doi: 10.1074/jbc.274.39.27867. [DOI] [PubMed] [Google Scholar]
  • 26.Hassan H, Reis CA, Bennett EP, Mirgorodskaya E, Roepstorff P, Hollingsworth MA, Burchell J, Taylor-Papadimitriou J, Clausen H. The Lectin Domain of UDP-N-acetyl-D-galactosamine:Polypeptide N-acetylgalactosaminyltransferase-T4 Directs Its Glycopeptide Specificities. J. Biol. Chem. 2000 Dec;275:38197–38205. doi: 10.1074/jbc.M005783200. [DOI] [PubMed] [Google Scholar]
  • 27.Ten Hagen KG, Bedi GS, Tetaert D, Kingsley PD, Hagen FK, Balys MM, Beres TM, Degand P, Tabak LA. Cloning and characterization of a ninth member of the UDP-GalNAc:polypeptide N acetylgalactosaminyl -transferase family, ppGaNTase-T9. J Biol Chem. 2001;276:17395–17404. doi: 10.1074/jbc.M009638200. [DOI] [PubMed] [Google Scholar]
  • 28.Pratt MR, Hang HC, Ten Hagen KG, Rarick J, Gerkin TA, Tabak LA, Bertozzi CR. Deconvoluting the functions of the polypeptide N-⍰-acetylgalactosaminyltransferase family members by glycopeptides substrate profiling. Chem &Biol. 2004;11:1009–1016. doi: 10.1016/j.chembiol.2004.05.009. [DOI] [PubMed] [Google Scholar]
  • 29.Gerkin TA, Ten Hagen KG, Jamison O. Conservation of peptide acceptor preferences between Drosophila and mammalian polypeptide-GalNAc trasnferase ortholog pairs. Glycobiol. 2008;18:861–870. doi: 10.1093/glycob/cwn073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Holmen Larsson JM, Karlsson H, Sjovall H, Hannson GC. A complex, but uniform O-glycosylation of the human MUC2 mucin from colonic biopsies analyzed by nanoLC/MS. Glycobiol. 2009;19:756–766. doi: 10.1093/glycob/cwp048. [DOI] [PubMed] [Google Scholar]
  • 31.Kabat EA, Bassett EW, Pryzwansky K, Lloyd KO, Kaplan ME, Layug EJ. Immunochemical studies on blood groups. XXXIII. The effects of alkaline borohydride and of alkali on blood group A, B and H substances. Biochem. 1965;4:1632–1638. doi: 10.1021/bi00884a027. [DOI] [PubMed] [Google Scholar]
  • 32.Rosen SD. Ligands for L-selectins: Homing, inflammation and beyond. Annu Rev Immunol. 2004;22:129–156. doi: 10.1146/annurev.immunol.21.090501.080131. [DOI] [PubMed] [Google Scholar]
  • 33.Tenno M, Ohtsubo K, Hagen FK, Ditto D, Zarbock A, Schaerli P, von Andrian UH, Ley K, Le D, Tabak LA, Marth JD. Initiation of protein O-glycosylation by the polypeptide GalNAcT-1 in vascular biology and humural immunity. Molec and Cell Biol. 2007;27:8783–8796. doi: 10.1128/MCB.01204-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Murray PA, Levine MJ, Tabak LA, Reddy MS. Specificty of salivary-bacterial interactions: II. Evidence for a lectin on Streptococcus sanguis with specificity for NeuAc⍰2,3Gal⍰1,3GalNAc sequence. Biochem Biophys Res Comm. 1982;106:390–396. doi: 10.1016/0006-291x(82)91122-6. [DOI] [PubMed] [Google Scholar]
  • 35.Boren T, Falk P, Roth KA, Larson G, Normark S. Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens. Science. 1993;262:1892–1895. doi: 10.1126/science.8018146. [DOI] [PubMed] [Google Scholar]
  • 36.Jentoft N. Why are proteins O-glycosylated? Trends in Biochem Sci. 1990;15:291–294. doi: 10.1016/0968-0004(90)90014-3. [DOI] [PubMed] [Google Scholar]
  • 37.Collins BE, Paulson JC. Cell surface biology mediated by low affinity multivalent protein-glycan interactions. Curr Opin in Chem Biol. 2004;8:1–9. doi: 10.1016/j.cbpa.2004.10.004. [DOI] [PubMed] [Google Scholar]
  • 38.Dam TK, Gerken TA, Cavada BS, Nascimento KS, Moura TR, Brewer CF. Binding studies of ⍰-GalNAc-specific lectins to the a-GalNAc (Tn-antigen) forms of porcine submaxillary mucin and its smaller fragments. J Biol Chem. 2007;282:28256–28263. doi: 10.1074/jbc.M704677200. [DOI] [PubMed] [Google Scholar]
  • 39.Rastan S, Thorpe SJ, Scudder P, Brown S, Gooi HC, Feizi T. Cell interactions in preimplantation embryos: evidence for involvement of saccharides of the poly-N-acetyllactosamine series. J. Embryol Exp Morph. 1985;87:115–128. [PubMed] [Google Scholar]
  • 40.Kemler R, Bainet C, Eisen H, Jacob F. Surface antigen in early differentiation. Proc Natl Acad Sci. 1977;74:4449–4452. doi: 10.1073/pnas.74.10.4449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Johnson LV. Wheat germ agglutinin induces compaction- and cavitation-like events in two-cell mouse embryos. Develop Biol. 1986;113:1–9. doi: 10.1016/0012-1606(86)90102-8. [DOI] [PubMed] [Google Scholar]
  • 42.Dealtry CB, Sellens MH. Lectin-induced abnormalities of mouse blastocyst hatching and outgrowth in vitro. Molec Reprod Devel. 1990;26:24–29. doi: 10.1002/mrd.1080260105. [DOI] [PubMed] [Google Scholar]
  • 43.Fenderson BA, Zehavi U, Hakomori S-I. A multivalent lacto-N-fucopentose III-lysyllysine conjugate decompacts preimplantation mouse embryos, while the free oligosaccharide is ineffective. J Exptl Med. 1984;160:1591–1596. doi: 10.1084/jem.160.5.1591. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Armant DR, Kaplan HA, Lennarz WJ. N-linked glycoprotein bosynthesis in the developing mouse embryo. Dev Biol. 1986;113:228–237. doi: 10.1016/0012-1606(86)90125-9. [DOI] [PubMed] [Google Scholar]
  • 45.Patsos G, Hebbe-Viton V, San Martin R, Paraskeva C, Gallagher T, Corfield A. Action of a library of O-glycosylation inhibitors on the growth of human colorectal cancer cells in culture. Bioch Soc Trans. 2005:33721–723. doi: 10.1042/BST0330721. [DOI] [PubMed] [Google Scholar]
  • 46.Murrey HE, Gama CI, Kalovidouris SA, Luo W-I, Driggers EM, Porton B, Hsieh-Wilson LC. Protein fucosylation regulates synapsin Ia/Ib expression and neuronal morphology in primary hippocampal neurons. Proc Natl Acad Sci. 2006;103:21–26. doi: 10.1073/pnas.0503381102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Haltiwanger RS, Lowe JB. Role of glycosylation in development. 2004;73:491–537. doi: 10.1146/annurev.biochem.73.011303.074043. [DOI] [PubMed] [Google Scholar]
  • 48.Caffaro CE, Hirschberg CB. Nucleotide sugar transporters of the Golgi apparatus: From basic science to diseases. Acc Chem Res. 2006;39:805–812. doi: 10.1021/ar0400239. [DOI] [PubMed] [Google Scholar]
  • 49.Schachter H, Freeze HH. Glycosylation diseases: Quo vadis? Biochim Biophys Acta. 2009;1792:925–930. doi: 10.1016/j.bbadis.2008.11.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Ten Hagen KG, Tran DT, Gerken TA, Stein DS, Zhang Z. Functional characterization and expression analysis of members of the UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase family from Drosophila melanogaster. J Biol Chem. 2003;278:35039–35048. doi: 10.1074/jbc.M303836200. [DOI] [PubMed] [Google Scholar]
  • 51.Ten Hagen KG, Tran D. A UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase is essential for viability in Drosophila melanogaster. J Biol Chem. 2002;277:22616–22622. doi: 10.1074/jbc.M201807200. [DOI] [PubMed] [Google Scholar]
  • 52.Schwientek T, Bennett EP, Flores C, Thacker J, Hollmann M, Reis CA, Behrens J, Mandel U, Keck B, Schafer MA, Haselmann K, Zubarev R, Roepstorff P, Burchell JM, Taylor-Papadimitriou J, Hollingsworth MA, Clausen H. J Biol Chem. 2002;277:22623–22638. doi: 10.1074/jbc.M202684200. [DOI] [PubMed] [Google Scholar]; Functional characterization of subfamilies of putative GalNAc:polypeptide N-acetylgalactosaminyltransferase in Drosophila melanogaster, Caenorhabditis elegans and mammals. J Biol Chem 2002;277:22623-22638
  • 53.Tian E, Ten Hagen KG. A UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase is required for epithelial tube formation. J Biol Chem. 2007;282:606–614. doi: 10.1074/jbc.M606268200. [DOI] [PubMed] [Google Scholar]
  • 54.Lin Y-R, Reddy BVVG, Irvine ID. Requirement for a core 1 galactosyltransferase in the Drosophila nervous system. Devel Dynam. 2008;237:3703–3714. doi: 10.1002/dvdy.21775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Xia L, Ju T, Westmuckett A, An g., Ivanciu L, McDaniel JM, Lupu F, Cummings RD, McEver RP. Defective angiogensis and fatal embryonic hemorrhage in mice lacking core 1-derived O-glycans. J Cell Biol. 2004;164:451–459. doi: 10.1083/jcb.200311112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Alexander WS, Viney EM, Zhang J-G, Metcalf D, Kauppi M, Hyland CD, Carpinelli MR, Stevenson W, Croker BA, Hilton AA, Ellis S, Selan C, Nandurkar HH, Goodnow CC, Kile BT, Nicola NA, Roberts AW, Hilton DJ. Thrombocytopenia and kidney disease in mice with a mutation in the C1galt1 gene. Proc Natl Acad Sci. 2006;103:16442–16447. doi: 10.1073/pnas.0607872103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Fu J, Gerhardt H, McDaniel JM, Xia B, Liu X, Ianciu L, Ny A, Hermans K, Silasi-Mansat R, McGee S, Nye E, Ju T, Ramirez MI, Carmeliet P, Cummings RD, Lupu F, Xia L. Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice. J Clin Invest. 2008;118:3725–3737. doi: 10.1172/JCI36077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Zhang L, Zhang Y, Ten Hagen KG. A mucin-type O-glycosyltransferase modulates cell adhesion during Drosophila development. J Biol Chem. 2008;283:34076–34086. doi: 10.1074/jbc.M804267200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Herr P, Korniychuk G, Yamamoto Y, Grubisic K, Oelgeschlager M. Regulation of TGF-⍰⍰signaling by N-acetylgalactosaminyltransferase-like 1 Develop. 2008;135:1813–1822. doi: 10.1242/dev.019323. [DOI] [PubMed] [Google Scholar]
  • 60.Ichikawa S, Sorenson AH, Austin AM, Mackenzie DS, Fritz TA, Moh A, Hui SL, Econs MJ. Ablation of Galnt3 gene leads to low-circulating intact fibroblast growth factor 23 (FgF23) concentrations and hyperphosphatemia despite increased Fgf23 expression. Endocrin. 2009;150:2543–2550. doi: 10.1210/en.2008-0877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.MMRC Strain Detail Sheet: 011647 – 129S5-Galnt10Gt(neo)78Lex/Mmnc
  • 62.Hennet T, Hagen F,K, Tabak LA, Marth JD. T-cell specific deletion of a polypeptide N-acetylgalactosaminyltransferase gene by site-directed recombination. Proc Natl Acad Sci. 1995;92:12070–12074. doi: 10.1073/pnas.92.26.12070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Dausset J, Moullec J, Bernard J. Acquired hemolytic anemia with polyagglutinability of red blood cells due to a new factor present in normal human serum (anti-Tn) Blood. 1959;XIV:1079–1093. [PubMed] [Google Scholar]
  • 64.Ju T, Cummings RD. Chaperone mutation in Tn syndrome. Nature. 2005;437:152. doi: 10.1038/4371252a. [DOI] [PubMed] [Google Scholar]
  • 65.Eijgenraam JW, van Kooten C. IgA1 glycosylation in IgA nephrophathy: as sweet as it can be. Kidney Intl. 2008;73:1106–1108. doi: 10.1038/ki.2008.16. [DOI] [PubMed] [Google Scholar]
  • 66.Iwase H, Tanaka A, Hiki Y, Kokubo T, Sano T, Ishii-Karakasa I, Hisatani K, Kobayashi Y, Hotta K. Analysis of the microheterogeneity of the IgA1 hinge glycopeptides having multiple O-linked oligosaccarides by capillary electrophoresis. Analyt Biochem. 2001;288:22–27. doi: 10.1006/abio.2000.4870. [DOI] [PubMed] [Google Scholar]
  • 67.Gharavi AG, Moldoveanu Z, Wyatt RJ, Barker CV, Woodford SY, Lifton RP, Mestecky J, Novak J, Julian BA. Aberrant IgA1 glycosylation is inherited in familial and sporadic IgA nephropathy. J Am Soc Nephrol. 2008;19:1008–1014. doi: 10.1681/ASN.2007091052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Kiryluk K, Gharavi AG, Izzzi C, Scolari F. IgA nephropathy – the case for a genetic basis becomes stronger. Nephrol Dial Tranplant. 2009 doi: 10.1093/ndt/gfp593. advanced access:doi: 1093/ndt/gfp593.j. [DOI] [PubMed] [Google Scholar]
  • 69.Suzuki H, Fan R, Zhang Z, Brown R, Hall S, Julian BA, Chatham WW, Suzuki Y, Wyatt RJ, Moldoveanu Z, Lee JY, Robinson J, Tomana M, Tomino Y, Mestecky J, Novak J. Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J Clin Invest. 2009;119:1668–1677. doi: 10.1172/JCI38468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Li G-S, Zhang H, Lv J-C, Shen Y, Wang HY. Variants of the C1GALT1 gene are associated with genetic susceptibility to IgA nephropathy. Kidney Intl. 2007;71:448–453. doi: 10.1038/sj.ki.5002088. [DOI] [PubMed] [Google Scholar]
  • 71.Sprecher E. Familial tumoral calcinosis: from characterization of a rare phenotype to the pathogenesis of ectopic calcification. J Invest Derm. 2009 doi: 10.1038/jid.2009.337. advance online:doi:10.1038/jid.2009.337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Kato K, Jeanneau C, Tarp MA, Benet-Pages A, Lorenz-Depiereux B, Bennett EP, Mandel U, Strom TM, Clausen H. Polypeptide GalNAc-transferase T3 and Familial tumoral calcinosis. J Biol Chem. 2006;281:18370–18377. doi: 10.1074/jbc.M602469200. [DOI] [PubMed] [Google Scholar]
  • 73.Sellers TA, Huang Y, Cunningham J, Goode EL, Sutphen R, Vierkant RA, Kelemen LE, Fredericksen ZS, Liebow M, Pankratz VS, Hartmann LC, Myer J, Iversen ES, Jr, Schildkraut JM, Phelan C. Association of single nucleotide polymorphisms in glycosylation genes with risk of epithelial ovarian cancer. Cancer Epidem Biomarkers Prev. 2008;17:397–404. doi: 10.1158/1055-9965.EPI-07-0565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.O'Halloran AM, Patterson CC, Horan P, Maree A, Curtin R, Stanton A, McKewon PP, Shields DC. Genetic polymorphisms in platelet-related proteins and coronary artery disease: investigation of candidate genes, including N-acetylgalactosaminyltransferase 4 (GALNT4) and sulphotransferase 1A1/2 (SULT1A1/2) J. Throm Thrombolys. 2009;27:175–184. doi: 10.1007/s11239-008-0196-z. [DOI] [PubMed] [Google Scholar]
  • 75.Guda K, Moinova H, He J, Jamison O, Ravi L, Natale L, Lutterbaugh J, Lawrence E, Lewis S, Willson JKV, Lowe J, Wiesner GL, Parmigiani G, Barnholtz-Sloan J, Dawson DW, Velculescu VE, Kinzler KW, Papadopoulos N, Vogelstein B, Willis J, Gerken TA, Markowitz SD. Inactivating germ-line and somatic mutations in polypeptide N-acetylgalactosaminyltransferase 12 in human colon cancers. Proc Natl Acad Sci. 2009;106:12921–12925. doi: 10.1073/pnas.0901454106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Velcich A, Yang W, Heyer J, Fragale A, Nicholas C, Viani S, Kucherlapati R, Lipkin M, Yang K, Augenlicht L. Colorectal cancer in mice genetically deficient in the mucin MUC2. Science. 2002;295:1726–1729. doi: 10.1126/science.1069094. [DOI] [PubMed] [Google Scholar]
  • 77.An G, Wei B, Xia B, McDaniel JM, Ju T, Cummings RD, Braun J, Xia L. Increased susceptibility to colitis and colorectal tumors in mice lacking core 3-derived O-glycans. J Exptl Med. 2007;204:1417–1429. doi: 10.1084/jem.20061929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Aoki K, Porterfield M, Lee SS, Dong B, Nguyen K, McGlamry KH, Tiemeyer M. The diversity of O-linked glycans expressed during Drosophila melanogaster development reflects state- and tissue-specific requiremnts for cell signaling. J Biol Chem. 2008;283:30385–30400. doi: 10.1074/jbc.M804925200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Julenius K, Molgaard A, Gupta R, Brunak S. Prediction, onservation analysis and structural characterization of mammalian mucin-type O-glycosylation sites. Glycobiol 15. 2004;15:153–164. doi: 10.1093/glycob/cwh151. [DOI] [PubMed] [Google Scholar]
  • 80.Chen Y-Z, Tang YR, Sheng ZY, Zhang Z. Prediction of mucin-type O-glycosylation sites in mammalian proteins using the composition of k-spaced amino acid pairs. BMC Bioinform. 2008;9:101–113. doi: 10.1186/1471-2105-9-101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Sakaki K, Nagamine N, Sakakibara Y. Support vector machine prediction of N- and O-glycosylation sites using whole sequence information and subcellular localization. Trans Bioinform. 2009;2:25–35. [Google Scholar]
  • 82.Lu L, Niu B, Zhao J, Liu L, Lu W-C, Liu XJ, Li Y-X, Cai Y-D. GalNAc-transferase specificity predition based on feature selection method. Peptides. 2009;30:359–364. doi: 10.1016/j.peptides.2008.09.020. [DOI] [PubMed] [Google Scholar]
  • 83.Gerkin TA, Raman J, Fritz T, Jamison O. Identification of common and unique peptide substrate preferences for UDP-GalNAc:polypeptide⍰- N acetylgalactosaminyltransferases T1 and T2 derived rom oriented random peptide substrates. J Biol Chem. 2006;281:32403–32416. doi: 10.1074/jbc.M605149200. [DOI] [PubMed] [Google Scholar]
  • 84.Perrine CL, Ganguli A, Wu P, Bertozzi CR, Fritz TA, Raman J, Tabak LA, Gerken TA. Glycopeptide-preferring polypeptide GalNAc transferase 10 (ppGalNAc T10), involved in mucin-type O-glycosylation, has a unique GalNAc-O-Ser/Thr-binding site in its catalytic domain not found in ppGalNAcT1 or T2. 2009;284:20387–20397. doi: 10.1074/jbc.M109.017236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Fritz TA, Hurley JH, Trinh L-B, Shiloach J, Tabak LA. The beginnings of mucin biosynthesis: The crystal structure of UDP-GalNAc:polypeptide⍰-N-acetylgalactosaminyltranserase-T1. Proc Natl Acad Sci. 2004;101:15307–15312. doi: 10.1073/pnas.0405657101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Fritz TA, Raman J, Tabak LA. Dynamic association between the catalytic and lectin domains of human UDP-GalNAc:polypeptide⍰-N-acetylgalactosaminyltranserase-2. J Biol Chem. 2006;281:8613–8619. doi: 10.1074/jbc.M513590200. [DOI] [PubMed] [Google Scholar]
  • 87.Kubota T, Shiba T, Sugioka S, Furukawa S, Sawaki H, Kato R, Wakatsuki S, Narimatsu H. Structural basis of carbohydrate transfer activity by human UDP-GalNAc:polypeptide⍰-N-acetylgalactosaminyltranserase (pp-GalNAc-T10) J Molec Biol. 2006;359:708–727. doi: 10.1016/j.jmb.2006.03.061. [DOI] [PubMed] [Google Scholar]
  • 88.Gross BJ, Swoboda JG, Walker S. A strategy to discover inhibitors of O-linked glycosylation. J Amer Chem Assoc. 2008;130:440–441. doi: 10.1021/ja078125s. [DOI] [PubMed] [Google Scholar]
  • 89.Yoshinao W, Michiko T. Tackling difficulties in the determination of O-glycosylation sites: Approaches to mucin-type glycoproteins. Trends Glycosci Glycotech. 2008;20:69–80. [Google Scholar]
  • 90.Jensen PH, Kolarich D, Packer NH. Mucin-type glycosylation- putting the pieces together. FEBS J. 2009 doi: 10.1111/j.1742-4658.2009.07429.x. doi:10.1111/j.1742-4658.07429.x. [DOI] [PubMed] [Google Scholar]
  • 91.Gerken TA, Owens CL, Pasumarty M. Determination of the site-specific O-glycosylation pattern of the porcine submaxillary mucin tandem repeat glycopeptides. J Biol Chem. 1997;272:9709–9719. doi: 10.1074/jbc.272.15.9709. [DOI] [PubMed] [Google Scholar]
  • 92.Singh PK, Hollingsworth MA. Cell surface-associated mucins in signal transduction. Trends Cell Biol. 2006;16:467–476. doi: 10.1016/j.tcb.2006.07.006. [DOI] [PubMed] [Google Scholar]
  • 93.Wagner KW, Punnoose EA, Januario Th., Lawrence DA, Pitti RM, Lancaster K, Lee D, von Goetz M, Yee SF, Totpal K, Huw L, Katta V, Cavet G, Hymonwitz SG, Amler L, Ashkenazi A. Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL. 2007;13:1070–1077. doi: 10.1038/nm1627. [DOI] [PubMed] [Google Scholar]
  • 94.Van Dyken SJ, Green RS, Marth JD. Stuctural and mechanistic features of protein O-glycosylation linked to CD8+ T-cell apoptosis. Molec Cell Biol. 2007;27:096–1111. doi: 10.1128/MCB.01750-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95.Workman HC, Sweeney C, Carraway KL., III The membrane mucin Muc4 inhibits apoptosis induced by multiple insults via ErbB2-dependent and ErbB2-independent mechanisms. Cancer Res. 2009;69:2845–2852. doi: 10.1158/0008-5472.CAN-08-2089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.Livet J, Weissman TA, Kang H, Draft RW, Lu J, Bennis RA, Sanes JR, Lichtman JW. Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature. 2007:56–62. doi: 10.1038/nature06293. [DOI] [PubMed] [Google Scholar]
  • 97.Laughlin ST, Bertozzi CR. Imaging the glycome. Proc Natl Acad Sci. 2009;106:12–17. doi: 10.1073/pnas.0811481106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Dehennaut V, Hanoulle X, Bodart J-F, Vilain J-P, Michalski JC, Landrieu I, Lippens G, Lefebvre T. Microinjection of recombinant O-GlcNAc transferase potentiates Xenopus oocytes M-phase entry. Biochem Biohpys Res Comm. 2008;369:539–546. doi: 10.1016/j.bbrc.2008.02.063. [DOI] [PubMed] [Google Scholar]
  • 99.Marth JD. A unified vision of the building blocks of life. Nature Cell Biol. 2008;10:1015–1016. doi: 10.1038/ncb0908-1015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100.Ten Hagen KG, Zhang L, Tian E, Zhang Y. Glycobiology on the fly: Developmental and mechanistic insights from Drosophila. Glycobiol. 2009;19:102–111. doi: 10.1093/glycob/cwn096. [DOI] [PMC free article] [PubMed] [Google Scholar]

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