Skip to main content

Mucin O-Glycan Branching Enzymes: Structure, Function, and Gene Regulation

  • Conference paper
  • First Online:
The Molecular Immunology of Complex Carbohydrates-3

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 705))

Abstract

Mucin O-glycans are conjugated carbohydrate chains that contain at the reducing terminus N-acetylgalactosamine linked covalently to serine/threonine in the peptide backbone. They are found in mucins and many nonmucin glycoproteins. The presence of a tandem repeat peptide heavily glycosylated with mucin O-glycans distinguishes mucins from other glycoproteins that contain mucin O-glycans. Muc14, -15, and -18, which do not contain a tandem repeat peptide, are the exceptions. To date, about six secreted and 14 membrane-tethered mucins have been reported based on cloned complementary DNA (cDNA) sequences [1, 2]. The functions of mucin O-glycans vary according to where they reside. For secreted mucins, O-glycans can retain water, maintain the viscoelastic properties of mucus secretion, and bind and clear inhaled and ingested pathogens, such as mycoplasma [3, 4], viruses [5], and bacteria [6]. This function depends primarily on heterogeneous carbohydrates, while the other two functions are determined by high carbohydrate content. High carbohydrate content and very heterogeneous carbohydrate structures found in secreted mucins enable them to perform the first line of innate immune defense at the epithelial surface of many mucus-secretory tissues, such as airways and the gastrointestinal tract. Under pathological conditions, overproduction of secreted mucins coupled with poor clearance of mucus causes obstructive lung diseases [7].

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Rose MC, Voynow JA (2006) Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol Rev 86:245–278

    PubMed  CAS  Google Scholar 

  2. Hollingsworth MA, Swanson BJ (2004) Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer 4:45–60

    PubMed  CAS  Google Scholar 

  3. Loomes LM, Uemura K, Childs RA, Paulson JC, Rogers GN, Scudder PR, Michalski JC, Hounsell EF, Taylor-Robinson D, Feizi T (1984) Erythrocyte receptors for mycoplasma pneumoniae are sialylated oligosaccharides of Ii antigen type. Nature 307:560–563

    PubMed  CAS  Google Scholar 

  4. Loveless RW, Feizi T (1989) Sialo-oligosaccharide receptors for mycoplasma pneumoniae and related oligosaccharides of poly-N-acetyllactosamine series are polarized at the cilia and apical-microvillar domains of the ciliated cells in human bronchial epithelium. Infect Immun 57:1285–1289

    PubMed  CAS  Google Scholar 

  5. Suzuki Y, Suzuki T, Matsumoto M (1983) Isolation and characterization of receptor sialoglycoprotein for hemagglutinating virus of Japan (sendai virus) from bovine erythrocyte membrane. J Biochem 93:1621–1633

    PubMed  CAS  Google Scholar 

  6. Andersson B, Dahmen J, Frejd T, Leffler H, Magnusson G, Noori G, Eden CS (1983) Identification of an active disaccharide unit of a glycoconjugate receptor for pneumococci attaching to human pharyngeal epithelial cells. J Exp Med 158:559–570

    PubMed  CAS  Google Scholar 

  7. Rose MC, Nickola TJ, Voynow JA (2001) Airway mucus obstruction: mucin glycoproteins, MUC gene regulation and goblet cell hyperplasia. Am J Respir Cell Mol Biol 25:533–537

    PubMed  CAS  Google Scholar 

  8. Van der Sluis M, De Koning BA, De Bruijn AC, Velcich A, Meijerink JP, Van Goudoever JB, Buller HA, Dekker J, Van Seuningen I, Renes IB, Einerhand AW (2006) Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131:117–129

    PubMed  Google Scholar 

  9. Velcich A, Yang W, Heyer J, Fragale A, Nicholas C, Viani S, Kucherlapati R, Lipkin M, Yang K, Augenlicht L (2002) Colorectal cancer in mice genetically deficient in the mucin Muc2. Science 295:1726–1729

    PubMed  CAS  Google Scholar 

  10. Singh PK, Hollingsworth MA (2006) Cell surface-associated mucins in signal transduction. Trends Cell Biol 16:467–476

    PubMed  CAS  Google Scholar 

  11. Carson DD, Julian J, Lessey BA, Prakobphol A, Fisher SJ (2006) MUC1 is a scaffold for selectin ligands in the human uterus. Front Biosci 11:2903–2908

    PubMed  CAS  Google Scholar 

  12. Schroeder JA, Masri AA, Adriance MC, Tessier JC, Kotlarczyk KL, Thompson MC, Gendler SJ (2004) MUC1 overexpression results in mammary gland tumorigenesis and prolonged alveolar differentiation. Oncogene 23:5739–5747

    PubMed  CAS  Google Scholar 

  13. Tsuboi S, Fukuda M (2001) Roles of O-linked oligosaccharides in immune responses. Bioessays 23:46–53

    PubMed  CAS  Google Scholar 

  14. McEver RP, Moore KL, Cummings RD (1995) Leukocyte trafficking mediated by selectin-carbohydrate interactions. J Biol Chem 270:11025–11028

    PubMed  CAS  Google Scholar 

  15. Shimodaira K, Nakayama J, Nakamura N, Hasebe O, Katsuyama T, Fukuda M (1997) Carcinoma-associated expression of core 2 beta-1, 6-N-acetylglucosaminyltransferase gene in human colorectal cancer: role of O-glycans in tumor progression. Cancer Res 57:5201–5206

    PubMed  CAS  Google Scholar 

  16. Williams D, Longmore G, Matta KL, Schachter H (1980) Mucin synthesis. II. Substrate specificity and product identification studies on canine submaxillary gland UDP-GlcNAc:Gal beta 1-3GalNAc(GlcNAc leads to GalNAc) beta 6-N-acetylglucosaminyltransferase. J Biol Chem 255:11253–11261

    PubMed  CAS  Google Scholar 

  17. Brockhausen I, Matta KL, Orr J, Schachter H (1985) Mucin synthesis, UDP-GlcNAc:GalNAc-R beta 3-N-acetylglucosaminyltransferase and UDP-GlcNAc:GlcNAc beta 1-3GalNAc-R (GlcNAc to GalNAc) beta 6-N-acetylglucosaminyltransferase from pig and rat colon mucosa. Biochemistry 24:1866–1874

    PubMed  CAS  Google Scholar 

  18. Brockhausen I, Matta KL, Orr J, Schachter H, Koenderman AH, van den Eijnden DH (1986) Mucin synthesis, conversion of R1-beta 1-3Gal-R2 to R1-beta 1-3(GlcNAc beta 1-6)gal-R2 and of R1-beta 1-3GalNAc-R2 to R1-beta 1-3(GlcNAc beta 1-6)GalNAc-R2 by a beta 6-N-acetylglucosaminyltransferase in pig gastric mucosa. Eur J Biochem 157:463–474

    PubMed  CAS  Google Scholar 

  19. Ropp PA, Little MR, Cheng PW (1991) Mucin biosynthesis: purification and characterization of a mucin beta 6N-acetylglucosaminyltransferase. J Biol Chem 266:23863–23871

    PubMed  CAS  Google Scholar 

  20. Bierhuizen MF, Fukuda M (1992) Expression cloning of a cDNA encoding UDP-GlcNAc:Gal beta 1-3-GalNAc-R (GlcNAc to GalNAc) beta 1-6GlcNAc transferase by gene transfer into CHO cells expressing polyoma large tumor antigen. Proc Natl Acad Sci USA 89:9326–9330

    PubMed  CAS  Google Scholar 

  21. Bierhuizen MF, Mattei MG, Fukuda M (1993) Expression of the developmental I antigen by a cloned human cDNA encoding a member of a beta-1, 6-N-acetylglucosaminyltransferase gene family. Genes Dev 7:468–478

    PubMed  CAS  Google Scholar 

  22. Schwientek T, Nomoto M, Levery SB, Merkx G, van Kessel AG, Bennett EP, Hollingsworth MA, Clausen H (1999) Control of O-glycan branch formation. Molecular cloning of human cDNA encoding a novel beta1, 6-N-acetylglucosaminyltransferase forming core 2 and core 4. J Biol Chem 274:4504–4512

    PubMed  CAS  Google Scholar 

  23. Yeh JC, Ong E, Fukuda M (1999) Molecular cloning and expression of a novel beta-1, 6-N-acetylglu-cosaminyltransferase that forms core 2, core 4, and I branches. J Biol Chem 274:3215–3221

    PubMed  CAS  Google Scholar 

  24. Schwientek T, Yeh JC, Levery SB, Keck B, Merkx G, van Kessel AG, Fukuda M, Clausen H (2000) Control of O-glycan branch formation. Molecular cloning and characterization of a novel thymus-associated core 2 beta1, 6-n-acetylglucosaminyltransferase. J Biol Chem 275:11106–11113

    PubMed  CAS  Google Scholar 

  25. Yen TY, Macher BA, Bryson S, Chang X, Tvaroska I, Tse R, Takeshita S, Lew AM, Datti A (2003) Highly conserved cysteines of mouse core 2 beta1, 6-N-acetylglucosaminyltransferase I form a network of disulfide bonds and include a thiol that affects enzyme activity. J Biol Chem 278:45864–45881

    PubMed  CAS  Google Scholar 

  26. Singh J, Khan GA, Kinarsky L, Cheng H, Wilken J, Choi KH, Bedows E, Sherman S, Cheng PW (2004) Identification of disulfide bonds among the nine core 2 N-acetylglucosaminyltransferase-M cysteines conserved in the mucin beta6-N-acetylglucosaminyltransferase family. J Biol Chem 279:38969–38977

    PubMed  CAS  Google Scholar 

  27. Bierhuizen MF, Maemura K, Kudo S, Fukuda M (1995) Genomic organization of core 2 and I branching beta-1, 6-N-acetylglucosaminyltransferases. Implication for evolution of the beta-1, 6-N-acetylglucosaminyltransferase gene family. Glycobiology 5:417–425

    PubMed  CAS  Google Scholar 

  28. Sekine M, Nara K, Suzuki A (1997) Tissue-specific regulation of mouse core 2 beta-1, 6-N-acetylglucosaminyltransferase. J Biol Chem 272:27246–27252

    PubMed  CAS  Google Scholar 

  29. Choi KH, Osorio FA, Cheng PW (2004) Mucin biosynthesis: bovine C2GnT-M gene, tissue-specific expression, and herpes virus-4 homologue. Am J Respir Cell Mol Biol 30:710–719

    PubMed  CAS  Google Scholar 

  30. Pak JE, Arnoux P, Zhou S, Sivarajah P, Satkunarajah M, Xing X, Rini JM (2006) X-ray crystal structure of leukocyte type core 2 beta1, 6-N-acetylglucosaminyltransferase. Evidence for a convergence of metal ion-independent glycosyltransferase mechanism. J Biol Chem 281:26693–26701

    PubMed  CAS  Google Scholar 

  31. Beum PV, Cheng PW (2001) Biosynthesis and function of beta 1, 6 branched mucin-type glycans. In: Wu AM (ed) The molecular immunology of complex carbohydrates-2. Acedemic, New York, pp 271–312

    Google Scholar 

  32. Brockhausen I (2006) Mucin-type O-glycans in human colon and breast cancer: glycodynamics and functions. EMBO Rep 7:599–604

    PubMed  CAS  Google Scholar 

  33. Clausen H, Bennett EP (1996) A family of UDP-GalNAc: polypeptide N-acetylgalactosaminyl-transferases control the initiation of mucin-type O-linked glycosylation. Glycobiology 6:635–646

    PubMed  CAS  Google Scholar 

  34. Elhammer AP, Poorman RA, Brown E, Maggiora LL, Hoogerheide JG, Kezdy FJ (1993) The specificity of UDP-GalNAc:Polypeptide N-acetylgalactosaminyltransferase as inferred from a database of in vivo substrates and from the in vitro glycosylation of proteins and peptides. J Biol Chem 268:10029–10038

    PubMed  CAS  Google Scholar 

  35. Wang Y, Agrwal N, Eckhardt AE, Stevens RD, Hill RL (1993) The acceptor substrate specificity of porcine submaxillary UDP-GalNAc:Polypeptide N-acetylgalactosaminyltransferase is dependent on the amino acid sequences adjacent to serine and threonine residues. J Biol Chem 268:22979–22983

    PubMed  CAS  Google Scholar 

  36. Wandall HH, Hassan H, Mirgorodskaya E, Kristensen AK, Roepstorff P, Bennett EP, Nielsen PA, Hollingsworth MA, Burchell J, Taylor-Papadimitriou J, Clausen H (1997) Substrate specificities of three members of the human UDP-N-acetyl-alpha-D-galactosamine:Polypeptide N-acetylgalactosaminyltransferase family, GalNAc-T1, -T2, and -T3. J Biol Chem 272:23503–23514

    PubMed  CAS  Google Scholar 

  37. Ju T, Aryal RP, Stowell CJ, Cummings RD (2008) Regulation of protein O-glycosylation by the endo-plasmic reticulum-localized molecular chaperone cosmc. J Cell Biol 182:531–542

    PubMed  CAS  Google Scholar 

  38. Uchimura K, Gauguet JM, Singer MS, Tsay D, Kannagi R, Muramatsu T, von Andrian UH, Rosen SD (2005) A major class of L-selectin ligands is eliminated in mice deficient in two sulfotransferases expressed in high endothelial venules. Nat Immunol 6:1105–1113

    PubMed  CAS  Google Scholar 

  39. Kawashima H, Petryniak B, Hiraoka N, Mitoma J, Huckaby V, Nakayama J, Uchimura K, Kadomatsu K, Muramatsu T, Lowe JB, Fukuda M (2005) N-acetylglucosamine-6-O-sulfotransferases 1 and 2 cooperatively control lymphocyte homing through L-selectin ligand biosynthesis in high endothelial venules. Nat Immunol 6:1096–1104

    PubMed  CAS  Google Scholar 

  40. Ujita M, McAuliffe J, Schwientek T, Almeida R, Hindsgaul O, Clausen H, Fukuda M (1998) Synthesis of poly-N-acetyllactosamine in core 2 branched O-glycans. The requirement of novel beta-1, 4-galactosyl-trans-ferase IV and beta-1, 3-n-acetylglucosaminyltransferase. J Biol Chem 273:34843–34849

    PubMed  CAS  Google Scholar 

  41. Sasaki K, Kurata-Miura K, Ujita M, Angata K, Nakagawa S, Sekine S, Nishi T, Fukuda M (1997) Expression cloning of cDNA encoding a human beta-1, 3-N-acetylglucosaminyltransferase that is essential for poly-N-acetyllactosamine synthesis. Proc Natl Acad Sci USA 94:14294–14299

    PubMed  CAS  Google Scholar 

  42. Watkins WM, Clarke JL (2001) The genetic regulation of fucosylated and sialylated antigens on developing myeloid cells. In: Wu AM (ed) The molecular immunology of complex carbohydrates-2. Acedemic, New York, pp 231–265

    Google Scholar 

  43. Iwai T, Inaba N, Naundorf A, Zhang Y, Gotoh M, Iwasaki H, Kudo T, Togayachi A, Ishizuka Y, Nakanishi H, Narimatsu H (2002) Molecular cloning and characterization of a novel UDP-GlcNAc:GalNAc-peptide beta1, 3-N-acetylglucosaminyltransferase (beta 3Gn-T6), an enzyme synthesizing the core 3 structure of O-glycans. J Biol Chem 277:12802–12809

    PubMed  CAS  Google Scholar 

  44. Zerfaoui M, Fukuda M, Langlet C, Mathieu S, Suzuki M, Lombardo D, El-Battari A (2002) The cytosolic and transmembrane domains of the beta 1, 6N-acetylglucosaminyltransferase (C2GnT) function as a cis to medial/Golgi-targeting determinant. Glycobiology 12:15–24

    PubMed  CAS  Google Scholar 

  45. Colley KJ (1997) Golgi localization of glycosyltransferases: more questions than answers. Glycobiology 7:1–13

    PubMed  CAS  Google Scholar 

  46. Yang X, Qin W, Lehotay M, Toki D, Dennis P, Schutzbach JS, Brockhausen I (2003) Soluble human core 2 beta6-N-acetylglucosaminyltransferase C2GnT1 requires its conserved cysteine residues for full activity. Biochim Biophys Acta 1648:62–74

    PubMed  CAS  Google Scholar 

  47. Tarbouriech N, Charnock SJ, Davies GJ (2001) Three-dimensional structures of the Mn and Mg dTDP complexes of the family GT-2 glycosyltransferase SpsA: a comparison with related NDP-sugar glycosyltrans-ferases. J Mol Biol 314:655–661

    PubMed  CAS  Google Scholar 

  48. Garinot-Schneider C, Lellouch AC, Geremia RA (2000) Identification of essential amino acid residues in the Sinorhizobium meliloti glucosyltransferase Exo. J Biol Chem 275:31407–31413

    PubMed  CAS  Google Scholar 

  49. Falkenberg VR, Fregien N (2007) Control of core 2 beta1, 6N-acetylglucosaminyltransferase-I transcription by Sp1 in lymphocytes and epithelial cells. Glycoconj J 24:511–519

    PubMed  CAS  Google Scholar 

  50. Tan S, Cheng PW (2007) Mucin biosynthesis: identification of the cis-regulatory elements of human C2GnT-M gene. Am J Respir Cell Mol Biol 36:737–745

    PubMed  CAS  Google Scholar 

  51. Sekine M, Taya C, Shitara H, Kikkawa Y, Akamatsu N, Kotani M, Miyazaki M, Suzuki A, Yonekawa H (2006) The cis-regulatory element Gsl5 is indispensable for proximal straight tubule cell-specific transcription of core 2 beta-1, 6-N-acetylglucosaminyltransferase in the mouse kidney. J Biol Chem 281:1008–1015

    PubMed  CAS  Google Scholar 

  52. Sekine M, Kikkawa Y, Takahama S, Tsuda K, Yonekawa H, Suzuki A (2002) Phylogenetic development of a regulatory gene for the core 2 GlcNAc transferase in mus musculus. J Biochem 132:387–393

    PubMed  CAS  Google Scholar 

  53. Sekine M, Taya C, Kikkawa Y, Yonekawa H, Takenaka M, Matsuoka Y, Imai E, Izawa M, Kannagi R, Suzuki A (2001) Regulation of mouse kidney tubular epithelial cell-specific expression of core 2 GlcNAc transferase. Eur J Biochem 268:1129–1135

    PubMed  CAS  Google Scholar 

  54. Falkenberg VR, Alvarez K, Roman C, Fregien N (2003) Multiple transcription initiation and alternative splicing in the 5’ untranslated region of the core 2 beta1-6N-acetylglucosaminyltransferase I gene. Glycobiology 13:411–418

    PubMed  CAS  Google Scholar 

  55. Hashimoto M, Tan S, Mori N, Cheng H, Cheng PW (2007) Mucin biosynthesis: molecular cloning and expression of mouse mucus-type core 2 beta1, 6N-acetylglucosaminyltransferase. Glycobiology 17:994–1006

    PubMed  CAS  Google Scholar 

  56. Inaba N, Hiruma T, Togayachi A, Iwasaki H, Wang XH, Furukawa Y, Sumi R, Kudo T, Fujimura K, Iwai T, Gotoh M, Nakamura M, Narimatsu H (2003) A novel I-branching beta-1, 6-N-acetylglucosaminyl-transferase involved in human blood group I antigen expression. Blood 101:2870–2876

    PubMed  CAS  Google Scholar 

  57. Twu YC, Chen CP, Hsieh CY, Tzeng CH, Sun CF, Wang SH, Chang MS, Yu LC (2007) I branching formation in erythroid differentiation is regulated by transcription factor C/EBPalpha. Blood 110:4526–4534

    PubMed  CAS  Google Scholar 

  58. Pras E, Raz J, Yahalom V, Frydman M, Garzozi HJ, Pras E, Hejtmancik JF (2004) A nonsense mutation in the glucosaminyl (N-acetyl) transferase 2 gene (GCNT2): association with autosomal recessive congenital cataracts. Invest Ophthalmol Vis Sci 45:1940–1945

    PubMed  Google Scholar 

  59. Ellies LG, Tsuboi S, Petryniak B, Lowe JB, Fukuda M, Marth JD (1998) Core 2 oligosaccharide biosynthesis distinguishes between selectin ligands essential for leukocyte homing and inflammation. Immunity 9:881–890

    PubMed  CAS  Google Scholar 

  60. Baum LG, Pang M, Perillo NL, Wu T, Delegeane A, Uittenbogaart CH, Fukuda M, Seilhamer JJ (1995) Human thymic epithelial cells express an endogenous lectin, galectin-1, which binds to core 2 O-glycans on thymocytes and T lymphoblastoid cells. J Exp Med 181:877–887

    PubMed  CAS  Google Scholar 

  61. Ellies LG, Tao W, Fellinger W, The HS, Ziltener HJ (1996) The CD43 130-kD peripheral T-cell activation antigen is downregulated in thymic positive selection. Blood 88:1725–1732

    PubMed  CAS  Google Scholar 

  62. Granovsky M, Fode C, Warren CE, Campbell RM, Marth JD, Pierce M, Fregien N, Dennis JW (1995) GlcNAc-transferase V and core 2 GlcNAc-transferase expression in the developing mouse embryo. Glycobiology 5:797–806

    PubMed  CAS  Google Scholar 

  63. Mitoma J, Petryniak B, Hiraoka N, Yeh JC, Lowe JB, Fukuda M (2003) Extended core 1 and core 2 branched O-glycans differentially modulate sialyl lewis X-type L-selectin ligand activity. J Biol Chem 278:9953–9961

    PubMed  CAS  Google Scholar 

  64. Lowe JB (2002) Glycosylation in the control of selectin counter-receptor structure and function. Immunol Rev 186:19–36

    PubMed  CAS  Google Scholar 

  65. Machida E, Nakayama J, Amano J, Fukuda M (2001) Clinicopathological significance of core 2 beta1, 6-N-acetylglucosaminyltransferase messenger RNA expressed in the pulmonary adenocarcinoma determined by in situ hybridization. Cancer Res 61:2226–2231

    PubMed  CAS  Google Scholar 

  66. Renkonen J, Rabina J, Mattila P, Grenman R, Renkonen R (2001) Core 2 beta1, 6-N-acetylglucosaminyl-transferases and alpha1, 3-fucosyltransferases regulate the synthesis of O-glycans on selectin ligands on oral cavity carcinoma cells. APMIS 109:500–506

    PubMed  CAS  Google Scholar 

  67. Beum PV, Singh J, Burdick M, Hollingsworth MA, Cheng PW (1999) Expression of core 2 beta-1, 6-N-acetylglucosaminyltransferase in a human pancreatic cancer cell line results in altered expression of MUC1 tumor-associated epitopes. J Biol Chem 274:24641–24648

    PubMed  CAS  Google Scholar 

  68. Brockhausen I, Kuhns W, Schachter H, Matta KL, Sutherland DR, Baker MA (1991) Biosynthesis of O-glycans in leukocytes from normal donors and from patients with leukemia: increase in O-glycan core 2 UDP-GlcNAc:Gal beta 3 GalNAc alpha-R (GlcNAc to GalNAc) beta(1-6)-N-acetylglucosaminyltransferase in leukemic cells. Cancer Res 51:1257–1263

    PubMed  CAS  Google Scholar 

  69. Heffernan M, Lotan R, Amos B, Palcic M, Takano R, Dennis JW (1993) Branching beta 1-6N-acetylglucosaminetransferases and polylactosamine expression in mouse F9 teratocarcinoma cells and differentiated counterparts. J Biol Chem 268:1242–1251

    PubMed  CAS  Google Scholar 

  70. Datti A, Dennis JW (1993) Regulation of UDP-GlcNAc:Gal beta 1-3GalNAc-R beta 1-6-N-acetylglucosaminyltransferase (GlcNAc to GalNAc) in chinese hamster ovary cells. J Biol Chem 268:5409–5416

    PubMed  CAS  Google Scholar 

  71. Nakamura M, Kudo T, Narimatsu H, Furukawa Y, Kikuchi J, Asakura S, Yang W, Iwase S, Hatake K, Miura Y (1998) Single glycosyltransferase, core 2 beta1  →  6-N-acetylglucosaminyltransferase, regulates cell surface sialyl-lex expression level in human pre-B lymphocytic leukemia cell line KM3 treated with phorbolester. J Biol Chem 273:26779–26789

    PubMed  CAS  Google Scholar 

  72. Kenney D, Cairns L, Remold-O’Donnell E, Peterson J, Rosen FS, Parkman R (1986) Morphological abnormalities in the lymphocytes of patients with the wiskott-aldrich syndrome. Blood 68:1329–1332

    PubMed  CAS  Google Scholar 

  73. Perry GS III, Spector BD, Schuman LM, Mandel JS, Anderson VE, McHugh RB, Hanson MR, Fahlstrom SM, Krivit W, Kersey JH (1980) The Wiskott-Aldrich syndrome in the United States and Canada (1892–1979). J Pediatr 97:72–78

    PubMed  Google Scholar 

  74. Ochs HD, Slichter SJ, Harker LA, Von Behrens WE, Clark RA, Wedgwood RJ (1980) The Wiskott-Aldrich syndrome: studies of lymphocytes, granulocytes, and platelets. Blood 55:243–252

    PubMed  CAS  Google Scholar 

  75. Parkman R, Remold-O’Donnell E, Kenney DM, Perrine S, Rosen FS (1981) Surface protein abnormalities in lymphocytes and platelets from patients with Wiskott-Aldrich syndrome. Lancet 2:1387–1389

    PubMed  CAS  Google Scholar 

  76. Remold-O’Donnell E, Kenney DM, Parkman R, Cairns L, Savage B, Rosen FS (1984) Characterization of a human lymphocyte surface sialoglycoprotein that is defective in Wiskott-Aldrich syndrome. J Exp Med 159:1705–1723

    PubMed  Google Scholar 

  77. Park JK, Rosenstein YJ, Remold-O’Donnell E, Bierer BE, Rosen FS, Burakoff SJ (1991) Enhancement of T-cell activation by the CD43 molecule whose expression is defective in Wiskott-Aldrich syndrome. Nature 350:706–709

    PubMed  CAS  Google Scholar 

  78. Manjunath N, Johnson RS, Staunton DE, Pasqualini R, Ardman B (1993) Targeted disruption of CD43 gene enhances T lymphocyte adhesion. J Immunol 151:1528–1534

    PubMed  CAS  Google Scholar 

  79. Lefebvre JC, Giordanengo V, Limouse M, Doglio A, Cucchiarini M, Monpoux F, Mariani R, Peyron JF (1994) Altered glycosylation of leukosialin, CD43, in HIV-1-infected cells of the CEM line. J Exp Med 180:1609–1617

    PubMed  CAS  Google Scholar 

  80. Orlacchio A, Sarchielli P, Gallai V, Datti A, Saccardi C, Palmerini CA (1997) Activity levels of a beta1, 6N-acetylglucosaminyltransferase in lymphomonocytes from multiple sclerosis patients. J Neurol Sci 151:177–183

    PubMed  CAS  Google Scholar 

  81. Nishio Y, Warren CE, Buczek-Thomas JA, Rulfs J, Koya D, Aiello LP, Feener EP, Miller TB Jr, Dennis JW, King GL (1995) Identification and characterization of a gene regulating enzymatic glycosylation which is induced by diabetes and hyperglycemia specifically in rat cardiac tissue. J Clin Invest 96:1759–1767

    PubMed  CAS  Google Scholar 

  82. Panicot L, Mas E, Thivolet C, Lombardo D (1999) Circulating antibodies against an exocrine pancreatic enzyme in type 1 diabetes. Diabetes 48:2316–2323

    PubMed  CAS  Google Scholar 

  83. Piller F, Piller V, Fox RI, Fukuda M (1988) Human T-lymphocyte activation is associated with changes in O-glycan biosynthesis. J Biol Chem 263:15146–15150

    Google Scholar 

  84. Fukuda M (2006) Roles of mucin-type O-glycans synthesized by core2beta1, 6-N-acetylglucosaminyltransferase. Methods Enzymol 416:332–346

    PubMed  CAS  Google Scholar 

  85. Sperandio M, Thatte A, Foy D, Ellies LG, Marth JD, Ley K (2001) Severe impairment of leukocyte rolling in venules of core 2 glucosaminyltransferase-deficient mice. Blood 97:3812–3819

    PubMed  CAS  Google Scholar 

  86. Kimura AK, Wigzell H (1978) Cell surface glycoproteins of murine cytotoxic T lymphocytes. I. T 145, a new cell surface glycoprotein selectively expressed on Ly 1−2+ cytotoxic T lymphocytes. J Exp Med 147:1418–1434

    PubMed  CAS  Google Scholar 

  87. Andersson LC, Gahmberg CG, Kimura AK, Wigzell H (1978) Activated human T lymphocytes display new surface glycoproteins. Proc Natl Acad Sci USA 75:3455–3458

    PubMed  CAS  Google Scholar 

  88. Dalziel M, Whitehouse C, McFarlane I, Brockhausen I, Gschmeissner S, Schwientek T, Clausen H, Burchell JM, Taylor-Papadimitriou J (2001) The relative activities of the C2GnT1 and ST3Gal-I glycosyltransferases determine O-glycan structure and expression of a tumor-associated epitope on MUC1. J Biol Chem 276:11007–11015

    PubMed  CAS  Google Scholar 

  89. Carlow DA, Ziltener HJ (2006) CD43 deficiency has no impact in competitive in vivo assays of neutrophil or activated T cell recruitment efficiency. J Immunol 177:6450–6459

    PubMed  CAS  Google Scholar 

  90. Grabie N, Delfs MW, Lim YC, Westrich JR, Luscinskas FW, Lichtman AH (2002) Beta-galactoside alpha2, 3-sialyltransferase-I gene expression during Th2 but not Th1 differentiation: implications for core2-glycan formation on cell surface proteins. Eur J Immunol 32:2766–2772

    PubMed  CAS  Google Scholar 

  91. Barran P, Fellinger W, Warren CE, Dennis JW, Ziltener HJ (1997) Modification of CD43 and other lymphocyte O-glycoproteins by core 2N-acetylglucosaminyltransferase. Glycobiology 7:129–136

    PubMed  CAS  Google Scholar 

  92. Kikuchi J, Shinohara H, Nonomura C, Ando H, Takaku S, Nojiri H, Nakamura M (2005) Not core 2 beta 1, 6-N-acetylglucosaminyltransferase-2 or -3 but-1 regulates sialyl-Lewis x expression in human precursor B cells. Glycobiology 15:271–280

    PubMed  CAS  Google Scholar 

  93. Fukuda M, Carlsson SR, Klock JC, Dell A (1986) Structures of O-linked oligosaccharides isolated from normal granulocytes, chronic myelogenous leukemia cells, and acute myelogenous leukemia cells. J Biol Chem 261:12796–12806

    PubMed  CAS  Google Scholar 

  94. Maemura K, Fukuda M (1992) Poly-N-acetyllactosaminyl O-glycans attached to leukosialin. The presence of sialyl Le(x) structures in O-glycans. J Biol Chem 267:24379–24386

    PubMed  CAS  Google Scholar 

  95. Yang J, Hirata T, Croce K, Merrill-Skoloff G, Tchernychev B, Williams E, Flaumenhaft R, Furie BC, Furie B (1999) Targeted gene disruption demonstrates that P-selectin glycoprotein ligand 1 (PSGL-1) is required for P-selectin-mediated but not E-selectin-mediated neutrophil rolling and migration. J Exp Med 190:1769–1782

    PubMed  CAS  Google Scholar 

  96. Shimizu Y, Shaw S, Graber N, Gopal TV, Horgan KJ, Van Seventer GA, Newman W (1991) Activation-independent binding of human memory T cells to adhesion molecule ELAM-1. Nature 349:799–802

    PubMed  CAS  Google Scholar 

  97. Von Andrian UH, Hansell P, Chambers JD, Berger EM, Torres Filho I, Butcher EC, Arfors KE (1992) L-selectin function is required for beta 2-integrin-mediated neutrophil adhesion at physiological shear rates in vivo. Am J Physiol 263:H1034–1044

    Google Scholar 

  98. Lowe JB (2003) Glycan-dependent leukocyte adhesion and recruitment in inflammation. Curr Opin Cell Biol 15:531–538

    PubMed  CAS  Google Scholar 

  99. Lenter M, Levinovitz A, Isenmann S, Vestweber D (1994) Monospecific and common glycoprotein ligands for E- and P-selectin on myeloid cells. J Cell Biol 125:471–481

    PubMed  CAS  Google Scholar 

  100. Lim YC, Xie H, Come CE, Alexander SI, Grusby MJ, Lichtman AH, Luscinskas FW (2001) IL-12, STAT4-dependent up-regulation of CD4(+) T cell core 2 beta-1, 6-n-acetylglucosaminyltransferase, an enzyme essential for biosynthesis of P-selectin ligands. J Immunol 167:4476–4484

    PubMed  CAS  Google Scholar 

  101. Honn KV, Tang DG, Crissman JD (1992) Platelets and cancer metastasis: a causal relationship? Cancer Metastasis Rev 11:325–351

    PubMed  CAS  Google Scholar 

  102. Karpatkin S, Pearlstein E (1981) Role of platelets in tumor cell metastases. Ann Intern Med 95:636–641

    PubMed  CAS  Google Scholar 

  103. Hiraoka N, Kawashima H, Petryniak B, Nakayama J, Mitoma J, Marth JD, Lowe JB, Fukuda M (2004) Core 2 branching beta1, 6-N-acetylglucosaminyltransferase and high endothelial venule-restricted sulfotransferase collaboratively control lymphocyte homing. J Biol Chem 279:3058–3067

    PubMed  CAS  Google Scholar 

  104. Broide DH, Miller M, Castaneda D, Nayar J, Cho JY, Roman M, Ellies LG, Sriramarao P (2002) Core 2 oligosaccharides mediate eosinophil and neutrophil peritoneal but not lung recruitment. Am J Physiol Lung Cell Mol Physiol 282:L259–L266

    PubMed  CAS  Google Scholar 

  105. Smith MJ, Smith BR, Lawrence MB, Snapp KR (2004) Functional analysis of the combined role of the O-linked branching enzyme core 2 beta1-6-N-glucosaminyltransferase and dimerization of P-selectin glycoprotein ligand-1 in rolling on P-selectin. J Biol Chem 279:21984–21991

    PubMed  CAS  Google Scholar 

  106. Li F, Wilkins PP, Crawley S, Weinstein J, Cummings RD, McEver RP (1996) Post-translational modifications of recombinant P-selectin glycoprotein ligand-1 required for binding to P- and E-selectin. J Biol Chem 271:3255–3264

    PubMed  CAS  Google Scholar 

  107. Kumar R, Camphausen RT, Sullivan FX, Cumming DA (1996) Core2 beta-1, 6-N-acetylglucosaminyl-transferase enzyme activity is critical for P-selectin glycoprotein ligand-1 binding to P-selectin. Blood 88:3872–3879

    PubMed  CAS  Google Scholar 

  108. Kanda H, Tanaka T, Matsumoto M, Umemoto E, Ebisuno Y, Kinoshita M, Noda M, Kannagi R, Hirata T, Murai T, Fukuda M, Miyasaka M (2004) Endomucin, a sialomucin expressed in high endothelial venules, supports L-selectin-mediated rolling. Int Immunol 16:1265–1274

    PubMed  CAS  Google Scholar 

  109. Prorok-Hamon M, Notel F, Mathieu S, Langlet C, Fukuda M, El-Battari A (2005) N-glycans of core2 beta(1, 6)-N-acetylglucosaminyltransferase-I (C2GnT-I) but not those of alpha(1, 3)-fucosyltransferase-VII (FucT-VII) are required for the synthesis of functional P-selectin glycoprotein ligand-1 (PSGL-1): effects on P-, L- and E-selectin binding. Biochem J 391:491–502

    PubMed  CAS  Google Scholar 

  110. Kikuchi J, Ozaki H, Nonomura C, Shinohara H, Iguchi S, Nojiri H, Hamada H, Kiuchi A, Nakamura M (2005) Transfection of antisense core 2 beta1, 6-N-acetylglucosaminyltransferase-1 cDNA suppresses selectin ligand expression and tissue infiltration of B-cell precursor leukemia cells. Leukemia 19:1934–1940

    PubMed  CAS  Google Scholar 

  111. Valenzuela HF, Pace KE, Cabrera PV, White R, Porvari K, Kaija H, Vihko P, Baum LG (2007) O-glycosylation regulates LNCaP prostate cancer cell susceptibility to apoptosis induced by galectin-1. Cancer Res 67:6155–6162

    PubMed  CAS  Google Scholar 

  112. Nguyen JT, Evans DP, Galvan M, Pace KE, Leitenberg D, Bui TN, Baum LG (2001) CD45 modulates galectin-1-induced T cell death: regulation by expression of core 2 O-glycans. J Immunol 167:5697–5707

    PubMed  CAS  Google Scholar 

  113. Stone EL, Ismail MN, Lee SH, Luu Y, Ramirez K, Haslam SM, Ho SB, Dell A, Fukuda MF, Marth JD (2009) Glycosyltransferase function in core 2-type protein O gycosylation. Mol Cell Biol 29:3770–3782

    PubMed  CAS  Google Scholar 

  114. Huang MC, Chen HY, Huang HC, Huang J, Liang JT, Shen TL, Lin NY, Ho CC, Cho IM, Hsu SM (2006) C2GnT-M is downregulated in colorectal cancer and its re-expression causes growth inhibition of colon cancer cells. Oncogene 25:3267–3276

    PubMed  CAS  Google Scholar 

  115. Brockhausen I (2006) Mucin-type O-glycans in human colon and breast cancer: glycodynamics and functions. EMBO Rep 7:599–604

    PubMed  CAS  Google Scholar 

  116. Ohyama C, Tsuboi S, Fukuda M (1999) Dual roles of sialyl Lewis x oligosaccharides in tumor metastasis and rejection by natural killer cells. EMBO J 18:1516–1525

    PubMed  CAS  Google Scholar 

  117. Berg EL, Robinson MK, Mansson O, Butcher EC, Magnani JL (1991) A carbohydrate domain common to both sialyl Le(a) and sialyl Le(x) is recognized by the endothelial cell leukocyte adhesion molecule ELAM-1. J Biol Chem 266:14869–14872

    PubMed  CAS  Google Scholar 

  118. Takada A, Ohmori K, Takahashi N, Tsuyuoka K, Yago A, Zenita K, Hasegawa A, Kannagi R (1991) Adhesion of human cancer cells to vascular endothelium mediated by a carbohydrate antigen, sialyl Lewis A. Biochem Biophys Res Commun 179:713–719

    PubMed  CAS  Google Scholar 

  119. Kannagi R (1997) Carbohydrate-mediated cell adhesion involved in hematogenous metastasis of cancer. Glycoconj J 14:577–584

    PubMed  CAS  Google Scholar 

  120. Hagisawa S, Ohyama C, Takahashi T, Endoh M, Moriya T, Nakayama J, Arai Y, Fukuda M (2005) Expression of core 2 beta1, 6-N-acetylglucosaminyltransferase facilitates prostate cancer progression. Glycobiology 15:1016–1024

    PubMed  CAS  Google Scholar 

  121. Nakayama J, Shimizu F, Katsuyama T (2002) Glycosyltransferase genes as tumor marker. Rinsho Byori Suppl 123:142–148

    CAS  Google Scholar 

  122. Dalziel M, Whitehouse C, McFarlane I, Brockhausen I, Gschmeissner S, Schwientek T, Clausen H, Burchell JM, Taylor-Papadimitriou J (2001) The relative activities of the C2GnT1 and ST3Gal-I glycosyltransferases determine O-glycan structure and expression of a tumor-associated epitope on MUC1. J Biol Chem 276:11007–11015

    PubMed  CAS  Google Scholar 

  123. Kim YJ, Borsig L, Varki NM, Varki A (1998) P-selectin deficiency attenuates tumor growth and metastasis. Proc Natl Acad Sci USA 95:9325–9330

    PubMed  CAS  Google Scholar 

  124. Qian F, Hanahan D, Weissman IL (2001) L-selectin can facilitate metastasis to lymph nodes in a transgenic mouse model of carcinogenesis. Proc Natl Acad Sci USA 98:3976–3981

    PubMed  CAS  Google Scholar 

  125. Cabrera PV, Amano M, Mitoma J, Chan J, Said J, Fukuda M, Baum LG (2006) Haploinsufficiency of C2GnT-I glycosyltransferase renders T lymphoma cells resistant to cell death. Blood 108:2399–2406

    PubMed  CAS  Google Scholar 

  126. Xia B, Royall JA, Damera G, Sachdev GP, Cummings RD (2005) Altered O-glycosylation and sulfation of airway mucins associated with cystic fibrosis. Glycobiology 15:747–775

    PubMed  CAS  Google Scholar 

  127. Iwai T, Kudo T, Kawamoto R, Kubota T, Togayachi A, Hiruma T, Okada T, Kawamoto T, Morozumi K, Narimatsu H (2005) Core 3 synthase is down-regulated in colon carcinoma and profoundly suppresses the metastatic potential of carcinoma cells. Proc Natl Acad Sci USA 102:4572–4577

    PubMed  CAS  Google Scholar 

  128. Hounsell EF, Fukuda M, Powell ME, Feizi T, Hakomori S (1980) A new O-glycosidically linked tri-hexosamine core structure in sheep gastric mucin: a preliminary note. Biochem Biophys Res Commun 92:1143–1150

    PubMed  CAS  Google Scholar 

  129. An G, Wei B, Xia B, McDaniel JM, Ju T, Cummings RD, Braun J, Xia L (2007) Increased susceptibility to colitis and colorectal tumors in mice lacking core 3-derived O-glycans. J Exp Med 204:1417–1429

    PubMed  CAS  Google Scholar 

  130. McBride DS, Brockhausen I, Kan FW (2005) Detection of glycosyltransferases in the golden hamster (Mesocricetus auratus) oviduct and evidence for the regulation of O-glycan biosynthesis during the estrous cycle. Biochim Biophys Acta 1721:107–115

    PubMed  CAS  Google Scholar 

  131. Beum PV, Basma H, Bastola DR, Cheng PW (2005) Mucin biosynthesis: upregulation of core 2 beta 1, 6N-acetylglucosaminyltransferase by retinoic acid and Th2 cytokines in a human airway epithelial cell line. Am J Physiol Lung Cell Mol Physiol 288:L116–L124

    PubMed  CAS  Google Scholar 

  132. Beum PV, Bastola DR, Cheng PW (2003) Mucin biosynthesis: epidermal growth factor downregulates core 2 enzymes in a human airway adenocarcinoma cell line. Am J Respir Cell Mol Biol 29:48–56

    PubMed  CAS  Google Scholar 

  133. White SJ, Underhill GH, Kaplan MH, Kansas GS (2001) Cutting edge: differential requirements for Stat4 in expression of glycosyltransferases responsible for selectin ligand formation in Th1 cells. J Immunol 167:628–631

    PubMed  CAS  Google Scholar 

  134. Ishibashi Y, Inouye Y, Okano T, Taniguchi A (2005) Regulation of sialyl-lewis x epitope expression by TNF-alpha and EGF in an airway carcinoma cell line. Glycoconj J 22:53–62

    PubMed  CAS  Google Scholar 

  135. Guo P, Zhang Y, Shen ZH, Zhang XY, Chen HL (2004) Effect of N-acetylglucosaminyltransferase V on the expressions of other glycosyltransferases. FEBS Lett 562:93–98

    PubMed  CAS  Google Scholar 

  136. Radhakrishnan P, Beum PV, Tan S, Cheng PW (2007) Butyrate induces sLex synthesis by stimulation of selective glycosyltransferase genes. Biochem Biophys Res Commun 359:457–462

    PubMed  CAS  Google Scholar 

  137. Yanagihara K, Seki M, Cheng PW (2001) Lipopolysaccharide induces mucus cell metaplasia in mouse lung. Am J Respir Cell Mol Biol 24:66–73

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors wish to acknowledge the support of the following funding agencies: NIH RO1 HL48282, R21 HL097238, Cystic Fibrosis Foundation, and the State of Nebraska-NRI Cancer Glycobiology Program, LB 595 and LB506.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Pi-Wan Cheng .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this paper

Cite this paper

Cheng, PW., Radhakrishnan, P. (2011). Mucin O-Glycan Branching Enzymes: Structure, Function, and Gene Regulation. In: Wu, A. (eds) The Molecular Immunology of Complex Carbohydrates-3. Advances in Experimental Medicine and Biology, vol 705. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-7877-6_25

Download citation

Publish with us

Policies and ethics