Key points are not available for this paper at this time.
Rare types of glycosylation often occur in a domain-specific manner and are involved in specific biological processes. In particular, O-fucose glycans are reported to regulate the functions of EGF domain-containing proteins such as Notch receptors. In the course of mass spectrometric analysis of O-glycans displayed on Drosophila Notch receptors expressed in S2 cells, we found an unusual O-linked N-acetylhexosamine (HexNAc) modification which occurs at a site distinct from those of O-fucose and O-glucose glycosylations. Modification site mapping by mass spectrometry and amino acid substitution studies revealed that O-HexNAc modification occurs on a serine or threonine located between the fifth and sixth cysteines within the EGF domain. This modification occurs simultaneously along with other closely positioned O-glycosylations. This modification was determined to be O-β-GlcNAc by galactosyltransferase labeling and β-N-acetyl-hexosaminidase digestion experiments and by immunoblotting with a specific antibody. O-GlcNAc modification occurs at multiple sites on Notch epidermal growth factor repeats. O-GlcNAc modification was also found on the extracellular domain of Delta, a ligand for Notch receptors. Although the O-GlcNAc modification is known to regulate a wide range of cellular processes, the list of known modified proteins has previously been limited to intracellular proteins in animals. Thus, the finding of O-GlcNAc modification in extracellular environments predicts a distinct glycosylation process that might be associated with a novel regulatory mechanism for Notch receptor activity. Rare types of glycosylation often occur in a domain-specific manner and are involved in specific biological processes. In particular, O-fucose glycans are reported to regulate the functions of EGF domain-containing proteins such as Notch receptors. In the course of mass spectrometric analysis of O-glycans displayed on Drosophila Notch receptors expressed in S2 cells, we found an unusual O-linked N-acetylhexosamine (HexNAc) modification which occurs at a site distinct from those of O-fucose and O-glucose glycosylations. Modification site mapping by mass spectrometry and amino acid substitution studies revealed that O-HexNAc modification occurs on a serine or threonine located between the fifth and sixth cysteines within the EGF domain. This modification occurs simultaneously along with other closely positioned O-glycosylations. This modification was determined to be O-β-GlcNAc by galactosyltransferase labeling and β-N-acetyl-hexosaminidase digestion experiments and by immunoblotting with a specific antibody. O-GlcNAc modification occurs at multiple sites on Notch epidermal growth factor repeats. O-GlcNAc modification was also found on the extracellular domain of Delta, a ligand for Notch receptors. Although the O-GlcNAc modification is known to regulate a wide range of cellular processes, the list of known modified proteins has previously been limited to intracellular proteins in animals. Thus, the finding of O-GlcNAc modification in extracellular environments predicts a distinct glycosylation process that might be associated with a novel regulatory mechanism for Notch receptor activity. Protein glycosylation is a common co- and post-translational modification that has critical biological functions at both the cellular and organismal levels. In addition to the generally observed types of glycosylation such as N-glycosylation and mucin-type O-glycosylation, several unusual glycans have recently been found to play important roles in specific biological processes. Such unusual glycosylations are often observed as specific modifications on certain protein domains. One such domain is the epidermal growth factor (EGF) 3The abbreviations used are:EGFepidermal growth factorHexNAcN-acetylhexosamineNeuAcN-acetylneuraminic acidGlcNAcN-acetylglucosaminePLAPplacental alkaline phosphataseECLE. crista galli lectinICNintracellular NotchECNextracellular Notchβ4GalT-1β-1,4-galactosyltransferase 1HPLChigh performance liquid chromatographyMALDI-TOFmatrix-assisted laser desorption ionization-time of flightMSmass spectrometryPBSphosphate-buffered salineOGTO-GlcNAc transferase 3The abbreviations used are:EGFepidermal growth factorHexNAcN-acetylhexosamineNeuAcN-acetylneuraminic acidGlcNAcN-acetylglucosaminePLAPplacental alkaline phosphataseECLE. crista galli lectinICNintracellular NotchECNextracellular Notchβ4GalT-1β-1,4-galactosyltransferase 1HPLChigh performance liquid chromatographyMALDI-TOFmatrix-assisted laser desorption ionization-time of flightMSmass spectrometryPBSphosphate-buffered salineOGTO-GlcNAc transferase domain characterized as a small domain of 30–40 amino acids that is stabilized by 3 disulfide bonds. Three types of unusual post-translational modifications have been found at conserved residues within certain EGF domains. These modifications comprise the β-hydroxylation of Asp or Asn residues, O-linked glucose (O-glucose), and O-linked fucose (O-fucose) (1Harris R.J. Spellman M.W. Glycobiology. 1993; 3: 219-224Crossref PubMed Scopus (221) Google Scholar). epidermal growth factor N-acetylhexosamine N-acetylneuraminic acid N-acetylglucosamine placental alkaline phosphatase E. crista galli lectin intracellular Notch extracellular Notch β-1,4-galactosyltransferase 1 high performance liquid chromatography matrix-assisted laser desorption ionization-time of flight mass spectrometry phosphate-buffered saline O-GlcNAc transferase epidermal growth factor N-acetylhexosamine N-acetylneuraminic acid N-acetylglucosamine placental alkaline phosphatase E. crista galli lectin intracellular Notch extracellular Notch β-1,4-galactosyltransferase 1 high performance liquid chromatography matrix-assisted laser desorption ionization-time of flight mass spectrometry phosphate-buffered saline O-GlcNAc transferase O-Fucose and O-glucose glycans have been reported in many proteins involved in blood coagulation and fibrolysis, which are relatively abundant in blood plasma. The consensus sequence for O-glucosylation is predicted to be C1XSXPC2 (C1 and C2 are the first and second conserved cysteine residues; X is any amino acid), and the carbohydrate structure of the fully elongated form is a trisaccharide, Xyl-α1,3-Xyl-α1,3-Glu-O-Ser (1Harris R.J. Spellman M.W. Glycobiology. 1993; 3: 219-224Crossref PubMed Scopus (221) Google Scholar). In contrast, the consensus sequence for O-fucosylation is proposed to be C2XXX(A/G/S)S/TC3 (2Haines N. Irvine K.D. Nat. Rev. Mol. Cell Biol. 2003; 4: 786-797Crossref PubMed Scopus (335) Google Scholar), and the fully elongated structure is a tetrasaccharide, NeuAc-α2,6/3-Gal-β1,4-Glc-NAc-β1,3-Fuc-O-Ser/Thr (1Harris R.J. Spellman M.W. Glycobiology. 1993; 3: 219-224Crossref PubMed Scopus (221) Google Scholar, 3Moloney D.J. Shair L.H. Lu F.M. Xia J. Locke R. Matta K.L. Haltiwanger R.S. J. Biol. Chem. 2000; 275: 9604-9611Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar). Recent studies have revealed that EGF-specific O-glycans are not limited to plasma glycoproteins and exist in less abundantly expressed cell surface glycoproteins involved in intercellular signal transduction, such as Notch receptors (3Moloney D.J. Shair L.H. Lu F.M. Xia J. Locke R. Matta K.L. Haltiwanger R.S. J. Biol. Chem. 2000; 275: 9604-9611Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar). Notch receptors mediate an evolutionarily conserved signaling that regulates a wide range of developmental processes (4Artavanis-Tsakonas S. Rand M.D. Lake R.J. Science. 1999; 284: 770-776Crossref PubMed Scopus (4874) Google Scholar). The extracellular domain of Notch receptors is mainly composed of tandemly repeated EGF domains. Drosophila Notch and mammalian Notch1 contain 36 EGF domains in the EGF repeats, many of which are expected to be O-glucosylated and O-fucosylated (2Haines N. Irvine K.D. Nat. Rev. Mol. Cell Biol. 2003; 4: 786-797Crossref PubMed Scopus (335) Google Scholar, 5Haltiwanger R.S. Stanley P. Biochim. Biophys. Acta. 2002; 1573: 328-335Crossref PubMed Scopus (85) Google Scholar). The biological significance of these rare O-glycans in EGF domains has been investigated by mutagenizing modifiable residues (6Bjoern S. Foster D.C. Thim L. Wiberg F.C. Christensen M. Komiyama Y. Pedersen A.H. Kisiel W. J. Biol. Chem. 1991; 266: 11051-11057Abstract Full Text PDF PubMed Google Scholar) or, more recently, by manipulating glycosyltransferase genes involved in the glycosylation process. The specific glycosyltransferases include O-fucosyltransferase 1 (Pofut1 in mammals and Ofut1 in Drosophila) that transfers fucose onto peptides via an α-O-linkage (7Wang Y. Shao L. Shi S. Harris R.J. Spellman M.W. Stanley P. Haltiwanger R.S. J. Biol. Chem. 2001; 276: 40338-40345Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar) and fringe-related gene products that transfer GlcNAc onto Fuc-O-Ser/Thr (8Moloney D.J. Panin V.M. Johnston S.H. Chen J. Shao L. Wilson R. Wang Y. Stanley P. Irvine K.D. Haltiwanger R.S. Vogt T.F. Nature. 2000; 406: 369-375Crossref PubMed Scopus (717) Google Scholar) (9Bruckner K. Perez L. Clausen H. Cohen S. Nature. 2000; 406: 411-415Crossref PubMed Scopus (590) Google Scholar). The down-regulation or mutation of Pofut1/Ofut1 genes results in the loss of Notch signaling activity, suggesting their essential roles in Notch signaling (10Okajima T. Irvine K.D. Cell. 2002; 111: 893-904Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar, 11Sasamura T. Sasaki N. Miyashita F. Nakao S. Ishikawa H.O. Ito M. Kitagawa M. Harigaya K. Spana E. Bilder D. Perrimon N. Matsuno K. Development. 2003; 130: 4785-4795Crossref PubMed Scopus (146) Google Scholar, 12Shi S. Stanley P. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 5234-5239Crossref PubMed Scopus (322) Google Scholar). The GlcNAc modification by Fringe is shown to modulate the physical interaction between Notch receptors and 2 types of Notch ligands, Delta and Serrate/Jagged (9Bruckner K. Perez L. Clausen H. Cohen S. Nature. 2000; 406: 411-415Crossref PubMed Scopus (590) Google Scholar, 13Stanley P. Curr. Opin. Struct. Biol. 2007; 17: 530-535Crossref PubMed Scopus (123) Google Scholar, 14Okajima T. Xu A. Irvine K.D. J. Biol. Chem. 2003; 278: 42340-42345Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar). Moreover, β-1,4-galactosyltransferase 1 (β4GalT-1), which adds galactose onto GlcNAc-β1,3-Fuc-O-Ser/Thr, is shown to be necessary for Fringe to exert its effect in mammalian cells (15Chen J. Moloney D.J. Stanley P. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 13716-13721Crossref PubMed Scopus (129) Google Scholar) but not in Drosophila (16Xu A. Haines N. Dlugosz M. Rana N.A. Takeuchi H. Haltiwanger R.S. Irvine K.D. J. Biol. Chem. 2007; 282: 35153-35162Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). All these examples emphasize the pivotal roles of O-fucose glycans on Notch receptors. In Drosophila the presence of O-fucose has been demonstrated in Notch fragments expressed in S2 cells (10Okajima T. Irvine K.D. Cell. 2002; 111: 893-904Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar, 14Okajima T. Xu A. Irvine K.D. J. Biol. Chem. 2003; 278: 42340-42345Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar, 16Xu A. Haines N. Dlugosz M. Rana N.A. Takeuchi H. Haltiwanger R.S. Irvine K.D. J. Biol. Chem. 2007; 282: 35153-35162Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 17Lei L. Xu A. Panin V.M. Irvine K.D. Development. 2003; 130: 6411-6421Crossref PubMed Scopus (78) Google Scholar, 18Panin V.M. Shao L. Lei L. Moloney D.J. Irvine K.D. Haltiwanger R.S. J. Biol. Chem. 2002; 277: 29945-29952Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar); however, until very recently the presence of O-glucose glycans had not been experimentally investigated (19Acar M. Jafar-Nejad H. Takeuchi H. A. D. Rana N.A. H. Haltiwanger R.S. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). In the course of mass spectrometric analysis to the of the O-glycans displayed on Notch EGF repeats, we a novel O-β-GlcNAc modification that a located between the fifth and sixth cysteines within the EGF domain. the of is the first of proteins in animals. and from Irvine was from of The the intracellular domain of Notch was from Drosophila was from Cohen The intracellular domain extracellular domain alkaline phosphatase and was to the of the as a The of the are in and the for are shown in and by the process. The sequence of was by was the and and was and as previously A. Lei L. Irvine K.D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The of the are shown in fragments a domain for and by and as a The products with and sites of (9Bruckner K. Perez L. Clausen H. Cohen S. Nature. 2000; 406: 411-415Crossref PubMed Scopus (590) Google Scholar). the was the sites of and a protein was used for the of cells in with was as previously (10Okajima T. Irvine K.D. Cell. 2002; 111: 893-904Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar). cell for the was with in a cell of with Protein was the of an and was in with in S2 cell was as previously (10Okajima T. Irvine K.D. Cell. 2002; 111: 893-904Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar). the of by such that on of the The used for are in of EGF EGF domains in the or with and with and the proteins with of with proteins with the The in a and was by with a at at a of between and was used for the The of was as was at Notch was by the addition of 1 to a of and to a of in a and of and of to the for at 3 of was and the was for in the digestion was at by the addition of 1 of was 2 of the was by with the of of and was with or and the analysis of proteins with the in the acid as a in 1 of acid and on the 1 of acid in acid was on the and as the of laser with the laser within the range was and and The mass range was at with the mass at the analysis of proteins with the in the with and an of The and as the analysis of small in the acid as a peptides in a and on the 1 of acid in was and an of laser with a laser of was a the with an of laser and with with glycosylation 1 1 the the in glycosylation 1 and at the was by the 3 with GlcNAc transferase was in the glycosylation 2 of in K. and of proteins from S2 cells as previously T. Y. M. K. T. K. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). at the 3 with phosphate-buffered saline and was by liquid digestion of was in 2 1 at the was with a and to digestion for was for 3 at to the of the Protein or and to a and with saline and the was with crista galli lectin for 1 3 with the was with for 3 with the lectin was in and 2 with was as previously PubMed Scopus Google Scholar). immunoblotting with other the the was with and and with the by in the immunoblotting with an in and was used as the The was a or The was by a or by to and the of the was with with the proteins by in with the proteins at for in and the of Notch cells in 1 1 and the was at for 2 Protein which with 2 of cells with and with for 3 with the cells with and in as cells with and in for at at and the with to a of 2 and to the of a O-HexNAc Modification on Notch the mass spectrometric analysis of glycans displayed on the EGF of Notch the EGF domain was on the that its amino acid sequence to the consensus of both O-fucose and O-glucose modifications Notch was expressed in S2 cells, from the and to analysis 1 at to the with disulfide bonds. The mass by from 1 to 2 the presence of This was as that to the with O-fucose on the that for Ofut1 the of the The mass from 2 to 3 3 to and to the presence of and The presence of be as a GlcNAc modification on a cell for was to of Notch in the was from the by and was with The was by mass spectrometry analysis of at and revealed that both from the The mass of the is Thus, the at to the with The at be as the O-fucosylated modified with and In the with mass to and observed those include an O-glucosylation site but not an O-fucosylation Thus, the at was to be glycans both O-fucose and O-glucose on the proposed structure in the O-fucose glycans to be with the other to however, as peptides with with the of the which to the presence of multiple from the to the the peptides by the peptides to the that a at The at the mass of the the sequence of which was by analysis Thus, the mass of mass is with the mass of analysis of the at a at which to the mass The loss of the is a of modifications such as O-GlcNAc and O-fucose PubMed Scopus Google Scholar, A. Haltiwanger R.S. PubMed Scopus Google Scholar); the presence of modification on the of a Modification the modification the of the was In the to both and peptides observed the occurs as and In contrast, the occurs as This the modification site to In the course of of the a of the was in analysis of the that a of the mass of the by mass M.D. Lu PubMed Scopus Google Scholar). The a distinct in the for mapping the modification The presence of and the of that threonine at is the modified amino These results that the is to via an the O-HexNAc modification was with by in The of the displayed The mass of between 1 at and the mass of the O-fucose the mass of and between 1 and 2 and between 2 and modification with and the of these with that of the of a mass to modification was In contrast, the of the O-fucosylation site mass to the mass to O-HexNAc was These that is not from the structure of the O-fucose the O-glucosylation site or with other sites and The of the of mass to and and in the a mass to was observed The of the glycosylation a that to to peptides these results that Notch is modified simultaneously with 3 O-glycans that are to distinct modification sites at and a to substitution O-HexNAc a mutation was the In the the mass to was but the to the form was more in the of the Thus, both and as modification sites for O-HexNAc the of O-HexNAc at these residues be of O-β-GlcNAc the structure of novel we a PubMed Scopus Google Scholar). This the specific of the a the with galactose was by the lectin with was by lectin with The of was by the the signal was observed the and the signal was by the addition of analysis of the products the mass to the modification with galactose These that is modified with that O-GlcNAc modification occurs on a of with a modified was and with the in the of Thus, we that is modified with the of the between and was with and to In the from the a was observed at that to with This the at was and the to the was observed These the of the O-HexNAc which is from mucin-type that is with Although the O-β-GlcNAc modification on Notch is an extracellular is known to occur on a of and a specific the serine or threonine GlcNAc the has been PubMed Scopus Google Scholar). O-β-GlcNAc modification on Notch be by the and to Although signal was in the a signal was in the EGF that O-β-GlcNAc modification on Notch an to O-GlcNAc modification on we on be in proteins from S2 cells, and in glycosyltransferase was from as an shown in was with GlcNAc by the and O-GlcNAc transferase R.S. J. Biol. Chem. Full Text PDF PubMed Google Scholar), the O-GlcNAc EGF domain modification for its activity. Thus, O-GlcNAc modification on EGF domains is to be by an as the O-GlcNAc modification not to be by down-regulation of known glycosyltransferase genes involved in specific and by with an of which the intracellular O-GlcNAc R.S. K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). O-β-GlcNAc Modification at on Notch EGF we O-β-GlcNAc modification occurs on the EGF of Notch receptors. Notch EGF with expressed in S2 cells and by with the antibody. was observed in but not in the This signal is not from the on the Notch receptors as results The signal was the with but not with that O-β-GlcNAc modification occurs on EGF of Notch receptors O-GlcNAc modification occurs on other EGF several of the The signal was observed in and but not in Although the of with not the of O-GlcNAc these results that O-β-GlcNAc modification occurs at multiple sites on Notch EGF such as and which contain at at the to the site on O-GlcNAc modification was also on Delta, a ligand for Notch which multiple residues at the and not acid sequence of the O-GlcNAc modification of Drosophila and Notch receptors. The amino acid sequence located between the fifth and sixth conserved cysteines of 36 EGF domains from Drosophila Notch and Notch1 are The O-GlcNAc modification site is by an conserved residues, and residues are in of O-GlcNAc on Notch the presence of O-GlcNAc modification on the the Notch receptor or the intracellular expressed in S2 cells, by antibody. with O-GlcNAc revealed the presence of O-GlcNAc modification on the Notch receptors but not on the intracellular that the is not the of Notch we used the cell that Notch receptors M.D. S. J. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar). Notch receptors and the presence of O-GlcNAc modification was by immunoblotting with O-GlcNAc the O-GlcNAc modification is on the cell cells with Notch fragments by O-GlcNAc that Notch is the Notch extracellular domain we of the that the of from the cells M.D. S. J. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar). small of proteins in the proteins by The by revealed that of the proteins at to Notch of intracellular O-GlcNAc transferase by with for not O-GlcNAc modification on Notch receptors these results demonstrated that the on the extracellular domain of Notch receptors occurs to the proposed structure of O-glycans on Notch receptors to the of an extracellular O-β-GlcNAc modification in Drosophila S2 in the was reported that a small of proteins was on the surface of J. Biol. Chem. Full Text PDF PubMed Google Scholar). to proteins on the cell surface of Biophys. 1991; PubMed Scopus Google Scholar). Although is that the presence of O-GlcNAc at the of the Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), such proteins have not been and O-GlcNAc is to be to the and Thus, the first of proteins in the extracellular O-GlcNAc modification is by the J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). This is not to be for the O-GlcNAc modification in as the O-linked modification on EGF domains occurs by the of or This is by the that for not O-GlcNAc on the extracellular domain of Notch receptors. the that in cells might to the on Notch receptors at the extracellular domain. might from to the of or by an O-GlcNAc transferase EGF domain modification for its suggesting that modification occurs in an Although O-GlcNAc have been reported in such as F. T. H. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar) and M. T. L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), the GlcNAc modification of and residues by these occurs via an Thus, we that the O-GlcNAc transferase for the O-GlcNAc modification of the Notch EGF is distinct from the O-GlcNAc in This is with the that genes for O-GlcNAc transferase have been in the of or F. T. H. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). Although is to that novel glycosyltransferases to might to the O-GlcNAc modification in the analysis of the domain of not to the of the proteins with the of or The that proteins have not been until that such modification is with a to the products of the EGF from S2 cells O-linked by on EGF repeats, the of products that from (16Xu A. Haines N. Dlugosz M. Rana N.A. Takeuchi H. Haltiwanger R.S. Irvine K.D. J. Biol. Chem. 2007; 282: 35153-35162Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). is to finding that many EGF domains in Drosophila are modified with O-GlcNAc as the residues at the to the O-β-GlcNAc modification site are relatively conserved Thus, that Notch is in S2 cells, modification on other sites occur or a limited of EGF domains are the used in these of other peptides and of the consensus sequence for O-GlcNAc modification on EGF domains be to these In addition to Notch and and Protein are reported to be O-fucosylated or O-glucosylated T. A. T. J. PubMed Scopus Google Scholar). with the of these plasma glycoproteins not contain In contrast, the residues are in both Notch receptors and Notch from animals. Thus, O-GlcNAc modification might be to regulate biological processes Although the O-GlcNAc modification was as a in S2 cells, the structure might be elongated in other cellular The that the structure that glycosylation occur or other glycosyltransferases with are In is for the of on EGF domains (15Chen J. Moloney D.J. Stanley P. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 13716-13721Crossref PubMed Scopus (129) Google Scholar). the O-GlcNAc modification occurs in be elongated of the Notch that the O-GlcNAc modification occurs simultaneously with other in the O-GlcNAc modification site not to other glycosylation In in O-fucose O-glucose modification sites not Thus, the O-GlcNAc modification and other on with has been that GlcNAc modification onto the O-fucose of EGF domains an essential in the of physical between Notch receptors and their (8Moloney D.J. Panin V.M. Johnston S.H. Chen J. Shao L. Wilson R. Wang Y. Stanley P. Irvine K.D. Haltiwanger R.S. Vogt T.F. Nature. 2000; 406: 369-375Crossref PubMed Scopus (717) Google Scholar, K. Perez L. Clausen H. Cohen S. Nature. 2000; 406: 411-415Crossref PubMed Scopus (590) Google Scholar). Fringe which the transfer of GlcNAc onto are shown to be involved in many developmental processes both in and Drosophila (2Haines N. Irvine K.D. Nat. Rev. Mol. Cell Biol. 2003; 4: 786-797Crossref PubMed Scopus (335) Google Scholar, 13Stanley P. Curr. Opin. Struct. Biol. 2007; 17: 530-535Crossref PubMed Scopus (123) Google Scholar). Although the of extracellular O-GlcNAc modification is might be associated with a novel of Notch receptor activity. is reported that in which GlcNAc modifications on Notch receptors are to a in the specific displayed more Notch with the S. M. M. H. Y. M. S. Nat. Cell Biol. 2001; 3: PubMed Scopus Google Scholar, K. Perrimon N. U. Nat. Cell Biol. 2001; 3: PubMed Scopus Google Scholar). Although not rare types of glycosylation are essential for protein S. Y. Haltiwanger R.S. Stanley P. J. Biol. Chem. 2007; 282: Full Text Full Text PDF PubMed Scopus Google Scholar), is that O-GlcNAc modification on Notch receptors is associated with a of the observed in The of the glycosyltransferase genes for O-GlcNAc modification and studies in Drosophila and the biological of novel post-translational the for Y. and R. Haltiwanger for and K. Irvine for on the with
Matsuura et al. (Fri,) studied this question.
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