Fringe is a glycosyltransferase that modifies Notch
Abstract
Notch receptors function in highly conserved intercellular signalling pathways that direct cell-fate decisions, proliferation and apoptosis in metazoans. Fringe proteins can positively and negatively modulate the ability of Notch ligands to activate the Notch receptor. Here we establish the biochemical mechanism of Fringe action. Drosophila and mammalian Fringe proteins possess a fucose-specific beta1,3 N-acetylglucosaminyltransferase activity that initiates elongation of O-linked fucose residues attached to epidermal growth factor-like sequence repeats of Notch. We obtained biological evidence that Fringe-dependent elongation of O-linked fucose on Notch modulates Notch signalling by using co-culture assays in mammalian cells and by expression of an enzymatically inactive Fringe mutant in Drosophila. The post-translational modification of Notch by Fringe represents a striking example of modulation of a signalling event by differential receptor glycosylation and identifies a mechanism that is likely to be relevant to other signalling pathways.
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Fringe is a glycosyltransferase that modifies Notch and thereby modulates Notch-Delta interactions.
“An entirely new fi eld opened up with the discovery that the Fringe molecule is a glycosyltransferase that modi fi es the important signaling protein Notch and thus modulates Notch -Delta interactions (182, 184).”
From Biological roles of glycans (2017) · cites this paper as [184]
Cites
Targeted gene expression as a means of altering cell fates and generating dominant phenotypes
Brand, A. H., & Perrimon, N. (1993) · Development · doi:10.1242/dev.118.2.401 · Cited by 9,510 · see citing works
Notch Signaling: Cell Fate Control and Signal Integration in Development
Artavanis-Tsakonas, S., Rand, M. D., & Lake, R. J. (1999) · Science · doi:10.1126/science.284.5415.770 · Cited by 5,909 · see citing works
A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain
De Strooper, B., Annaert, W., Cupers, P., Saftig, P., Craessaerts, K., Mumm, J. S., Schroeter, E. H., Schrijvers, V., Wolfe, M. S., Ray, W. J., et al. (1999) · Nature · doi:10.1038/19083 · Cited by 2,100 · see citing works
A Novel Proteolytic Cleavage Involved in Notch Signaling
Brou, C., Logeat, F., Gupta-Rossi, N., Chable-Bessia, C., Bail, O. L., Doedens, J. R., Cumano, A., Roux, P., Black, R. A., & Israël, A. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)80417-7 · Cited by 1,089 · see citing works
A Ligand-Induced Extracellular Cleavage Regulates γ-Secretase-like Proteolytic Activation of Notch1
Mumm, J. S., Schroeter, E. H., Saxena, M. T., Griesemer, A. D., Tian, X., Pan, D., Ray, W. J., & Kopan, R. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)80416-5 · Cited by 852 · see citing works
Rebay, I., Fleming, R. J., Fehon, R. G., Cherbas, L., Cherbas, P. T., & Artavanis‐Tsakonas, S. (1991) · Cell · doi:10.1016/0092-8674(91)90064-6 · Cited by 772 · see citing works
Cheng, H.-J., Nakamoto, M., Bergemann, A. D., & Flanagan, J. G. (1995) · Cell · doi:10.1016/0092-8674(95)90426-3 · Cited by 738 · see citing works
Specificities of heparan sulphate proteoglycans in developmental processes
Perrimon, N., & Bernfield, M. R. (2000) · Nature · doi:10.1038/35008000 · Cited by 713 · see citing works
Jagged: A mammalian ligand that activates notch1
Lindsell, C. E., Shawber, C. J., Boulter, J., & Weinmaster, G. (1995) · Cell · doi:10.1016/0092-8674(95)90294-5 · Cited by 604 · see citing works
Fringe modulates Notch–ligand interactions
Panin, V. M., Papayannopoulos, V., Wilson, R., & Irvine, K. D. (1997) · Nature · doi:10.1038/43191 · Cited by 587 · see citing works
Self-citationHuman cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10)
Kotenko, S. V., Saccani, S., Izotova, L. S., Mirochnitchenko, O. V., & Pestka, S. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.4.1695 · Cited by 519 · see citing works
Hsieh, J. J.-D., Henkel, T., Salmon, P., Robey, E. A., Peterson, M. G., & Hayward, S. D. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.3.952 · Cited by 451 · see citing works
Rebay, I., Fehon, R. G., & Artavanis‐Tsakonas, S. (1993) · Cell · doi:10.1016/0092-8674(93)90423-n · Cited by 413 · see citing works
Hirschberg, C. B., Robbins, P. W., & Abeijón, C. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.49 · Cited by 385 · see citing works
Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2
Hicks, C. D., Johnston, S. H., diSibio, G., Collazo, A., Vogt, T., & Weinmaster, G. (2000) · Nature Cell Biology · doi:10.1038/35019553 · Cited by 373 · see citing works
Self-citationWiggins, C. A. R., & Munro, S. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.14.7945 · Cited by 366 · see citing works
Irvine, K. D., & Wieschaus, E. F. (1994) · Cell · doi:10.1016/0092-8674(94)90545-2 · Cited by 341 · see citing works
Self-citationMoloney, D. J., Shair, L. H., Lu, F. M., Xia, J. L., Locke, R. D., Matta, K. L., & Haltiwanger, R. S. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.13.9604 · Cited by 336 · see citing works
Self-citationA family of mammalian Fringe genes implicated in boundary determination and the Notch pathway
Johnston, S. H., Rauskolb, C., Wilson, R., Prabhakaran, B., Irvine, K. D., & Vogt, T. (1997) · Development · doi:10.1242/dev.124.11.2245 · Cited by 294 · see citing works
Self-citationKim, J., Irvine, K. D., & Carroll, S. B. (1995) · Cell · doi:10.1016/0092-8674(95)90476-x · Cited by 262 · see citing works
Self-citationO-Linked fucose and other post-translational modifications unique to EGF modules
Harris, R. J., & Spellman, M. W. (1993) · Glycobiology · doi:10.1093/glycob/3.3.219 · Cited by 261 · see citing works
Fleming, R. J., Gu, Y., & Hukriede, N. A. (1997) · Development · doi:10.1242/dev.124.15.2973 · Cited by 259 · see citing works
Beyer, T. A., Sadler, J. E., Rearick, J. I., Paulson, J. C., & Hill, R. L. (1981) · Advances in enzymology and related areas of molecular biology/Advances in enzymology and related subjects · doi:10.1002/9780470122976.ch2 · Cited by 224 · see citing works
Stanley, P., Narasimhan, S., Siminovitch, L., & Schachter, H. (1975) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.72.9.3323 · Cited by 222 · see citing works
Self-citationKelley, M. R., Kidd, S., Deutsch, W. A., et al. (1987) · Cell · doi:10.1016/0092-8674(87)90123-1 · Cited by 218 · see citing works
Fringe, Notch, and making developmental boundaries
Irvine, K. D. (1999) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(99)80066-5 · Cited by 191 · see citing works
Self-citationNotch signalling pathway and human diseases
Joutel, A., & Tournier‐Lasserve, E. (1998) · Seminars in Cell and Developmental Biology · doi:10.1006/scdb.1998.0261 · Cited by 189 · see citing works
Cohen, B. L., Bashirullah, A., Dagnino, L., Campbell, C. E., Fisher, W. W., Leow, C. C., Whiting, E., Ryan, D., Zinyk, D. L., Boulianne, G. L., et al. (1997) · Nature Genetics · doi:10.1038/ng0797-283 · Cited by 166 · see citing works
Sullivan, F. X., Kumar, R., Kriz, R., Stahl, M., Xu, G., Rouse, J. C., Chang, X.-J., Boodhoo, A., Potvin, B. W., & Cumming, D. A. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.14.8193 · Cited by 166 · see citing works
Roles of the Notch gene in Drosophila wing morphogenesis
de Celis, J. F., & Garcı́a-Bellido, A. (1994) · Mechanisms of Development · doi:10.1016/0925-4773(94)90080-9 · Cited by 145 · see citing works
Lübke, T., FIGURA, K. V., Körner, C., & Marquardt, T. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.37.25986 · Cited by 133 · see citing works
Dorsal—ventral signaling in limb development
Irvine, K. D., & Vogt, T. (1997) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(97)80090-7 · Cited by 131 · see citing works
Self-citationThe Abruptex domain of Notch regulates negative interactions between Notch, its ligands and Fringe
de Celis, J. F., & Bray, S. J. (2000) · Development · doi:10.1242/dev.127.6.1291 · Cited by 128 · see citing works
Klueg, K. M., & Muskavitch, M. A. T. (1999) · Journal of Cell Science · doi:10.1242/jcs.112.19.3289 · Cited by 127 · see citing works
Robertson, M. A., Etchison, J. R., Robertson, J. S., Summers, D. F., & Stanley, P. (1978) · Cell · doi:10.1016/0092-8674(78)90325-2 · Cited by 125 · see citing works
Self-citationKlein, T., & Arias, A. M. (1998) · Development · doi:10.1242/dev.125.15.2951 · Cited by 122 · see citing works
Secreted Fringe-like Signaling Molecules May Be Glycosyltransferases
Yuan, Y. P., Schultz, J., Mlodzik, M., & Peer Bork, B. (1997) · Cell · doi:10.1016/s0092-8674(00)81852-8 · Cited by 110 · see citing works
Οhyama, C., Smith, P. L., Angata, K., Fukuda, M. N., Lowe, J. B., & Fukuda, M. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.23.14582 · Cited by 93 · see citing works
FGF-8 isoforms differ in NIH3T3 cell transforming potential.
MacArthur, C. A., Lawshé, A., Shankar, D. B., Heikinheimo, M., & Shackleford, G. M. (1995) · PubMed · Cited by 91 · see citing works
Ripka, J., Adamany, A. M., & Stanley, P. (1986) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(86)90031-7 · Cited by 81 · see citing works
Self-citationPanin, V. M., & Irvine, K. D. (1998) · Seminars in Cell and Developmental Biology · doi:10.1006/scdb.1998.0263 · Cited by 79 · see citing works
Self-citationLu, F. M., & Lux, S. E. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.11.5663 · Cited by 75 · see citing works
Fringe forms a complex with Notch
Ju, B., Jeong, S., Bae, E., et al. (2000) · Nature · doi:10.1038/35012090 · Cited by 74 · see citing works
The O-Linked Fucose Glycosylation Pathway
Moloney, D. J., Lin, A. I., & Haltiwanger, R. S. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.30.19046 · Cited by 54 · see citing works
Self-citationMoloney, D. J. (1999) · Glycobiology · doi:10.1093/glycob/9.7.679 · Cited by 51 · see citing works
Self-citationDiseases of abnormal protein glycosylation: an emerging area.
Kornfeld, S. (1998) · Journal of Clinical Investigation · doi:10.1172/jci3140 · Cited by 50 · see citing works
The Effect of O-Fucosylation on the First EGF-like Domain from Human Blood Coagulation Factor VII
Kao, Y., Lee, G. F., Wang, Y., Starovasnik, M. A., Kelley, R. F., Spellman, M. W., & Lerner, L. E. (1999) · Biochemistry · doi:10.1021/bi990234z · Cited by 43 · see citing works
Self-citationLectin-resistant CHO cells: Selection of four new pea lectin-resistant phenotypes
Ripka, J., & Stanley, P. (1986) · Somatic Cell and Molecular Genetics · doi:10.1007/bf01560727 · Cited by 26 · see citing works
Self-citationZhang, Y., Malinovskii, V. A., Fiedler, T. J., et al. (1999) · Glycobiology · doi:10.1093/glycob/9.8.815 · Cited by 22 · see citing works
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Varki, A. (2017) · Glycobiology · doi:10.1093/glycob/cww086 · Cited by 2,635 · see citing works
“An entirely new field opened up with the discovery that the Fringe molecule is a glycosyltransferase that modifies the important signaling protein Notch and thus modulates Notch–Delta interactions (182, 184).”
BackgroundNotch signalling: a simple pathway becomes complex
Bray, S. J. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2009 · Cited by 2,620 · see citing works
Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation
Demetriou, M., Granovsky, M., Quaggin, S., & Dennis, J. W. (2001) · Nature · doi:10.1038/35055582 · Cited by 901 · see citing works
Role of Glycosylation in Development
Haltiwanger, R. S., & Lowe, J. B. (2004) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.73.011303.074043 · Cited by 757 · see citing works
Self-citationYoshida, A., Kobayashi, K., Manya, H., Taniguchi, K., Kano, H., Mizuno, M., Inazu, T., Mitsuhashi, H., Takahashi, S., Takeuchi, M., et al. (2001) · Developmental Cell · doi:10.1016/s1534-5807(01)00070-3 · Cited by 706 · see citing works
Wang, X., Inoue, S., Gu, J., Miyoshi, E., Noda, K., Li, W., Mizuno-Horikawa, Y., Nakano, M., Asahi, M., Takahashi, M., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507375102 · Cited by 476 · see citing works
Regulation of Notch Signaling by O-Linked Fucose
Okajima, T., & Irvine, K. D. (2002) · Cell · doi:10.1016/s0092-8674(02)01114-5 · Cited by 386 · see citing works
Self-citationProtein <i>O</i> -fucosyltransferase 1 is an essential component of Notch signaling pathways
Shi, S., & Stanley, P. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0831126100 · Cited by 381 · see citing works
Self-citationRumi Is a CAP10 Domain Glycosyltransferase that Modifies Notch and Is Required for Notch Signaling
Acar, M., Jafar-Nejad, H., Takeuchi, H., Rajan, A., Ibrani, D., Rana, N. A., Pan, H., Haltiwanger, R. S., & Bellen, H. J. (2008) · Cell · doi:10.1016/j.cell.2007.12.016 · Cited by 306 · see citing works
Self-citationSchwientek, T., Bennett, E. P., Flores, C., Thacker, J., Hollmann, M., Reis, C. A., Behrens, J., Mandel, U., Keck, B., Schäfer, M. A., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202684200 · Cited by 181 · see citing works
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Takeuchi, H., & Haltiwanger, R. S. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.05.115 · Cited by 166 · see citing works
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May, P., Bock, H. H., Nimpf, J., & Herz, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305858200 · Cited by 142 · see citing works
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Hagen, K. G. T., & Tran, D. T. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201807200 · Cited by 89 · see citing works
Yang, S.-A., Wang, W.-D., Chen, C.-T., Tseng, C.-Y., Chen, Y.-N., & Hsu, H.-J. (2013) · Developmental Biology · doi:10.1016/j.ydbio.2013.07.018 · Cited by 37 · see citing works
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- Authors
- Moloney, 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.
- Affiliations
- State University of New York (US)
- Rutgers, The State University of New Jersey (US)
- Princeton University (US)
- Albert Einstein College of Medicine (US)
- Genentech (US)
- Corresponding author
- Stanley, Pamela
- Irvine, Kenneth D.
- Haltiwanger, Robert S.
- Vogt, Thomas F.
- ORCID
- Venue
- Nature
- Published
- 2000-07
- Volume
- 406
- Issue
- 6794
- Pages
- 369-375
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2162097271
- Cited by
- 852
- References
- 49
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 14 · 2023: 15 · 2022: 23 · 2021: 18 · 2020: 28 · 2019: 19 · 2018: 31 · 2017: 30 · 2016: 22 · 2015: 20 · 2014: 32 · 2013: 27 · 2012: 32
- FWCI
- 24.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- fringe, Notch receptor, glycosyltransferases, receptor glycosylation, epidermal growth factor-like repeats, Drosophila, mammalian cells
- MeSH terms
- Animals, Catalysis, Cell Line, Drosophila, Epidermal Growth Factor, Fucose, Cricetinae, Membrane Proteins, Polysaccharides, Proteins, Recombinant Proteins, Transfection, Signal Transduction, Mutagenesis, Site-Directed, CHO Cells, Glycosyltransferases, N-Acetylglucosaminyltransferases, Drosophila Proteins, Receptors, Notch
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