Abstract
Fringe provides a clear example of the role that carbohydrate modifications can play in regulating signal transduction events. Fringe was originally identified for its role in dorsal/ventral boundary formation during Drosophila wing development (Irvine and Wieschaus 1994). Fringe functions by altering the response of the Notch receptor to its ligands, potentiating signaling from Delta and inhibiting that from Serrate (Fleming et al. 1997; Panin et al. 1997). Fringe modulates Notch activity by altering the structure of the O-fucose glycans on the Epidermal Growth Factor-like (EGF) repeats in the extracellular domain of Notch (Bruckner et al. 2000; Moloney et al. 2000a). O-Fucose modifications occur between the second and third conserved cysteines of an EGF repeat at the consensus site C2-X-X-X-X-(S/T)-C3, where X can be any amino acid and S/T is the modification site (Rana and Haltiwanger 2011). Numerous cell surface and secreted proteins have EGF repeats containing these sites. Fringe catalyzes the addition of a ß-linked GlcNAc to the 3′-hydroxyl of O-fucose, which can be further elongated to a tetrasaccharide with the structure NeuAcα2-3/6Galß1-4GlcNAcß1-3Fuc in mammals (Moloney et al. 2000b; Rana and Haltiwanger 2011), but only to the disaccharide GlcNAcß1-3Fuc in flies (Xu et al. 2007). The glycosyltransferase activity of fringe is essential for its ability to modulate Notch signaling (Bruckner et al. 2000; Moloney et al. 2000a), demonstrating that signal transduction events can be regulated by alterations in the glycosylation state of receptors.
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References
Bruckner K, Perez L, Clausen H, Cohen S (2000) Glycosyltransferase activity of Fringe modulates Notch-Delta interactions. Nature 406:411–415
Chillakuri CR, Sheppard D, Lea SM, Handford PA (2012) Notch receptor-ligand binding and activation: insights from molecular studies. Sem Cell Dev Biol 23:421–428
De Celis JF, Bray SJ (2000) The Abruptex domain of Notch regulates negative interactions between Notch, its ligands and Fringe. Development 127:1291–1302
Evrard YA, Lun Y, Aulehla A, Gan L, Johnson RL (1998) Lunatic fringe is an essential mediator of somite segmentation and patterning. Nature 394:377–381
Fleming RJ, Gu Y, Hukriede NA (1997) Serrate-mediated activation of Notch is specifically blocked by the product of the gene fringe in the dorsal compartment of the Drosophila wing imaginal disc. Development 124:2973–2981
Ge C, Stanley P (2008) The O-fucose glycan in the ligand-binding domain of Notch1 regulates embryogenesis and T cell development. Proc Natl Acad Sci U S A 105:1539–1544
Hambleton S, Valeyev NV, Muranyi A, Knott V, Werner JM, McMichael AJ, Handford PA, Downing AK (2004) Structural and functional properties of the human notch-1 ligand binding region. Structure (Camb) 12:2173–2183
Irvine KD (1999) Fringe, Notch, and making developmental boundaries. Curr Opin Genet Dev 9:434–441
Irvine KD, Wieschaus E (1994) Fringe, a boundary-specific signaling molecule, mediates interactions between dorsal and ventral cells during Drosophila wing development. Cell 79:595–606
Jinek M, Chen YW, Clausen H, Cohen SM, Conti E (2006) Structural insights into the Notch-modifying glycosyltransferase Fringe. Nat Struct Mol Biol 13:945–946
Johnston SH, Rauskolb C, Wilson R, Prabhakaran B, Irvine KD, Vogt TF (1997) A family of mammalian Fringe genes implicated in boundary determination and the Notch pathway. Development 124:2245–2254
Joutel A, Tournier-Lasserve E (1998) Notch signalling pathway and human diseases. Semin Cell Dev Biol 9:619–625
Koch U, Lacombe TA, Holland D, Bowman JL, Cohen BL, Egan SE, Guidos CJ (2001) Subversion of the T/B lineage decision in the thymus by lunatic fringe-mediated inhibition of Notch-1. Immunity 15:225–236
Kopan R, Ilagan MX (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137:216–233
Laufer E, Dahn R, Orozco OE, Yeo C-Y, Pisenti J, Henrique D, Abbott UK, Fallon JF, Tabin C (1997) Expression of Radical fringe in limb-bud ectoderm regulates apical ectodermal ridge formation. Nature 386:366–373
Luther KB, Schindelin H, Haltiwanger RS (2009) Structural and mechanistic insights into lunatic fringe from a kinetic analysis of enzyme mutants. J Biol Chem 284:3294–3305
Moloney DJ, Panin VM, Johnston SH, Chen J, Shao L, Wilson R, Wang Y, Stanley P, Irvine KD, Haltiwanger RS, Vogt TF (2000a) Fringe is a glycosyltransferase that modifies Notch. Nature 406:369–375
Moloney DJ, Shair L, Lu FM, Xia J, Locke R, Matta KL, Haltiwanger RS (2000b) Mammalian Notch1 is modified with two unusual forms of O-linked glycosylation found on epidermal growth factor-like modules. J Biol Chem 275:9604–9611
Moran JL, Shifley ET, Levorse JM, Mani S, Ostmann K, Perez-Balaguer A, Walker DM, Vogt TF, Cole SE (2009) Manic fringe is not required for embryonic development, and fringe family members do not exhibit redundant functions in the axial skeleton, limb, or hindbrain. Dev Dyn 238:1803–1812
Morgan TH (1919) A demonstration of genes modifying the character Notch. In: Contributions to the genetics of Drosophila melanogaster. Carnegie Institute of Washington, Washington, DC, pp 343–388
Munro S, Freeman M (2000) The notch signalling regulator fringe acts in the Golgi apparatus and requires the glycosyltransferase signature motif DXD. Curr Biol 10:813–820
Panin VM, Papayannopoulos V, Wilson R, Irvine KD (1997) Fringe modulates notch ligand interactions. Nature 387:908–912
Panin VM, Shao L, Lei L, Moloney DJ, Irvine KD, Haltiwanger RS (2002) Notch ligands are substrates for EGF protein O-fucosyltransferase and Fringe. J Biol Chem 277:29945–29952
Rampal R, Arboleda-Velasquez JF, Nita-Lazar A, Kosik KS, Haltiwanger RS (2005a) Highly conserved O-fucose sites have distinct effects on Notch1 function. J Biol Chem 280:32133–32140
Rampal R, Li AS, Moloney DJ, Georgiou SA, Luther KB, Nita-Lazar A, Haltiwanger RS (2005b) Lunatic Fringe, Manic Fringe, and Radical Fringe recognize similar specificity determinants in O-Fucosylated epidermal growth factor-like repeats. J Biol Chem 280:42454–42463
Rampal R, Luther KB, Haltiwanger RS (2007) Notch signaling in normal and disease States: possible therapies related to glycosylation. Curr Mol Med 7:427–445
Rana NA, Haltiwanger RS (2011) Fringe benefits: functional and structural impacts of Oglycosylation on the extracellular domain of Notch receptors. Curr Opin Struct Biol 21:583–589
Rodriguez-Esteban C, Schwabe JWR, De La Pena J, Foys B, Eshelman B, Izpisua Belmonte JC (1997) Radical fringe positions the apical ectodermal ridge at the dorsoventral boundary of the vertebrate limb. Nature 386:360–366
Ryan MJ, Bales C, Nelson A, Gonzalez DM, Underkoffler L, Segalov M, Wilson-Rawls J, Cole SE, Moran JL, Russo P, Spinner NB, Kusumi K, Loomes KM (2008) Bile duct proliferation in Jag1/fringe heterozygous mice identifies candidate modifiers of the Alagille syndrome hepatic phenotype. Hepatology 48:1989–1997
Shao L, Moloney DJ, Haltiwanger RS (2003) Fringe modifies O-Fucose on mouse Notch1 at epidermal growth factor-like repeats within the ligand-binding site and the Abruptex region. J Biol Chem 278:7775–7782
Shifley ET, Cole SE (2008) Lunatic fringe protein processing by proprotein convertases may contribute to the short protein half-life in the segmentation clock. Biochimica et biophysica acta 1783:2384–2390
Shifley ET, Vanhorn KM, Perez-Balaguer A, Franklin JD, Weinstein M, Cole SE (2008) Oscillatory lunatic fringe activity is crucial for segmentation of the anterior but not posterior skeleton. Development 135:899–908
Sparrow DB, Chapman G, Wouters MA, Whittock NV, Ellard S, Fatkin D, Turnpenny PD, Kusumi K, Sillence D, Dunwoodie SL (2006) Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. Am J Hum Genet 78:28–37
Stanley P, Guidos CJ (2009) Regulation of Notch signaling during T- and B-cell development by O-fucose glycans. Immunol Rev 230:201–215
Takeuchi H, Haltiwanger RS (2010) Role of glycosylation of Notch in development. Semin Cell Dev Biol 21:638–645
Tan JB, Xu K, Cretegny K, Visan I, Yuan JS, Egan SE, Guidos CJ (2009) Lunatic and manic fringe cooperatively enhance marginal zone B cell precursor competition for delta-like 1 in splenic endothelial niches. Immunity 30:254–263
Visan I, Tan JB, Yuan JS, Harper JA, Koch U, Guidos CJ (2006) Regulation of T lymphopoiesis by Notch1 and Lunatic fringe-mediated competition for intrathymic niches. Nat Immunol 7:634–643
Xu A, Haines N, Dlugosz M, Rana NA, Takeuchi H, Haltiwanger RS, Irvine KD (2007) In vitro reconstitution of the modulation of Drosophila notch-ligand binding by fringe. J Biol Chem 282:35153–35162
Xu K, Nieuwenhuis E, Cohen BL, Wang W, Canty AJ, Danska JS, Coultas L, Rossant J, Wu MY, Piscione TD, Nagy A, Gossler A, Hicks GG, Hui CC, Henkelman RM, Yu LX, Sled JG, Gridley T, Egan SE (2010) Lunatic Fringe-mediated Notch signaling is required for lung alveogenesis. Am J Physiol Lung Cell Mol Physiol 298:L45–56
Yamamoto S, Charng W-L, Rana NA, Kakuda S, Jaiswal M, Bayat V, Xiong B, Zhang K, Sandoval H, David G, Wang H, Haltiwanger RS, Bellen HJ (2012) A mutation in EGF repeat-8 of Notch discriminates between Serrate/Jagged and Delta family ligands. Science 338:1229–1232
Yang LT, Nichols JT, Yao C, Manilay JO, Robey EA, Weinmaster G (2005) Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1. Mol Biol Cell 16:927–942
Zhang N, Gridley T (1998) Defects in somite formation in lunatic fringe-deficient mice. Nature 394:374–377
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Haltiwanger, R.S. (2014). Fringe (UDP-GlcNAc: O-Fucosylpeptide ß1,3 N-Acetylglucosaminyltransferase). In: Taniguchi, N., Honke, K., Fukuda, M., Narimatsu, H., Yamaguchi, Y., Angata, T. (eds) Handbook of Glycosyltransferases and Related Genes. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54240-7_47
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DOI: https://doi.org/10.1007/978-4-431-54240-7_47
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