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UGA BCMB 8020 - Haltiwanger2002

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593Recent studies from several laboratories have providedevidence that cell surface complex carbohydrates play keyroles in the regulation of developmentally relevant signaltransduction events. The demonstration that Fringe, a knownmodifier of Notch function, is a fucose-specificN-acetylglucosaminyltransferase provided strong evidence thatthe Notch signaling pathway could be regulated by alterationsof O-fucose structures. More recently, the demonstration thatO-fucose modification of Cripto is essential for Nodal-dependent signaling provides further evidence of a role forglycosylation in signal transduction. These and other examplesprovide a new paradigm for the regulation of signaltransduction events by glycosylation.AddressDepartment of Biochemistry and Cell Biology, Institute for Cell andDevelopmental Biology, State University of New York at Stony Brook,Stony Brook, New York 11794-5215, USACurrent Opinion in Structural Biology 2002, 12:593–5980959-440X/02/$ — see front matter© 2002 Elsevier Science Ltd. All rights reserved.Abbreviations CFC Cripto, FRL-1, CrypticCSL CBF1, Suppressor of hairless, Lag-1EGF epidermal growth factorGlcNAc N-acetylglucosamine GPI glycosyl phosphatidyl inositolO-FucT-1 GDP-fucose: protein O-fucosyltransferase 1 TGFββtransforming growth factor βuPA urinary-type plasminogen activatorIntroductionThe discovery of the complexity and diversity of complexcarbohydrates on the cell surface led researchers over30 years ago to hypothesize that glycoconjugates play rolesin communication between cells and in the transfer ofinformation from the outside of the cell to the inside [1].As this type of communication is essential for numerousstages of development, specific carbohydrate modificationswere proposed to play roles in particular biological eventsat the cell surface. Over the years, numerous observationshave supported this concept. Early on, many of the stage-specific embryonic antigens (e.g. SSEA-1, SSEA-3,SSEA-4, HNK-1) were demonstrated to be specific carbohydrate structures [2]. For instance, SSEA-1 is theLewis x oligosaccharide, SSEA-3 and SSEA-4 are glycolipidsof the globo series, and HNK-1 is a sulfated glycan. Theexpression of unique glycan structures at specific stagesimplied a particular function for that structure. Thedemonstration that the presence or absence of polysialicacid alters homotypic interactions of the neural cell adhesionmolecule (NCAM) added further support [2]. More recently,the demonstration of embryonic lethality resulting fromthe genetic ablation of several glycosyltransferases hasrevealed that particular carbohydrate structures are essentialfor development to proceed past certain stages [3].Nonetheless, with the exception of NCAM, identifyingexamples of particular carbohydrate structures on specificproteins mediating such effects was, for many years, elusive. Recent work has begun to identify some of thesemolecules. The first examples came with the demonstrationthat cell surface heparan sulfate proteoglycans play anessential role in Wnt, hedgehog, FGF (fibroblast growthfactor) and TGFβ (transforming growth factor β) super-family pathways. More recently, O-fucose modifications ofepidermal growth factor (EGF)-like repeats have beenshown to modulate Notch, TGFβ family (Nodal) and urinary-type plasminogen activator (uPA) signal transduction.Several excellent recent reviews have been written concerning the role of heparan sulfate proteoglycans indevelopment [4–6] and thus will not be considered furtherhere. This review will focus on the recent studies of theO-fucose modifications of EGF repeats of Notch, Criptoand uPA.Involvement of O-fucose modifications of EGFrepeats in signal transductionO-linked carbohydrate modifications of EGF repeatsFucose O-linked to serine or threonine was first observedover 25 years ago as amino acid fucosides isolated fromhuman urine [7]. The first protein reported to bear O-fucosewas uPA [8], quickly followed by tissue-type plasminogenactivator and several clotting factors (factors VI, IX and XII)[9]. Comparison of the sequences surrounding the sites ofO-fucose modification on these proteins showed the fucose tobe localized to a putative consensus sequence within EGFrepeats. EGF repeats are small (approximately 40 aminoacid) protein motifs originally observed in epidermal growthfactor. They are defined by the presence of six conservedcysteine residues that form three disulfide bonds (Figure 1;[10]). EGF repeats occur in dozens of cell surface andsecreted proteins, and are known to play roles inprotein–protein interactions. The O-fucose modificationoccurs between the second and third conserved cysteines ofthe putative consensus sequence C2XXGGS/TC3[9].Proteins predicted to be modified with O-fucose based onthe presence of this consensus sequence have been demon-strated to bear the modification [11•–14•], indicating that it can be used to make accurate predictions about whether a protein will bear O-fucose (Table 1). Recent work has suggested that the originally proposed consensus site is toonarrow and that O-fucose modifications occur more broadlythan predicted [14•]. As a result, a broader consensus site,C2X3−5S/TC3, has recently been proposed.Regulation of signal transduction pathways in developmentby glycosylationRobert S HaltiwangerThe enzyme responsible for the addition of O-fucose toEGF repeats, GDP-fucose: protein O-fucosyltransferase 1(O-FucT-1), has been identified and cloned [15,16].O-FucT-1 appears to be a type II membrane glycoproteinlike most glycosyltransferases involved in the addition ofsugars to proteins. It will not fucosylate synthetic peptidescontaining the consensus sequence for O-fucose addition,but requires a properly folded EGF repeat containing theconsensus sequence (Figure 1; [15,17]). Homologs havebeen identified in species from Caenorhabditis elegans tohumans, an expression pattern that is consistent with thedistribution of proteins containing EGF repeats.The structure of the EGF repeat from factor VII with andwithout the O-fucose has been determined using NMR[18]. Although the O-fucose presents a significant epitopeon one face of the EGF repeat, no major


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