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• W1976978560 abstract "Cell-surface glycoprotein receptors have varying numbers of N-glycan sites. In this issue of Cell, Lau et al., 2007Lau K.S. Partridge E.A. Grigorian A. Silvescu C.I. Reinhold V.N. Demetriou M. Dennis J.W. Cell. 2007; (this issue)PubMed Google Scholar report that increasing intracellular UDP-GlcNAc leads to increased branching of N-glycans, increased receptor association with cell-surface galectin-3, and enhanced signaling. They also show that the kinetics of this response differ between growth-promoting receptors, which have 8–16 N-glycans, and those that induce growth arrest, which have very few N-glycans, suggesting that hexosamine flux may regulate the transition from growth to arrest. Cell-surface glycoprotein receptors have varying numbers of N-glycan sites. In this issue of Cell, Lau et al., 2007Lau K.S. Partridge E.A. Grigorian A. Silvescu C.I. Reinhold V.N. Demetriou M. Dennis J.W. Cell. 2007; (this issue)PubMed Google Scholar report that increasing intracellular UDP-GlcNAc leads to increased branching of N-glycans, increased receptor association with cell-surface galectin-3, and enhanced signaling. They also show that the kinetics of this response differ between growth-promoting receptors, which have 8–16 N-glycans, and those that induce growth arrest, which have very few N-glycans, suggesting that hexosamine flux may regulate the transition from growth to arrest. There is a large complement of N-glycans linked via asparagine in N-X-S/T motifs to glycoproteins of the plasma membrane, the molecular frontier of the cell. Glycoproteins may have many sites of N-glycan addition, and each site has the potential to be modified by tens of different N-glycan structures. This heterogeneity, which leads to multiple glycoforms of an individual glycoprotein, has traditionally been dismissed as a tolerable sloppiness in biosynthesis because N-glycans perform general functions in the folding, secretion, and solubility of glycoproteins. However, gene-targeting experiments have identified dramatic biological consequences of abolishing or reducing N-glycan branching in the Golgi (Lowe and Marth, 2003Lowe J.B. Marth J.D. Annu. Rev. Biochem. 2003; 72: 643-691Crossref PubMed Scopus (507) Google Scholar). The paper by Lau et al., 2007Lau K.S. Partridge E.A. Grigorian A. Silvescu C.I. Reinhold V.N. Demetriou M. Dennis J.W. Cell. 2007; (this issue)PubMed Google Scholar now suggests a method to the madness of N-glycan complexity. The authors' hypothesis links the evolutionary origins of the number of N-glycan sites in receptors that regulate growth with metabolic flux through the hexosamine pathway that regulates N-glycan branching in the Golgi. They show that changes in this flux affect the residence time of receptors on the cell surface by modulating the interactions of branched N-glycans with galectin-3, a glycan-binding protein. The galectin-3 lattice restricts endocytosis and thus hinders the downregulation of signaling. Their findings suggest that growth-promoting receptors, which have high numbers of N-glycans, and receptors that cause growth arrest, which have few N-glycans, are affected differently by metabolic flux through the hexosamine pathway. The differential association of growth- and arrest-promoting receptors with the galectin lattice is proposed as a mechanism to achieve balance between cellular growth and arrest prior to cell differentiation. However, to appreciate this big picture, it is helpful to start at the beginning. The Dennis lab originally showed that tumor cells with a mutation in a gene needed to synthesize a particular branch in complex N-glycans make few tumors, and the tumors that do arise metastasize poorly (Dennis et al., 1987Dennis J.W. Laferte S. Waghorne C. Breitman M.L. Kerbel R.S. Science. 1987; 236: 582-585Crossref PubMed Scopus (824) Google Scholar). Similar effects were seen in mice with the same mutation expressing Polyoma middle T antigen (PyMT)(Granovsky et al., 2000Granovsky M. Fata J. Pawling J. Muller W.J. Khokha R. Dennis J.W. Nat. Med. 2000; 6: 306-312Crossref PubMed Scopus (429) Google Scholar). The defective gene in each case was Mgat5, which codes for the glycosyltransferase Mgat5 (or GlcNAc-TV) that catalyses the addition of a β1,6-linked GlcNAc to form a tri- or tetra-antennary N-glycan (Figure 1A). In general, the more GlcNAc branches per N-glycan, the more Gal residues are added and elongated to form polylactosamine [Galβ1,4GlcNAc]n. Galectins bind Gal and form specific crosslinked lattices with glycoproteins (Brewer et al., 2002Brewer C.F. Miceli M.C. Baum L.G. Curr. Opin. Struct. Biol. 2002; 12: 616-623Crossref PubMed Scopus (354) Google Scholar). Glycoprotein receptors in wild-type tumor cells associate with galectin-3 at the cell surface, whereas the same receptors in cells lacking Mgat5 reside largely in endosomes (Partridge et al., 2004Partridge E.A. Le Roy C. Di Guglielmo G.M. Pawling J. Cheung P. Granovsky M. Nabi I.R. Wrana J.L. Dennis J.W. Science. 2004; 306: 120-124Crossref PubMed Scopus (554) Google Scholar). The effects of loss of Mgat5 on signaling strength are much greater for receptors with many N-glycan sites (such as EGFR, PDGFR, FGFR, and IGFR) versus those with few N-glycans (such as TGFβRI and TGFβRII). Differential cell-surface residency of growth-modulating receptors could explain the differences in cell proliferation, cytoskeletal organization, signal transduction, and T cell activation between wild-type cells and those lacking Mgat5 (Demetriou et al., 2001Demetriou M. Granovsky M. Quaggin S. Dennis J.W. Nature. 2001; 409: 733-739Crossref PubMed Scopus (695) Google Scholar, Lagana et al., 2006Lagana A. Goetz J.G. Cheung P. Raz A. Dennis J.W. Nabi I.R. Mol. Cell. Biol. 2006; 26: 3181-3193Crossref PubMed Scopus (151) Google Scholar, Partridge et al., 2004Partridge E.A. Le Roy C. Di Guglielmo G.M. Pawling J. Cheung P. Granovsky M. Nabi I.R. Wrana J.L. Dennis J.W. Science. 2004; 306: 120-124Crossref PubMed Scopus (554) Google Scholar). The new work by Lau et al., 2007Lau K.S. Partridge E.A. Grigorian A. Silvescu C.I. Reinhold V.N. Demetriou M. Dennis J.W. Cell. 2007; (this issue)PubMed Google Scholar provides a mechanistic basis for the differences in N-glycan site multiplicity (n) between growth-promoting receptors (which have a high n) and receptors that promote growth arrest (which have a low n). The paper shows that the poor signaling responses to EGF or TGFβ of PyMT tumor cells lacking Mgat5 are largely overcome by growth in the presence of high concentrations of N-acetylglucosamine (GlcNAc). Increasing intracellular UDP-GlcNAc promotes a switch-like increase in Golgi N-glycan branching, enhances the association of EGFR or TGFβR with galectin-3 promoting cell-surface residency, and leads to an increase in signaling. However, with increasing UDP-GlcNAc, the signaling response to EGF is hyperbolic, whereas the response to TGFβ is switch-like (Figure 1B). Although the same growth conditions also enhance signaling in tumor cells that express Mgat5, the kinetics are not switch-like and instead are hyperbolic. Thus, tumor cells lacking Mgat5 reveal that N-glycan branching in the Golgi may be ultrasensitive to metabolic flux through the hexosamine pathway. Furthermore, signaling kinetics in those cells also depend on the multiplicity of N-glycans in a receptor. The kinetics are hyperbolic for the growth-promoting receptors EGFR, PDGFR, IGFR, and FGFR (8–16 N-glycans) and switch-like for TGFβR, which induces growth arrest, and also for GLUT4, which regulates glucose transport (1–2 N-glycans). GLUT2 also requires branched N-glycans to function at the cell surface (Ohtsubo et al., 2005Ohtsubo K. Takamatsu S. Minowa M.T. Yoshida A. Takeuchi M. Marth J.D. Cell. 2005; 123: 1307-1321Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar). The kinetics of the signaling responses hold true in CHO and NuMG cells, whereas the CHO mutant Lec1 that makes no branched N-glycans does not exhibit switch-like responses to increasing UDP-GlcNAc. The authors use these observations as a springboard for computer simulations to model the ultrasensitivity of Golgi N-glycan branching to hexosamine flux and how N-glycan multiplicity regulates glycoprotein cell-surface expression and signaling. Kinetic parameters used in the simulations for some but not all of the glycosylation activities needed for N-glycan synthesis were determined in vitro, and the binding constants used for galectin-3 were selected from a subset of published data. However, it is not clear whether these parameters reflect conditions in vivo, and the simulations include a large number of assumptions. For example, although the presence of N-glycans that are more highly branched will enhance binding to galectins (Hirabayashi et al., 2002Hirabayashi J. Hashidate T. Arata Y. Nishi N. Nakamura T. Hirashima M. Urashima T. Oka T. Futai M. Muller W.E. et al.Biochim. Biophys. Acta. 2002; 1572: 232-254Crossref PubMed Scopus (764) Google Scholar), lattice formation is a complex process and is not simply a function of binding affinities between galectins and N-glycans. A glycoprotein with three N-glycans and nine lactosamine units exhibits a 1000-fold range of galectin-3 binding constants (Dam et al., 2005Dam T.K. Gabius H.J. Andre S. Kaltner H. Lensch M. Brewer C.F. Biochemistry. 2005; 44: 12564-12571Crossref PubMed Scopus (185) Google Scholar). In addition, galectin-3 oligomerizes through its N-terminal domain and forms a lattice that has recently been visualized on the cell surface and that varies with cell state (Nieminen et al., 2007Nieminen J. Kuno A. Hirabayashi J. Sato S. J. Biol. Chem. 2007; 282: 1374-1383Crossref PubMed Scopus (171) Google Scholar). However, excellent support for the final model is provided by data examining the effects of increasing UDP-GlcNAc on proliferation versus growth arrest in NuMG mammary tumor cells and on surface expression of CTLA4 in activated T cells lacking Mgat5. The overall conclusion is that metabolic flux through the hexosamine pathway regulates UDP-GlcNAc levels in the Golgi; N-glycan branching is ultrasensitive to increases in UDP-GlcNAc levels; glycoprotein receptors have evolved with low or high numbers of N-glycan sites so they may take advantage of differential N-glycan branching to regulate the strength of their association with a cell-surface galectin lattice. This in turn controls their rate of endocytosis and thereby their signaling activity. Arrest receptors are kept in check by their comparatively high rate of endocytosis, due to their weak association with the galectin lattice and the delay in their response to increasing UDP-GlcNAc. However, once the “switch” occurs, their cell-surface numbers and residence times increase, eventually overcoming growth-promoting receptors to induce arrest and differentiation (Figure 1B). The next steps are to test the model. A direct test would be to convert a growth-promoting receptor with high n to one with low n and show that hyperbolic responses to increasing UDP-GlcNAc become switch-like. This requires removing N-glycan sites that are not required for folding and trafficking, a feat that may be difficult. Another prediction would be that overexpression of the UDP-GlcNAc transporter should cause all responses to occur at lower concentrations of GlcNAc. Galectin-3 and Mgat5 double-knockout mice should be investigated, although there are 15 galectins, and redundancy may be a problem. The predicted differential strength of receptor associations with the galectin lattice should be tested directly by photobleaching experiments and the galectin-3 lattice visualized under different growth conditions. Finally, it will be important to use mass spectrometry with heavy isotopes to prove that the increase in intracellular UDP-GlcNAc does indeed lead to the production of more highly branched N-glycans. These experiments will undoubtedly be forthcoming. Meanwhile, in an experimental tour de force, Lau et al., 2007Lau K.S. Partridge E.A. Grigorian A. Silvescu C.I. Reinhold V.N. Demetriou M. Dennis J.W. Cell. 2007; (this issue)PubMed Google Scholar have identified a new paradigm for fine-tuning the regulation of cell growth and differentiation in mammals by a mechanism that involves the regulation of receptor signaling by N-glycan site number and N-glycan branching controlled by metabolic flux. Thanks to C. Fred Brewer and John Hanover for helpful discussions. Complex N-Glycan Number and Degree of Branching Cooperate to Regulate Cell Proliferation and DifferentiationLau et al.CellApril 06, 2007In BriefThe number of N-glycans (n) is a distinct feature of each glycoprotein sequence and cooperates with the physical properties of the Golgi N-glycan-branching pathway to regulate surface glycoprotein levels. The Golgi pathway is ultrasensitive to hexosamine flux for the production of tri- and tetra-antennary N-glycans, which bind to galectins and form a molecular lattice that opposes glycoprotein endocytosis. Glycoproteins with few N-glycans (e.g., TβR, CTLA-4, and GLUT4) exhibit enhanced cell-surface expression with switch-like responses to increasing hexosamine concentration, whereas glycoproteins with high numbers of N-glycans (e.g., EGFR, IGFR, FGFR, and PDGFR) exhibit hyperbolic responses. Full-Text PDF Open Archive" @default.
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• W1976978560 date "2007-04-01" @default.
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• W1976978560 title "A Method to the Madness of N-Glycan Complexity?" @default.
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