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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Curr Opin Struct Biol. Author manuscript; available in PMC Oct 1, 2008.
Published in final edited form as:
PMCID: PMC2141538
NIHMSID: NIHMS34390

Regulation of Notch Signaling by Glycosylation

Summary

Notch receptors are ~300 kd cell surface glycoproteins whose activation by Notch ligands regulates cell fate decisions in the metazoa. The extracellular domain of Notch receptors has many epidermal growth factor-like repeats that are glycosylated with O-fucose and O-glucose glycans as well as N-glycans. Disruption of O-fucose glycan synthesis leads to severe Notch signaling defects in Drosophila and mammals. Removal or addition of O-fucose glycan consensus sites on Notch receptors also leads to Notch signaling defects. Ligand binding and ligand-induced Notch signaling assays have provided insights into how changes in the O-fucose glycans of Notch receptors alter Notch signaling.

Introduction

Notch signaling controls the fate of many cell types in the metazoa and dysregulation of Notch signaling leads to developmental defects or cancer [1]. In the canonical Notch signaling pathway the Notch ligands Delta or Serrate (in Drosophila) and Delta-like or Jagged (in mammals) bind to the extracellular domain of Notch receptors (NECD) on apposing cells and two sequential proteolytic cleavages ensue. The first, caused by an ADAM (disintegrin and metalloprotease), occurs close to the Notch transmembrane region on the outside of the cell. The second occurs within the transmembrane domain of Notch and is induced by a complex of proteins that include presenilins with γ-secretase activity. The released Notch intracellular domain (NICD) complexes with the transcriptional repressor CSL (CBF-1/Suppressor-of-hairless/Lag-1), recruits the co-activator Mastermind (Maml) and activates Notch target genes, including transcriptional regulators such as Hes and Hey genes. Drosophila contains one Notch receptor and two Notch ligands whereas mammals have four Notch receptors and five Notch ligands (three Delta and two Jagged).

Interest in the roles of glycans in Notch signaling began with the discovery that the Drosophila Fringe gene (FNG), a known regulator of Notch signaling, encodes a glycosyltransferase which transfers N-acetylglucosamine (GlcNAc) to fucose on Notch epidermal growth factor-like (EGF) repeats [2,3] (Fig. 1). Fringe may modify other proteins that contain a Fuc-O-EGF domain, including Notch ligands [4]. The EGF repeats of mammalian Notch1 produced in cultured cells carry O-fucose glycans, O-glucose glycans and complex N-glycans (Fig. 2). All Notch receptors have consensus sequences known to be modified by these glycans. Mutant mice lacking complex N-glycans, or core 1-derived mucin O-glycans, or numerous other sugars are not defective in Notch signaling during embryonic development [5,6]. However, inactivation of glycosyltransferases or other activities required for O-fucose glycan synthesis gives rise to Notch signaling defects in Drosophila [7], zebrafish [8], sea urchin [9] and mammals [10] (Table 1). Glycosyltransferases involved in glycolipid synthesis are also necessary for Notch signaling [11], an indirect effect that probably has to do with the appropriate organization of Notch receptors in membrane domains. This review will focus on recent mechanistic insights into how the O-fucose glycans of Drosophila and mammalian Notch receptors are proposed to regulate Notch signaling.

Fig. 1
Canonical Notch signal transduction pathway
Fig. 2
The Glycans of Mouse Notch1
Table 1
In vivo consequences of modifying O-fucose glycans

Notch receptors lacking O-fucose glycans

Notch receptors lacking O-fucose are inactive and the question is why? To determine if Notch devoid of O-fucose binds to Notch ligands, soluble Dros. Notch ECD linked to alkaline phosphatase (N-AP) produced from S2 cells in the presence and absence of OFUT1 was investigated for binding to S2 cells expressing Delta or Serrate [12]. N-AP from control cells binds well to both ligands, though binding is not saturable. N-AP from S2 cells lacking OFUT1 did not bind to Delta/S2 or Serrate/S2 cells, consistent with a role for O-fucose in ligand recognition. However, N-AP is secreted poorly in the absence of OFUT1. Drosophila S2 cells have an appreciable level of endogenous OFUT1 and efficiently secrete N-AP that binds Notch ligands. However, overexpression of OFUT1 produces N-AP with enhanced ligand binding activity without apparently increasing its O-fucose content. This result indicated a fucose-transfer-independent activity of OFUT1.

Two groups have now shown that Dros. OFUT1 binds directly to Notch when both Notch and OFUT1 are overexpressed in S2 cells [13,14]. Each group proposes that OFUT1 is necessary for the stable cell surface expression of Notch receptors. However, there are three proposed mechanisms for how OFUT1 functions. Okajima et al. [13] provide evidence that Notch is trapped in the endoplasmic reticulum (ER) in the absence of OFUT1. A mouse mutant Pofut1 that lacks fucosyltransferase activity, Pofut1 R245A, enhances the secretion and ligand binding ability of soluble N-AP from S2 cells lacking OFUT1 [13]. In addition, transgenic expression of Pofut1 R245A in an ofut1 - clone partially rescues cell surface expression of Notch [13]. Sasamura et al. [14] use deconvoluted confocal micrographs to conclude that Notch does not completely colocalize with conventional ER markers in Drosophila cells lacking OFUT1. By tracking Notch in live cells in real time, Sasamura et al [14] find that Notch is expressed equivalently at early times on the surface of ofut1- and wild type cells, but is rapidly endocytosed in the absence of OFUT1 and accumulates in a novel endocytic compartment. Exogenously added OFUT1 reduces Notch accumulation and the authors suggest that secreted OFUT1 bound to cell surface Notch regulates constitutive endocytosis of Notch receptors [14]. In a related paper, however, the same authors conclude that OFUT1 is necessary for transcytosis of Notch at the cell surface to the subapical complex of the adherens junctions [15]. Clearly, technical issues regarding the basis for an antibody to accumulate in a particular compartment in a live cell, and the resolving power of confocal images for localization to intracellular compartments of small Drosophila cells, need to be further investigated. Most critical is to determine whether Notch receptors made in ofut1- cells expressing mouse Pofut1 R245A at temporally regulated, physiological levels, may signal upon encountering Notch ligands.

Notch receptors in the absence of Fringe

In the Drosophila wing disc Fringe enhances Notch signaling induced by Delta and inhibits Notch signaling induced by Serrate to restrict Notch signaling to a stripe of cells at the dorsal/ventral boundary [7]. Notch receptors made in the absence of Fringe are predicted to bear O-fucose at 23 of 36 EGF repeats in Dros. Notch. The action of Fringe alters Notch ligand binding. Thus soluble Dros. N-AP co-expressed with Fringe in S2 cells binds much better to Delta/S2 cells and significantly worse to Serrate/S2 cells compared to N-AP containing O-fucose but not modified by Fringe [12,16]. However, to investigate roles for sugars in O-fucose glycans directly, it will be important to develop cell-free, in vitro binding assays with purified Notch and ligand ECDs bearing structurally-characterized glycans. Even so, such assays may not appropriately reflect in vivo interactions between Notch and ligands which occur in specialized, dynamic, plasma membrane compartments of apposing cells. In this regard, atomic force microscopy may provide the most physiologically relevant data [17].

Overexpression of mammalian Fringe genes in cultured cells alters Notch signaling levels. In general, Lunatic Fringe (Lfng) and Manic Fringe (Mfng) inhibit Jagged1-induced Notch signaling and increase Delta1-induced Notch signaling. However, differences between the effects of Lfng and Mfng on Notch2 signaling have been observed [18], and Radical Fringe (Rfng) overexpression in NIH3T3 cells enhances both Delta1- and Jagged1-induced Notch signaling [19]. Lfng, Mfng and Rfng differ in in vitro specific activity [20], and their activities may not be equivalent in different cell types. The same concerns apply to defining the effects of Fringe on ligand binding. In general, the binding of soluble Delta1 ECD to Notch1 or Notch2 assayed by flow cytometry or immunofluorescence microscopy has conformed to predictions [19,21]. By contrast, Delta3 does not bind to Notch1 nor activate Notch signaling [22]. In addition, Jagged1 binding is not significantly altered by overexpression of Lfng, Mfng or Rfng, despite the fact that Jagged1-induced Notch1 signaling is affected by each Fringe in signaling assays [19]. This finding led to the proposal that O-fucose modified by Fringe may primarily affect the strength of Notch-ligand binding rather than recognition of Notch by ligands [19]. Elegant assays that follow the endocytosis of Notch1 into Delta1- or Jagged1-expressing cells [21] suggest that Notch endocytosis into the ligand-expressing cell, long known to be essential for Notch signaling to be initiated, occurs before the ADAM cleavage (Fig. 1) rather than afterwards, as previously believed. It will be of great interest to perform these endocytosis assays in cells expressing Notch in the presence and absence of the three mammalian Fringe enzymes. Of concern in transfection assays in cultured cells however, are effects of overexpressed Fringe that potentially modify Notch EGF repeats which are not normally substrates for Fringe under physiological conditions. In addition, there may be activities in transfected cells that further modify Notch EGF repeats after they have been acted on by Fringe. For example, in CHO cells the action of Fringe is followed by elongation of the GlcNAβ(1,3)Fuc-O disaccharide by a Gal residue to which a sialic acid may be added to give sialic acidα(2,3)Galβ(1,4)GlcNAcβ(1,3)Fuc-O [23]. Indeed Lfng and Mfng were found to be necessary but not sufficient for a Fringe effect in a CHO co-culture signaling assay [24]. The addition of Gal was required to obtain modulation of Notch signaling by Fringe. Gal has been found in N-linked glycans of Drosophila embryos [25] and therefore a Gal-transferase that may potentially add Gal to O-fucose glycans is expected to exist in Drosophila. In mice lacking β4GalT-1, several Notch target genes involved in somitogenesis are poorly expressed at mid-gestation, and the majority of late term embryos have an extra lumbar vertebra [26]. Mice express five additional β4GalTs that may ameliorate a defective Notch signaling phenotype when only β4GalT-1 is absent.

Elimination or Acquisition of O-Fucose Sites in Notch

In CHO cells, Fringe modifies O-fucose on many, but not all, Notch1 EGF repeats in Notch1 ECD fragments that have the consensus O-fucose site C2X4-5T/SC3 [27]. Thus mutation of an O-fucose consensus site eliminates not only the transfer of O-fucose to Notch but also the effects of Fringe at that site. One of the most conserved O-fucose sites on all Notch receptors, including those of C. elegans, is in EGF 12 [28]. Deletion experiments have confirmed that EGF 11 and 12 constitute the Notch ligand binding domain [28]. While Notch1 EGF repeats 11-13 made in E.coli, and therefore not O-fucosylated, bind to Delta-expressing cells, this was only observed after tetramerization of the Notch fragment [29]. In fact, elimination of O-fucose from EGF 12 has profound conequences for Notch signaling. In Drosophila, conversion of Thr to Ala in Notch EGF 12 generates Notch that is hyperactive in response to ligands when ectopically expressed, leading to the conclusion that the O-fucose glycan at EGF 12 suppresses Notch activity [16]. Binding experiments performed with Dros. N-AP produced in S2 cells expressing different levels of OFUT1 or Fringe show that N-AP lacking EGF 11 and 12 has no ligand binding activity [28]. However, NAP with a point mutation eliminating only the O-fucose site in EGF 12 (N-AP 12f) binds well to Delta/S2 and Serrate/S2 cells. In fact, ligand binding is greater for N-AP 12f than N-AP, consistent with the evidence that this O-fucose site suppresses Notch signaling in Drosophila [16]. In addition, binding to Delta/S2 cels is increased and to Serrate/S2 cells is decreased for N-AP 12f modified by Fringe, albeit the respective fold-increase or -decrease is not as great as obtained for control N-AP. Removal of O-fucose from Dros. Notch EGF repeats 24, 26, 24 and 26 or 31 has no effect in an ectopic Notch signaling assay [16]. In vitro binding assays showed a less than 50% decrease in binding of Delta or Serrate to N-AP lacking O-fucose in EGF repeats 23 to 32, but no effect on Fringe enhancement of Delta1 binding or inhibition of Serrate binding [28].

In stark contrast and surprisingly, the 12f mutation in mammalian Notch1 has the opposite effect and causes inhibition of Notch signaling induced by Delta1 or Jagged1 [30,31]. Therefore the O-fucose in EGF 12 in the ligand binding domain of Notch1 is important for positive ligand interactions. O-fucose itself appears to be the key since replacement of the Thr in Notch1 EGF 12 with Ser which acccepts fucose, does not affect Notch1 signaling [31]. Removal of other conserved O-fucose sites in Notch1 at EGF 26 and 27 also has consequences. In CHO cells, Notch1 lacking O-fucose at EGF 26 responds better to both Delta1/L and Jagged1/L cells whereas removal of O-fucose from EGF 27 inhibits signaling induced by both ligands [30]. In the latter case, the basis for reduced signaling appears to be a reduction in Notch processing by furin protease in the Golgi. Therefore, removal of O-fucose from an EGF repeat gives rise to various consequences that are not predictable, and apparently not conserved between Drosophila and mammals. It will be important to replace the Ser or Thr that normally carries fucose with Thr or Ser, respectively, to be sure that loss of the fucose and not the amino acid change is the basis of an observed phenotype [31]. In addition, experiments to determine O-fucose functions should be performed in vivo with Notch mutants expressed at physiological levels from the endogenous locus.

There is one example of a gain-of-function phenotype due to the acquisition of O-fucose in Dros. Notch EGF 14 which has no O-fucose consensus site [32]. In the Notch split mutation, a Thr is introduced into EGF 14 and becomes O-fucosylated. This causes neuronal precursor cells to be stimulated by R8 Delta-containing cells in the ommatidium of the eye, to differentiate and then die. This phenotype does not depend on Fringe which suggests that the acquisition of a single O-fucose in EGF 14 may cause Notch in neuronal precursor cells to be inappropriately activated by Delta1 in R8 cells.

Conclusions

The O-fucose glycans of Notch receptors are important modulators of Notch signaling. Complete removal by mutating OFUT1/Pofut1 results in severe, global Notch signaling defects. In Drosophila this appears to be due in part to the loss of chaperone effects of OFUT1. However, O-fucose itself as well as Fringe, are necessary for boundary formations in the wing disc, eyes and legs. Binding of Dros. Notch ECD to ligand-expressing cells shows that Fringe causes increased binding of Delta and decreased binding of Serrate. Some variations on this theme are observed in mammalian cells that have several non-redundant Notch receptors, Notch ligands and Fringes. However, in vitro assays are fraught with potential problems. They may not reflect binding interactions that occur in membrane-anchored, potentially oligomeric Notch receptors and ligands, highly organized in a cell membrane and poised to be endocytosed. Thus, it is of key importance to develop methods to determine the precise structure of each O-fucose glycan on Notch isolated from specialized cell types in vivo. Steps in this direction have been initiated [33] but the sensitivity of mass spectroscopic techniques is currently not up to the task of analysing site-specific glycosylation in small numbers of cells such as might be obtained by laser capture microscopy.

Acknowledgments

The author acknowledges the many contributions to this field for which original references could not be given due to space limitations. This work was supported by National Institutes of Health grant RO1 CA 95022 to P. S.

Abbreviations

Pofut1
protein O-fucosyltransferase 1
Lfng
Lunatic Fringe
Mfng
Manic Fringe
Rfng
Radical Fringe
NECD
Notch extracellular domain
NICD
Notch intracelluar domain
N-AP
NECD-alkaline phosphatase
EGF
epidermal growth factor
ER
endoplasmic reticulum
CSL
CBF-1/Suppressor-of-hairless/Lag-1
Maml
Mastermind-like

Footnotes

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