Glycosylation regulates Notch signalling

Haines, Nicola; Irvine, Kenneth D.

doi:10.1038/nrm1228

Cited by 561 publications

(324 citation statements)

References 118 publications

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“…The O-fucose glycans of Notch are critical regulators of Notch signaling (49,50). Thus it is important to understand all the factors required for their synthesis.…”

Section: Discussionmentioning

confidence: 99%

Slc35c2 Promotes Notch1 Fucosylation and Is Required for Optimal Notch Signaling in Mammalian Cells

Hou

Shi

et al. 2010

Journal of Biological Chemistry

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Mammalian Notch receptors require modification by fucose on epidermal growth factor-like (EGF) repeats of their extracellular domain to respond optimally to signal induction by canonical Notch ligands. Inactivation of the Golgi GDP-fucose transporter Slc35c1 in mouse or human does not cause marked defects in Notch signaling during development, and shows milder fucosylation defects than those observed in mice unable to synthesize GDP-fucose, indicating the existence of another mechanism for GDP-fucose transport into the secretory pathway. We show here that fibroblasts from mice or humans lacking Slc35c1 exhibit robust Notch signaling in co-culture signaling assays. A potential candidate for a second GDP-fucose transporter is the related gene Slc35c2. Overexpression of Slc35c2 reduces expression of the fucosylated epitopes Lewis X and sialylated Lewis X in CHO cells, indicating competition with Slc35c1. The fucosylation of a Notch1 EGF repeat fragment that occurs in the endoplasmic reticulum was increased in CHO transfectants overexpressing Slc35c2. In CHO cells with low levels of Slc35c2, both Delta1-and Jagged1-induced Notch signaling were reduced, and the fucosylation of a Notch1 fragment was also decreased. Immunofluorescence microscopy of rat intestinal epithelial cells and HeLa cells, and analysis of rat liver membrane fractions showed that Slc35c2 is primarily colocalized with markers of the cis-Golgi network and endoplasmic reticulum-Golgi intermediate compartment (ERGIC). The combined results suggest that Slc35c2 is either a GDP-fucose transporter that competes with Slc35c1 for GDP-fucose, or a factor that otherwise enhances the fucosylation of Notch and is required for optimal Notch signaling in mammalian cells.

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“…The O-fucose glycans of Notch are critical regulators of Notch signaling (49,50). Thus it is important to understand all the factors required for their synthesis.…”

Section: Discussionmentioning

confidence: 99%

Slc35c2 Promotes Notch1 Fucosylation and Is Required for Optimal Notch Signaling in Mammalian Cells

Hou

Shi

et al. 2010

Journal of Biological Chemistry

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“…Initially, however, mutation screening in a series of affected subjects with diverse radiological phenotypes failed to identify any positive cases. LFNG encodes a glycosyltransferase that post-translationally modifies the Notch family of cell surface receptors, a key step in the regulation of this signaling pathway (Haines and Irvine, 2003). The LFNG protein is a fucose-specific ␤-1,3-N-acetylglucosaminyltransferase (Bruckner et al, 2000;Moloney et al, 2000) that functions in the Golgi to post-translationally modify the Notch receptors, altering their signaling properties (Haines and Irvine, 2003).…”

Section: Lunatic Fringementioning

confidence: 99%

“…LFNG encodes a glycosyltransferase that post-translationally modifies the Notch family of cell surface receptors, a key step in the regulation of this signaling pathway (Haines and Irvine, 2003). The LFNG protein is a fucose-specific ␤-1,3-N-acetylglucosaminyltransferase (Bruckner et al, 2000;Moloney et al, 2000) that functions in the Golgi to post-translationally modify the Notch receptors, altering their signaling properties (Haines and Irvine, 2003). Earlier studies have shown that Lfng gene expression is severely disregulated in Dll3-null mice, suggesting that Lfng expression is dependent on Dll3 function Kusumi et al, 2004).…”

Section: Lunatic Fringementioning

confidence: 99%

Abnormal vertebral segmentation and the notch signaling pathway in man

Turnpenny

Alman

Cornier

et al. 2007

Developmental Dynamics

145

120

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Abnormal vertebral segmentation (AVS) in man is a relatively common congenital malformation but cannot be subjected to the scientific analysis that is applied in animal models. Nevertheless, some spectacular advances in the cell biology and molecular genetics of somitogenesis in animal models have proved to be directly relevant to human disease. Some advances in our understanding have come through DNA linkage analysis in families demonstrating a clustering of AVS cases, as well as adopting a candidate gene approach. Only rarely do AVS phenotypes follow clear Mendelian inheritance, but three genes-DLL3, MESP2, and LNFG-have now been identified for spondylocostal dysostosis (SCD). SCD is characterized by extensive hemivertebrae, trunkal shortening, and abnormally aligned ribs with points of fusion. In familial cases clearly following a Mendelian pattern, autosomal recessive inheritance is more common than autosomal dominant and the genes identified are functional within the Notch signaling pathway. Other genes within the pathway cause diverse phenotypes such as Alagille syndrome (AGS) and CADASIL, conditions that may have their origin in defective vasculogenesis. Here, we deal mainly with SCD and AGS, and present a new classification system for AVS phenotypes, for which, hitherto, the terminology has been inconsistent and confusing.

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“…In particular, the structure of accessible carbohydrates present at the cell surface is part of the cell 'glycome' and is determined by the coordinated expression of genes including glycosyltransferases, glycosidases and nucleotide-sugar transporters. These enzymes and transporters participate in the functional regulation of a number of other proteins and receptors, such as members of the Wnt and Notch families, galectins, membrane lectins or selectins, whose activities are dependent upon their glycosylation or the glycosylation of their ligands [1][2][3]. Glycosaminoglycans (GAGs) constitute a specific type of glycans of major importance since, depending upon their nature, electrostatic charge and abundance, they modulate the locally available concentrations of various intercellular mediators in the vicinity of the cell surface.…”

Section: Introductionmentioning

confidence: 99%

Glycotranscriptome study reveals an enzymatic switch modulating glycosaminoglycan synthesis during B‐cell development and activation

et al. 2011

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B-cell fate and responses are modulated by soluble mediators and direct cellular interactions. Migration properties also vary during differentiation, commitment and activation. In many cells, modulation of responses to stimuli involves cell surface glycans, whose architecture depends on the simultaneous expression of multiple enzymes. By looking at the glycosylation-related gene expression patterns among B-cell populations, we determined in this study that the strongest variations were observed for CSGalNAcT-1 and EXTL1. These are enzymes involved in the biosynthesis of alternative forms of glycosaminoglycans (GAGs), namely chondroitin sulfate and heparan sulfate, respectively. These two enzymes showed inverse fluctuations in progenitors, resting B cells and activated B cells, suggesting a developmentally regulated switch between chondroitin and heparan sulfate synthesis. To explore whether these variations contributed to optimal B-cell differentiation, we overexpressed EXTL1 in the B-cell lineage of transgenic mice, yielding a partial differentiation blockade at the pro-B to pre-B transition. In the periphery, this defect was almost fully compensated for in vivo, with normal-size B-cell compartments and normal serum immunoglobulin levels in the transgenic EXTL1 mice. The peripheral B cells from EXTL1 transgenics were only affected with regard to their in vitro responses to polyclonal activation, showing reduced proliferation. Together the data suggest that despite their low amounts in lymphocytes, the heparan sulfate chains decorating the endogenous GAGs appear to be regulators of B-cell physiology.

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Glycosylation regulates Notch signalling

Cited by 561 publications

References 118 publications

Slc35c2 Promotes Notch1 Fucosylation and Is Required for Optimal Notch Signaling in Mammalian Cells

Slc35c2 Promotes Notch1 Fucosylation and Is Required for Optimal Notch Signaling in Mammalian Cells

Abnormal vertebral segmentation and the notch signaling pathway in man

Glycotranscriptome study reveals an enzymatic switch modulating glycosaminoglycan synthesis during B‐cell development and activation

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