Identification of Glycosyltransferase 8 Family Members as Xylosyltransferases Acting on O-Glucosylated Notch Epidermal Growth Factor Repeats

Sethi, Maya K.; Buettner, Falk F. R.; Krylov, Vadim B.; Takeuchi, Hideyuki; Nifantiev, Nikolay E.; Haltiwanger, Robert S.; Gerardy‐Schahn, Rita; Bakker, Hans

doi:10.1074/jbc.c109.065409

Cited by 117 publications

(87 citation statements)

References 29 publications

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“…C. elegans has protein O-fucosyltransferase 1 (Loriol et al 2006), but no close homologue of Fringe, the transferase that adds GlcNAc to Fucose-O-EGF (Bruckner et al 2000;Moloney et al 2000). The O-glucose glycans on EGF repeats appear to have emerged with Notch signaling in the metazoa (Acar et al 2008;Sethi et al 2010).…”

Section: O-glycosylationmentioning

confidence: 99%

Golgi Glycosylation

Stanley

2011

Cold Spring Harbor Perspectives in Biology

363

283

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Section: O-glycosylationmentioning

confidence: 99%

Golgi Glycosylation

Stanley

2011

Cold Spring Harbor Perspectives in Biology

363

283

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“…However, this GT family is polyspecific, and not all enzymes are involved in cellwall/extracellular matrix metabolism. In plants, the GAUT subfamily comprises galacturonosyltransferases required for homogalacturonan synthesis (143), but fungal and animal GT8s are involved in glycogen metabolism (72) and Notch receptor glycosylation (122). The brown alga Ectocarpus possesses three GT8s, one closely related to animal GT8, whereas the other GT8s cluster within the plant subfamily PGSIP-B (143).…”

Section: Differentiation and Cell-wall Diversitymentioning

confidence: 99%

Evolution and Diversity of Plant Cell Walls: From Algae to Flowering Plants

Popper

Michel

Hervé

et al. 2011

Annu. Rev. Plant Biol.

620

483

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All photosynthetic multicellular Eukaryotes, including land plants and algae, have cells that are surrounded by a dynamic, complex, carbohydrate-rich cell wall. The cell wall exerts considerable biological and biomechanical control over individual cells and organisms, thus playing a key role in their environmental interactions. This has resulted in compositional variation that is dependent on developmental stage, cell type, and season. Further variation is evident that has a phylogenetic basis. Plants and algae have a complex phylogenetic history, including acquisition of genes responsible for carbohydrate synthesis and modification through a series of primary (leading to red algae, green algae, and land plants) and secondary (generating brown algae, diatoms, and dinoflagellates) endosymbiotic events. Therefore, organisms that have the shared features of photosynthesis and possession of a cell wall do not form a monophyletic group. Yet they contain some common wall components that can be explained increasingly by genetic and biochemical evidence. 567

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“…Recent work shows that elimination of mouse Rumi also results in Notch-like phenotypes in mice (49). In addition, genes encoding the O-glucose-␣1,3-xylosyltransferase have recently been identified (two distinct genes encode enzymes with this activity: GXYLT1 and GXYLT2) (52). The gene encoding the xyloside-␣1,3-xylosyltransferase has not yet been identified.…”

mentioning

confidence: 99%

O-Glucose Trisaccharide Is Present at High but Variable Stoichiometry at Multiple Sites on Mouse Notch1

Rana¹,

Nita‐Lazar²,

Takeuchi

et al. 2011

Journal of Biological Chemistry

Self Cite

120

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Notch activity is regulated by both O-fucosylation and O-glucosylation, and Notch receptors contain multiple predicted sites for both. Here we examine the occupancy of the predicted O-glucose sites on mouse Notch1 (mN1) using the consensus sequence C 1 XSXPC 2 . We show that all of the predicted sites are modified, although the efficiency of modifying O-glucose sites is site-and cell type-dependent. For instance, although most sites are modified at high stoichiometries, the site at EGF 27 is only partially glucosylated, and the occupancy of the site at EGF 4 varies with cell type. O-Glucose is also found at a novel, nontraditional consensus site at EGF 9. Based on this finding, we propose a revision of the consensus sequence for O-glucosylation to allow alanine N-terminal to cysteine 2: C 1 XSX(A/P)C 2 . We also show through biochemical and mass spectral analyses that serine is the only hydroxyamino acid that is modified with O-glucose on EGF repeats. The O-glucose at all sites is efficiently elongated to the trisaccharide Xyl-Xyl-Glc. To establish the functional importance of individual O-glucose sites in mN1, we used a cell-based signaling assay. Elimination of most individual sites shows little or no effect on mN1 activation, suggesting that the major effects of O-glucose are mediated by modification of multiple sites. Interestingly, elimination of the site in EGF 28, found in the Abruptex region of Notch, does significantly reduce activity. These results demonstrate that, like O-fucose, the O-glucose modifications of EGF repeats occur extensively on mN1, and they play important roles in Notch function.The Notch family of single-pass transmembrane receptors is essential for early metazoan development, activating the expression of many genes involved in cell differentiation and tissue morphogenesis (1-3). Defects in Notch signaling have been implicated in a number of human diseases, including several forms of cancer, vascular defects such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (4 -6), multiple sclerosis (6), and a number of developmental syndromes (4, 7-10). The canonical Notch signaling pathway is initiated by the interaction of Notch with its ligand on an apposed cell. Upon ligand binding, Notch undergoes presenilin-1-dependent proteolysis, releasing a soluble Notch intracellular domain, which enters the cell nucleus to interact directly with the transcription factors from the CSL family and regulate Notch target genes (2). There are four members of the Notch family in vertebrates (Notch1 to Notch4) interacting with several classes of Notch ligands: ligands of the DSL family (Delta-like 1, 3, and 4 and Jagged 1 and 2) (1) and newly characterized ligands without the DSL domain, such as DNER and MAGP-1 and -2 (11-13).The Notch proteins consist of a large extracellular domain (ECD), 5 a transmembrane region, and a large intracellular domain (1, 2, 14). The majority of the ECD consists of tandem epidermal growth factor-like (EGF) repeats (36 EGF repeats are ...

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Identification of Glycosyltransferase 8 Family Members as Xylosyltransferases Acting on O-Glucosylated Notch Epidermal Growth Factor Repeats

Cited by 117 publications

References 29 publications

Golgi Glycosylation

Golgi Glycosylation

Evolution and Diversity of Plant Cell Walls: From Algae to Flowering Plants

O-Glucose Trisaccharide Is Present at High but Variable Stoichiometry at Multiple Sites on Mouse Notch1

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