Molecular Recognition by LARGE Is Essential for Expression of Functional Dystroglycan

Kanagawa, Motoi; Saito, Fumiaki; Kunz, Stefan; Yoshida‐Moriguchi, Takako; Barresi, Rita; Kobayashi, Yvonne M.; Muschler, John; Dumanski, Jan P.; Michele, Daniel E.; Oldstone, Michael B. A.; Campbell, Kevin P.

doi:10.1016/j.cell.2004.06.003

Cited by 244 publications

(288 citation statements)

References 46 publications

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“…In contrast, in experiments using cell lines, forced expression of LARGE always yields an extensively glycosylated ␣-DG that appears as a band of Ն200 kDa on SDS-PAGE (Figs. 2-5) (37,38,41), implying the presence of an unidentified machinery that negatively regulates the glycosylation of ␣-DG in vivo. Hence, we propose HNK-1ST to be one such suppressive factor for ␣-DG function, acting as a "molecular brake" to generate properly glycosylated ␣-DG.…”

Section: Discussionmentioning

confidence: 99%

Human Natural Killer-1 Sulfotransferase (HNK-1ST)-induced Sulfate Transfer Regulates Laminin-binding Glycans on α-Dystroglycan

Nakagawa¹,

Manya²,

Toda³

et al. 2012

Journal of Biological Chemistry

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Background: ␣-Dystroglycan undergoes extensive glycosylation required for the interaction between ␣-dystroglycan and its ligands such as laminin. Results: HNK-1ST suppressed the glycosylation and reduced the ligand binding activity of ␣-dystroglycan. Conclusion:The sulfotransferase activity of HNK-1ST is essential for the modulation of ␣-dystroglycan. Significance: This study identifies a novel role for HNK-1ST as a regulator of the functional glycans on ␣-dystroglycan other than HNK-1 biosynthesis.

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Section: Discussionmentioning

confidence: 99%

Human Natural Killer-1 Sulfotransferase (HNK-1ST)-induced Sulfate Transfer Regulates Laminin-binding Glycans on α-Dystroglycan

Nakagawa¹,

Manya²,

Toda³

et al. 2012

Journal of Biological Chemistry

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“…For example, COSMC is necessary for T-synthase to move along the secretory pathway and to be active in the Golgi (Wang et al 2010). In another example, the putative glycosyltansferase Large must physically associate with a-dystroglycan to be functional in modifying this substrate in the Golgi (Kanagawa et al 2004). Recently, inhibitors of glycosyltransferase activities have been discovered.…”

Section: Regulation and Uses Of Golgi Glycosylation Regulation Of Golmentioning

confidence: 99%

Golgi Glycosylation

Stanley

2011

Cold Spring Harbor Perspectives in Biology

362

283

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“…So far, 7 glycosyltransferases or glycosyltransferase-like genes, including POMT1, POMT2, POMGnT1, Fukutin, Fukutin-related protein, LARGE, and LARGE2, have been found to be involved in ␣-DG functional glycosylation (4). Among these molecules, LARGE is of particular interest because it was shown to be functionally able to bypass the O-mannose glycosylation defects in cells derived from patients with severe muscular dystrophy (9,10). LARGE was discovered as a gene defective in meningioma (11) and was shown to be a causative gene for muscular dystrophy (LARGE myd ) in mice (12) and in humans (13).…”

mentioning

confidence: 99%

Tumor suppressor function of laminin-binding α-dystroglycan requires a distinct β3- N -acetylglucosaminyltransferase

Bao

Kobayashi

Hatakeyama

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

117

159

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␣-Dystroglycan (␣-DG) represents a highly glycosylated cell surface molecule that is expressed in the epithelial cell-basement membrane (BM) interface and plays an essential role in epithelium development and tissue organization. The ␣-DG-mediated epithelial cell-BM interaction is often impaired in invasive carcinomas, yet roles and underlying mechanisms of such an impaired interaction in tumor progression remain unclear. We report here a suppressor function of laminin-binding glycans on ␣-DG in tumor progression. In aggressive prostate and breast carcinoma cell lines, lamininbinding glycans are dramatically decreased, although the amount of ␣-DG and ␤-dystroglycan is maintained. The decrease of lamininbinding glycans and consequent increased cell migration were associated with the decreased expression of ␤3-N-acetylglucosaminyltransferase-1 (␤3GnT1). Forced expression of ␤3GnT1 in aggressive cancer cells restored the laminin-binding glycans and decreased tumor formation. ␤3GnT1 was found to be required for laminin-binding glycan synthesis through formation of a complex with LARGE, thus regulating the function of LARGE. Interaction of the laminin-binding glycans with laminin and other adhesive molecules in BM attenuates tumor cell migratory potential by antagonizing ERK/AKT phosphorylation induced by the components in the ECM. These results identify a previously undescribed role of carbohydrate-dependent cell-BM interaction in tumor suppression and its control by ␤3GnT1 and LARGE.glycosylation ͉ cell adhesion ͉ basement membrane ͉ carcinoma I nteraction of epithelial cells with basement membrane (BM) is mediated by cell adhesion molecules, which operate at the interface of epithelial cell-ECM and regulate cell growth, motility, and differentiation by integrating signals from ECM or soluble factors (1-3). One of the most important epithelial cell-BM interactions is mediated by ␣-dystroglycan (␣-DG) on epithelial cells (4).␣-DG is a cell surface receptor for several major BM proteins, including laminin, perlecan, and agrin. A laminin G-like domain in all these glycoproteins binds to a unique glycan structure attached to ␣-DG, and this interaction has been shown to be critical in assembling BM (5, 6). This unique glycan structure is referred to as laminin-binding glycans hereafter. ␣-DG is not attached directly to the plasma membrane but is bound to it through attachment to the transmembrane protein ␤-dystroglycan (␤-DG), which binds to the cytoplasmic protein dystrophin, which, in turn, binds to the actin cytoskeleton and many adaptor molecules involved in cellular signaling (4,5).␣-DG is highly glycosylated and contains both N-linked glycans and mucin type O-glycans. The mucin type O-glycans are clustered in a mucin-like domain at the N-terminal of mature ␣-DG, which includes unique O-mannosyl glycans and sialic acid ␣233Gal␤134GlcNAc␤132Man␣13Ser/Thr (7). Defects in glycosylation of the O-mannosyl glycans have been shown to cause muscular dystrophy (8). So far, 7 glycosyltransferases or glycosyltransferase-like ...

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Molecular Recognition by LARGE Is Essential for Expression of Functional Dystroglycan

Cited by 244 publications

References 46 publications

Human Natural Killer-1 Sulfotransferase (HNK-1ST)-induced Sulfate Transfer Regulates Laminin-binding Glycans on α-Dystroglycan

Human Natural Killer-1 Sulfotransferase (HNK-1ST)-induced Sulfate Transfer Regulates Laminin-binding Glycans on α-Dystroglycan

Golgi Glycosylation

Tumor suppressor function of laminin-binding α-dystroglycan requires a distinct β3- N -acetylglucosaminyltransferase

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