Mouse Large Can Modify Complex N- and Mucin O-Glycans on α-Dystroglycan to Induce Laminin Binding

Patnaik, Santosh K.; Stanley, Pamela

doi:10.1074/jbc.m500069200

Cited by 88 publications

(115 citation statements)

References 83 publications

(73 reference statements)

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“…S3B). Consistent with this observation, Lec15 cells that express little dolichol mannose-phosphate, which is required for POMT1 function, displayed a decreased amount of the glycans (14), which can be restored by transfection of DPM2 cDNA (Fig. S4G), and POMT1-deficient mice had no laminin- binding glycans and died before birth (26).…”

Section: Expression Of ␤3gnt1 Directs the Synthesis Of Laminin-bindinsupporting

confidence: 65%

“…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). LARGE displays 2 distinct structural domains homologous to UDP-glucose protein glucosyltransferase (14) and ␤3-Nacetylglucosaminyltransferase 1 (␤3GnT1) (11). ␤3GnT1 was originally identified by expression cloning as an enzyme that synthesizes i-antigen, a linear poly-N-acetyllactosamine, on human fetal red blood cell (15).…”

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confidence: 99%

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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.

110

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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Section: Expression Of ␤3gnt1 Directs the Synthesis Of Laminin-bindinsupporting

confidence: 65%

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.

110

159

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“…Reduction or loss of IIH6 reactivity can be rescued by forced expression of LARGE (34,35). It has been shown that exogenously expressed LARGE can overcome defects in the lamininbinding activity of ␣-DG in fukutin-or POMGnT1-deficient cells or tissues (26,34).…”

Section: Discussionmentioning

confidence: 99%

Absence of Post-phosphoryl Modification in Dystroglycanopathy Mouse Models and Wild-type Tissues Expressing Non-laminin Binding Form of α-Dystroglycan

Kuga

Kanagawa

Sudo

et al. 2012

Journal of Biological Chemistry

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Background:The biosynthetic pathway for the ligand-binding moiety of ␣-dystroglycan, defects in which cause dystroglycanopathy, remains unclear. Results:The phosphodiester-linked moiety on O-mannose is absent in dystroglycanopathy models and in wild-type lung and testis. Conclusion: Post-phosphoryl modification is a key determinant of the functional expression of ␣-dystroglycan as a laminin receptor. Significance: This work expands our understanding of the molecular mechanism of a unique post-translational modification.

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“…Using CHO CELL mutants, Patnaik and Stanley have shown that LARGE does not require sialic acid, galactose or fucose to glycosylate α-dystroglycan. 59 Similarly, Combs and Ervasti have shown that enzymatic removal of sialic acid, galactose and N-acetylglucosamine from α-dystroglycan actually stimulates its binding to laminin, 60 much as LARGE overexpression does. 57 Again, this evidence indicates that these carbohydrates are not synthesized by LARGE.…”

Section: Dystroglycanopathy-gene Function: Some Mysteries Remainmentioning

confidence: 96%

Mechanisms of Disease: congenital muscular dystrophies—glycosylation takes center stage

Martin

2006

Nat Rev Neurol

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SUMMARYRecent studies have defined a group of muscular dystrophies, now termed the dystroglycanopathies, as novel disorders of glycosylation. These conditions include Walker-Warburg syndrome, muscleeye-brain disease, Fukuyama-type congenital muscular dystrophy, congenital muscular dystrophy types 1C and 1D, and limb-girdle muscular dystrophy type 2I. Although clinical findings can be highly variable, dystroglycanopathies are all characterized by cortical malformations and ocular defects at the more severe end of the clinical spectrum, in addition to muscular dystrophy. All of these disorders are defined by the underglycosylation of α-dystroglycan. Defective glycosylation of dystroglycan severs the link between this important cell adhesion molecule and the extracellular matrix, thereby contributing to cellular pathology. Recent experiments indicate that glycosylation might not only define forms of muscular dystrophy but also provide an avenue to the development of therapies for these disorders.

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Mouse Large Can Modify Complex N- and Mucin O-Glycans on α-Dystroglycan to Induce Laminin Binding

Cited by 88 publications

References 83 publications

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

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

Absence of Post-phosphoryl Modification in Dystroglycanopathy Mouse Models and Wild-type Tissues Expressing Non-laminin Binding Form of α-Dystroglycan

Mechanisms of Disease: congenital muscular dystrophies—glycosylation takes center stage

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