title: Tumor suppressor function of laminin-binding alpha-dystroglycan requires a distinct beta3-N-acetylglucosaminyltransferase.
abstract: Alpha-dystroglycan (alpha-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 alpha-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 alpha-DG in tumor progression. In aggressive prostate and breast carcinoma cell lines, laminin-binding glycans are dramatically decreased, although the amount of alpha-DG and beta-dystroglycan is maintained. The decrease of laminin-binding glycans and consequent increased cell migration were associated with the decreased expression of beta3-N-acetylglucosaminyltransferase-1 (beta3GnT1). Forced expression of beta3GnT1 in aggressive cancer cells restored the laminin-binding glycans and decreased tumor formation. beta3GnT1 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 beta3GnT1 and LARGE.
authors: Tumor Microenvironment Program, Cancer Research Center, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
authors: Xingfeng
authors: X
authors: Bao
authors: Motohiro
authors: M
authors: Kobayashi
authors: Shingo
authors: S
authors: Hatakeyama
authors: Kiyohiko
authors: K
authors: Angata
authors: Donald
authors: D
authors: Gullberg
authors: Jun
authors: J
authors: Nakayama
authors: Michiko N
authors: MN
authors: Fukuda
authors: Minoru
authors: M
authors: Fukuda
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology; D002465:Cell Movement; D049030:Dystroglycans / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006031:Glycosylation; D006801:Humans; D016023:Integrins / Q000378:metabolism; D007797:Laminin / Q000378:metabolism*; D008024:Ligands; D008297:Male; D008954:Models, Biological; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D010641:Phenotype; D011134:Polysaccharides / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology; D011485:Protein Binding; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D016023:Integrins; D007797:Laminin; D008024:Ligands; D011134:Polysaccharides; D025521:Tumor Suppressor Proteins; D049030:Dystroglycans; C117674:LARGE1 protein, human; D017351:N-Acetylglucosaminyltransferases