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Galectin Binding to Mgat5-Modified N-Glycans Regulates Fibronectin Matrix Remodeling in Tumor Cells

2006; Taylor & Francis; Volume: 26; Issue: 8 Linguagem: Inglês

10.1128/mcb.26.8.3181-3193.2006

1098-5549

Annick Lagana, Jacky G. Goetz, Pam Cheung, Avraham Raz, James Dennis, Ivan R. Nabi,

Signaling Pathways in Disease

Oncogenic signaling stimulates the dynamic remodeling of actin microfilaments and substrate adhesions, essential for cell spreading and motility.Transformation is associated with increased expression of ␤1,6GlcNAcbranched N-glycans, products of Golgi ␤1,6-acetylglucosaminyltransferase V (Mgat5) and the favored ligand for galectins.Herein we report that fibronectin fibrillogenesis and fibronectin-dependent cell spreading are deficient in Mgat5 ؊/؊ mammary epithelial tumor cells and inhibited in Mgat5 ؉/؉ cells by blocking Golgi N-glycan processing with swainsonine or by competitive inhibition of galectin binding.At an optimum dosage, exogenous galectin-3 added to Mgat5 ؉/؉ cells activates focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K), recruits conformationally active ␣5␤1-integrin to fibrillar adhesions, and increases F-actin turnover.RGD peptide inhibits PI3K-dependent fibronectin matrix remodeling and fibronectin-dependent cell motility, while galectin-3 stimulates and overrides the inhibitory effects of RGD.Antibodies to the galectin-3 N-terminal oligomerization domain stimulate ␣5␤1 activation and recruitment to fibrillar adhesions in Mgat5 ؉/؉ cells, an effect that is blocked by disrupting galectin-glycan binding.Our results demonstrate that fibronectin polymerization and tumor cell motility are regulated by galectin-3 binding to branched N-glycan ligands that stimulate focal adhesion remodeling, FAK and PI3K activation, local F-actin instability, and ␣5␤1 translocation to fibrillar adhesions.