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Molecular and Cellular Biology, April 2006, p. 3181-3193, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.3181-3193.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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

Annick Lagana,1,{dagger} Jacky G. Goetz,1,2,{dagger} Pam Cheung,3 Avraham Raz,4 James W. Dennis,3 and Ivan R. Nabi1,2*

Department of Pathology and Cell Biology, Université de Montréal, Québec, Canada,1 Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada,2 Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada,3 Karmanos Cancer Institute, Detroit, Michigan4

Received 22 September 2005/ Returned for modification 1 November 2005/ Accepted 21 January 2006

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 ß1,6GlcNAc-branched N-glycans, products of Golgi ß1,6-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 {alpha}5ß1-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 {alpha}5ß1 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 {alpha}5ß1 translocation to fibrillar adhesions.

* Corresponding author. Mailing address: Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada. Phone: (604) 822-7000. Fax: (604) 822-2316. E-mail: ivan.robert.nabi{at}ubc.ca.

{dagger} These authors contributed equally.

Molecular and Cellular Biology, April 2006, p. 3181-3193, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.3181-3193.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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