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J. Biol. Chem., Vol. 283, Issue 51, 35445-35454, December 19, 2008

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Tetraspanin CD151 Regulates Glycosylation of 3β1 Integrin^*

Gouri Baldwin, Vera Novitskaya, Rafal Sadej, Ewa Pochec, Anna Litynska, Christoph Hartmann^¶, Janelle Williams^||, Leonie Ashman^||, Johannes A. Eble^¶, and Fedor Berditchevski¹

From the Cancer Research UK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom, the ^||School of Biomedical Sciences, Medical Sciences Building, University of Newcastle, Callaghan, New South Wales 2308, Australia, the ^¶Centre for Molecular Medicine Department, Vascular Matrix Biology Excellence Cluster, Cardio-Pulmonary System, Frankfurt University Hospital, 60590 Frankfurt-on-Main, Germany, and the Department of Glycoconjugate Biochemistry, Jagiellonian University, Ingardena 6, 30-060 Krakow, Poland

The tetraspanin CD151 forms a stoichiometric complex with integrin 3β1 and regulates its endocytosis. We observed that down-regulation of CD151 in various epithelial cell lines changed glycosylation of 3β1. In contrast, glycosylation of other transmembrane proteins, including those associated with CD151 (e.g. 6β1, CD82, CD63, and emmprin/CD147) was not affected. The detailed analysis has shown that depletion of CD151 resulted in the reduction of Fuc1–2Gal and bisecting GlcNAc-β(14) linkage on N-glycans of the 3 integrin subunit. The modulatory activity of CD151 toward 3β1 was specific, because stable knockdown of three other tetraspanins (i.e. CD9, CD63, and CD81) did not affect glycosylation of the integrin. Analysis of 3 glycosylation in CD151-depleted breast cancer cells with reconstituted expression of various CD151 mutants has shown that a direct contact with integrin is required but not sufficient for the modulatory activity of the tetraspanin toward 3β1. We also found that glycosylation of CD151 is also critical; Asn¹⁵⁹ Gln mutation in the large extracellular loop did not affect interactions of CD151 with other tetraspanins or 3β1 but negated its modulatory function. Changes in the glycosylation pattern of 3β1 observed in CD151-depleted cells correlated with a dramatic decrease in cell migration toward laminin-332. Migration toward fibronectin or static adhesion of cells to extracellular matrix ligands was not affected. Importantly, reconstituted expression of the wild-type CD151 but not glycosylation-deficient mutant restored the migratory potential of the cells. These results demonstrate that CD151 plays an important role in post-translation modification of 3β1 integrin and strongly suggest that changes in integrin glycosylation are critical for the promigratory activity of this tetraspanin.

Received for publication, August 19, 2008 , and in revised form, October 6, 2008.

^* This work was supported by Cancer Research UK Grant C1322/A5705 (to F. B.) and Deutsche Forschungsgemeinschaft Grant EXC147/1 (to J. A. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Cancer Research UK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom. Tel.: 44-121-414-2801; Fax: 44-121-414-4486; E-mail: f.berditchevski{at}bham.ac.uk.

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