Four-transmembrane-domain proteins of the tetraspanin superfamily are the organizers of specific microdomains at the membrane [TERMs (tetraspanin-enriched microdomains)] that incorporate various transmembrane receptors and modulate their activities. The structural aspects of the organization of TERM are poorly understood. In the present study, we investigated the role of gangliosides in the assembly and stability of TERM. We demonstrated that inhibition of the glycosphingolipid biosynthetic pathway with specific inhibitors of glucosylceramide synthase [NB-DGJ (N-butyldeoxygalactonojirimycin) and PPMP (D-threo-1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol·HCl)] resulted in specific weakening of the interactions involving tetraspanin CD82. Furthermore, ectopic expression of the plasma-membrane-bound sialidase Neu3 in mammary epithelial cells also affected stability of the complexes containing CD82: its association with tetraspanin CD151 was decreased, but the association with EGFR [EGF (epidermal growth factor) receptor] was enhanced. The destabilization of the CD82-containing complexes upon ganglioside depletion correlated with the re-distribution of the proteins within plasma membrane. Importantly, depletion of gangliosides affected EGF-induced signalling only in the presence of CD82. Taken together, our results provide strong evidence that gangliosides play an important role in supporting the integrity of CD82-enriched microdomains. Furthermore, these results demonstrate that the association between different tetraspanins in TERM is controlled by distinct mechanisms and identify Neu3 as a first physiological regulator of the integrity of these microdomains.
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Research Article|
November 14 2006
Gangliosides play an important role in the organization of CD82-enriched microdomains
Elena Odintsova;
Elena Odintsova
1
*Cancer Research U.K. Institute for Cancer Studies, The University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
1To whom correspondence should be addressed (email odintsoe@bham.ac.uk).
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Terry D. Butters;
Terry D. Butters
†Department of Biochemistry, Glycobiology Institute, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K.
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Eugenio Monti;
Eugenio Monti
‡Department of Biomedical Sciences and Biotechnologies, School of Medicine, University of Brescia, viale Europa 11, 25123 Brescia, Italy
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Hein Sprong;
Hein Sprong
§Department of Membrane Enzymology, Bijvoet Center and Institute of Biomembranes, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
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Gerrit van Meer;
Gerrit van Meer
§Department of Membrane Enzymology, Bijvoet Center and Institute of Biomembranes, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
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Fedor Berditchevski
Fedor Berditchevski
*Cancer Research U.K. Institute for Cancer Studies, The University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
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Publisher: Portland Press Ltd
Received:
February 15 2006
Revision Received:
June 19 2006
Accepted:
July 24 2006
Accepted Manuscript online:
July 24 2006
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 400 (2): 315–325.
Article history
Received:
February 15 2006
Revision Received:
June 19 2006
Accepted:
July 24 2006
Accepted Manuscript online:
July 24 2006
Citation
Elena Odintsova, Terry D. Butters, Eugenio Monti, Hein Sprong, Gerrit van Meer, Fedor Berditchevski; Gangliosides play an important role in the organization of CD82-enriched microdomains. Biochem J 1 December 2006; 400 (2): 315–325. doi: https://doi.org/10.1042/BJ20060259
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