Inhibition of lipid raft-dependent signaling by a dystrophy-associated mutant of caveolin-3

Carozzi, A. J., Roy, S., Morrow, I. C., Pol, A., Wyse, B., Clyde-Smith, J., Prior, I. A., Nixon, S. J., Hancock, J. F. and Parton, R. G. (2002) Inhibition of lipid raft-dependent signaling by a dystrophy-associated mutant of caveolin-3. Journal of Biological Chemistry, 277 20: 17944-17949. doi:10.1074/jbc.M110879200

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Author Carozzi, A. J.
Roy, S.
Morrow, I. C.
Pol, A.
Wyse, B.
Clyde-Smith, J.
Prior, I. A.
Nixon, S. J.
Hancock, J. F.
Parton, R. G.
Title Inhibition of lipid raft-dependent signaling by a dystrophy-associated mutant of caveolin-3
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2002
Sub-type Article (original research)
DOI 10.1074/jbc.M110879200
Open Access Status File (Publisher version)
Volume 277
Issue 20
Start page 17944
End page 17949
Total pages 6
Editor H. Tabor
Place of publication Bethesda, USA
Publisher American Society for Biochemistry & Molecular Biology
Collection year 2002
Language eng
Subject C1
320303 Medical Biochemistry - Lipids
730118 Organs, diseases and abnormal conditions not elsewhere classified
Abstract Specific point mutations in caveolin-3, a predominantly muscle-specific member of the caveolin family, have been implicated in limb-girdle muscular dystrophy and in rippling muscle disease. We examined the effect of these mutations on caveolin-3 localization and function. Using two independent assay systems, Raf activation in fibroblasts and neurite extension in PC12 cells, we show that one of the caveolin-3 point mutants, caveolin-3-C71W, specifically inhibits signaling by activated H-Ras but not by K-Ras. To gain insights into the effect of the mutant protein on H-Ras signaling, we examined the localization of the mutant proteins in fibroblastic cells and in differentiating myotubes. Unlike the previously characterized caveolin-3-DGV mutant, the inhibitory caveolin-3-C71W mutant reached the plasma membrane and colocalized with wild type caveolins. In BHK cells, caveolin-3-C71W associated with caveolae and in differentiating muscle cells with the developing T-tubule system. In contrast, the caveolin-3-P104L mutant accumulated in the Golgi complex and had no effect on H-Ras-mediated Raf activation. Inhibition by caveolin-3-C71W was rescued by cholesterol addition, suggesting that the mutant protein perturbs cholesterol-rich raft domains. Thus, we have demonstrated that a naturally occurring caveolin-3 mutation can inhibit signaling involving cholesterol-sensitive raft domains.
Keyword Biochemistry & Molecular Biology
Girdle Muscular-dystrophy
Developing T-tubules
Glycoprotein Complex
Binding Protein
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
Centre for Integrated Preclinical Drug Development Publications
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Created: Tue, 14 Aug 2007, 17:00:47 EST