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- Title
Dominant-negative caveolin inhibits H-Ras function by disrupting cholesterol-rich plasma membrane domains.
- Authors
Roy, Sandrine; Luetterforst, Robert; Harding, Angus; Apolloni, Ann; Etheridge, Maria; Stang, Espen; Rolls, Barbara; Hancock, John F.; Parton, Robert G.
- Abstract
The plasma membrane pits known as caveolae have been implicated both in cholesterol homeostasis and in signal transduction. Cav[SUPDGV] and Cav[SUPKSY], two dominant-negative amino-terminal truncation mutants of caveolin, the major structural protein of caveolae, significantly inhibited caveola-mediated SV40 infection, and were assayed for effects on Ras function. We find that Cav[SUPDGV] completely blocked Raf activation mediated by H-Ras, but not that mediated by K-Ras. Strikingly, the inhibitory effect of Cav[SUPDGV] on H-Ras signalling was completely reversed by replenishing cell membranes with cholesterol and was mimicked by cyclodextrin treatment, which depletes membrane cholesterol. These results provide a crucial link between the cholesterol-trafficking role of caveolin and its postulated role in signal transduction through cholesterol-rich surface domains. They also provide direct evidence that H-Ras and K-Ras, which are targeted to the plasma membrane by different carboxy-terminal anchors, operate in functionally distinct microdomains of the plasma membrane.
- Subjects
CELL membranes; CHOLESTEROL; HOMEOSTASIS; GENETIC transduction
- Publication
Nature Cell Biology, 1999, Vol 1, Issue 2, p98
- ISSN
1465-7392
- Publication type
Article
- DOI
10.1038/10067