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J Cell Biol. 2014 Mar 3;204(5):777-92. doi: 10.1083/jcb.201307055. Epub 2014 Feb 24.

Caveolae regulate the nanoscale organization of the plasma membrane to remotely control Ras signaling.

Author information

1
The University of Queensland, Institute for Molecular Bioscience, Queensland 4072, Australia.

Abstract

The molecular mechanisms whereby caveolae exert control over cellular signaling have to date remained elusive. We have therefore explored the role caveolae play in modulating Ras signaling. Lipidomic and gene array analyses revealed that caveolin-1 (CAV1) deficiency results in altered cellular lipid composition, and plasma membrane (PM) phosphatidylserine distribution. These changes correlated with increased K-Ras expression and extensive isoform-specific perturbation of Ras spatial organization: in CAV1-deficient cells K-RasG12V nanoclustering and MAPK activation were enhanced, whereas GTP-dependent lateral segregation of H-Ras was abolished resulting in compromised signal output from H-RasG12V nanoclusters. These changes in Ras nanoclustering were phenocopied by the down-regulation of Cavin1, another crucial caveolar structural component, and by acute loss of caveolae in response to increased osmotic pressure. Thus, we postulate that caveolae remotely regulate Ras nanoclustering and signal transduction by controlling PM organization. Similarly, caveolae transduce mechanical stress into PM lipid alterations that, in turn, modulate Ras PM organization.

PMID:
24567358
PMCID:
PMC3941050
DOI:
10.1083/jcb.201307055
[Indexed for MEDLINE]
Free PMC Article

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