title: Caveolae regulate the nanoscale organization of the plasma membrane to remotely control Ras signaling.
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.
authors.affiliation: The University of Queensland, Institute for Molecular Bioscience, Queensland 4072, Australia.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ariotti
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Fernández-Rojo
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Hill
authors.forename: Travis L
authors.initials: TL
authors.lastname: Rodkey
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Inder
authors.forename: Lukas B
authors.initials: LB
authors.lastname: Tanner
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
authors.forename: John F
authors.initials: JF
authors.lastname: Hancock
authors.forename: Robert G
authors.initials: RG
authors.lastname: Parton
mesh_terms: D000818:Animals; D021941:Caveolae / Q000378:metabolism / Q000502:physiology*; D051242:Caveolin 1 / Q000235:genetics*; D015536:Down-Regulation; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C495541:Cav1 protein, mouse; D051242:Caveolin 1; D008563:Membrane Lipids; D018631:ras Proteins