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

Author:

Ariotti Nicholas1,Fernández-Rojo Manuel A.1,Zhou Yong2,Hill Michelle M.1,Rodkey Travis L.2,Inder Kerry L.1,Tanner Lukas B.3,Wenk Markus R.3,Hancock John F.2,Parton Robert G.1

Affiliation:

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

2. Department of Integrative Biology and Pharmacology, The University of Texas Medical School-Houston, Houston, TX 77030

3. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Centre for Life Sciences, 117456 Singapore

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.

Publisher

Rockefeller University Press

Subject

Cell Biology

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