Remote Control of Cell Signaling through Caveolae Mechanics

Abstract

Caveolae are invaginated plasma membrane nanodomains traditionally associated with membrane trafficking and signaling. These multifunctional organelles are also essential mechanosensors mediating the cell response to mechanical stress. We investigated the role of caveolae mechanics in regulating various signaling pathways. Single molecule imaging and super resolution microscopy revealed that mechanical stress rapidly triggers caveolae disassembly and the release of caveolin-1 scaffolds, which exhibit enhanced diffusion at the plasma membrane. This promoted direct interaction between the caveolin-1 scaffolding domain and the tyrosine kinase JAK1, leading to the inhibition of its catalytic activity. A similar process was observed for eNOS, PTEN, and PTP1B. Remote control of signaling by caveolae was validated by a theoretical model based on caveolae thermodynamics. These findings establish a novel mechanotransduction paradigm where signaling information is decoded remotely from the initial mechanosensing caveola, through dynamic and reversible assembly of tension-controlled complexes between signaling effectors and caveolin-1 scaffolds.