Diffusing caveolin-1 scaffolds regulate mechanosignalling

Mani SK(#)(1)(2)(3), Tardif N(#)(1)(2)(3)(4), Rossier O(#)(5)(6), Khater
IM(7)(8), Zhou X(5)(6), Breton V(1)(2)(3), Nunes Vicente F(5)(6)(9),
Radhakrishnan AV(5)(6)(10), Gracia C(1)(2)(3), Gonzalez Troncoso P(1)(2)(3),
Brito I(11), Ruez R(1)(2)(3)(12), Dewulf M(1)(2)(3), Hamarneh G(7), Nabi IR(13),
Cuniasse P(14), Sens P(15), Giannone G(5)(6), Blouin CM(16)(17)(18), Lamaze
C(19)(20)(21).

Author information:
(1)Membrane Mechanics and Dynamics of Intracellular Signalling Laboratory,
Institut Curie-Centre de Recherche, PSL Research University, Paris, France.
(2)Institut National de la Santé et de la Recherche Médicale (INSERM), U1339,
Paris, France.
(3)Centre National de la Recherche Scientifique (CNRS), UMR3666, Paris, France.
(4)GlaxoSmithKline, Rueil-Malmaison, France.
(5)Interdisciplinary Institute for Neuroscience, University of Bordeaux,
Bordeaux, France.
(6)UMR 5297 CNRS, Bordeaux, France.
(7)School of Computing Science, Simon Fraser University, Burnaby, British
Columbia, Canada.
(8)Department of Electrical and Computer Engineering, Faculty of Engineering and
Technology, Birzeit University, Birzeit, Palestine.
(9)Cell Biology and Biophysics Unit, European Molecular Biology Laboratory,
Heidelberg, Germany.
(10)Somaiya Centre for Integrated Science Education and Research, SciSER-Physics
Department, Somaiya Vidyavihar University, Mumbai, India.
(11)Institut Curie, PSL University, INSERM U900, Mines Paris Tech, Paris,
France.
(12)ALIRI Bioanalysis, Loos, France.
(13)Department of Cellular and Physiological Sciences, University of British
Columbia, Vancouver, British Columbia, Canada.
(14)Institute for Integrative Biology of the Cell (I2BC), Université
Paris-Saclay, CEA, CNRS, Gif-sur-Yvette, France.
(15)Institut Curie, PSL Research University, Sorbonne University, CNRS UMR168,
Paris, France.
(16)Membrane Mechanics and Dynamics of Intracellular Signalling Laboratory,
Institut Curie-Centre de Recherche, PSL Research University, Paris, France.
.
(17)Institut National de la Santé et de la Recherche Médicale (INSERM), U1339,
Paris, France. .
(18)Centre National de la Recherche Scientifique (CNRS), UMR3666, Paris, France.
.
(19)Membrane Mechanics and Dynamics of Intracellular Signalling Laboratory,
Institut Curie-Centre de Recherche, PSL Research University, Paris, France.
.
(20)Institut National de la Santé et de la Recherche Médicale (INSERM), U1339,
Paris, France. .
(21)Centre National de la Recherche Scientifique (CNRS), UMR3666, Paris, France.
.
(#)Contributed equally

Caveolae are invaginated plasma membrane nanodomains traditionally associated
with membrane trafficking and signalling. These multifunctional organelles are
also essential mechanosensors mediating the cell response to mechanical stress.
We investigated the role of caveolae mechanics in regulating various signalling
pathways. Single-molecule imaging and super-resolution microscopy revealed that
mechanical stress rapidly triggers caveolae disassembly and the release of
caveolin-1 scaffolds, which then 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. The control
of signalling by diffusing Cav1 scaffolds was further validated by a theoretical
model based on caveolae thermodynamics. These findings establish a
mechanotransduction paradigm in which signalling information is decoded remotely
from the initial mechanosensing caveola, through dynamic and reversible assembly
of tension-controlled complexes between signalling effectors and caveolin-1
scaffolds.

© 2026. The Author(s), under exclusive licence to Springer Nature Limited.

DOI: 10.1038/s41556-026-01966-0
PMID: 42225832

Conflict of interest statement: Competing interests: The authors declare no
competing interests.

Auteurs Bordeaux Neurocampus