Journal
JOURNAL OF CELL BIOLOGY
Volume 220, Issue 2, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201910079
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Funding
- Agence Nationale de la Recherche (ANR) program [ANR-13-JSV2-0003-01]
- Ligue Contre le Cancer as Equipe labellisee Ligue 2014 [EL2014.LNCC/CAR]
- Spanish Ministry of Economy, Industry, and Competitiveness [RTI2018-099718]
- institutional Maria deMaeztu Program for Units of Excellence in Research and Development
- FEDER funds
- ANR
- ARC Foundation
- European Marie Sklodowska-Curie funding program
- discovery platform and informatics group at EDyP
- Proteomics French Infrastructure [ANR-10-INBS-08-01]
- Labex GRAL [ANR-10-LABX-49-01]
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TRPV4 calcium channel co-localizes with beta 1-integrins at the invadosome periphery and regulates its activation, dependent on its ability to sense ROS. TRPV4 mediates invadosome function through activation of ROS/calcium-sensitive kinase Ask1 and binding with motor protein MYO1C.
Invadosomes support cell invasion by coupling both acto-adhesive and extracellular matrix degradative functions, which are apparently antagonistic. beta 1-integrin dynamics regulate this coupling, but the actual sensing mechanism and effectors involved have not yet been elucidated. Using genetic and reverse genetic approaches combined with biochemical and imaging techniques, we now show that the calcium channel TRPV4 colocalizes with beta 1-integrins at the invadosome periphery and regulates its activation and the coupling of acto-adhesive and degradative functions. TRPV4-mediated regulation of podosome function depends on its ability to sense reactive oxygen species (ROS) in invadosomes' microenvironment and involves activation of the ROS/calcium-sensitive kinase Ask1 and binding of the motor MYO1C. Furthermore, disease-associated TRPV4 gain-of-function mutations that modulate ECM degradation are also implicated in the ROS response, which provides new perspectives in our understanding of the pathophysiology of TRPV4 channelopathies.
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