Cross-talk between the calcium channel TRPV4 and reactive oxygen species interlocks adhesive and degradative functions of invadosomes

J Cell Biol. 2021 Feb 1;220(2):e201910079. doi: 10.1083/jcb.201910079.


Invadosomes support cell invasion by coupling both acto-adhesive and extracellular matrix degradative functions, which are apparently antagonistic. β1-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 β1-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Calcium / metabolism
  • Cell Adhesion
  • Cysteine / metabolism
  • Dithionitrobenzoic Acid
  • Extracellular Matrix / metabolism
  • HEK293 Cells
  • Humans
  • Hydrogen Peroxide / metabolism
  • Integrin beta1 / metabolism
  • MAP Kinase Kinase Kinase 5 / metabolism
  • Mice
  • Models, Biological
  • Myosin Type I / metabolism
  • Podosomes / metabolism*
  • Protein Transport
  • RAW 264.7 Cells
  • Reactive Oxygen Species / metabolism*
  • TRPV Cation Channels / metabolism*


  • Actins
  • Integrin beta1
  • Myo1c protein, mouse
  • Reactive Oxygen Species
  • TRPV Cation Channels
  • Trpv4 protein, mouse
  • Dithionitrobenzoic Acid
  • Hydrogen Peroxide
  • MAP Kinase Kinase Kinase 5
  • Map3k5 protein, mouse
  • Myosin Type I
  • Cysteine
  • Calcium