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Force-induced apoptosis mediated by the Rac/Pak/p38 signalling pathway is regulated by filamin A

Yulia Shifrin1, Vanessa I Pinto, Abbas Hassanali

  • 1Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, ON, Canada, M5S 3E2.

The Biochemical Journal
|April 12, 2012
PubMed

Insights

Filamin A protects cells from mechanical force-induced apoptosis by regulating Rac-dependent signals. This pathway involves p21-activated kinase 1 (Pak1) and p38 kinase, crucial for cell survival under stress.

Area of Science:

  • Cell Biology
  • Mechanobiology
  • Biochemistry

Background:

  • Cells encounter mechanical forces, which can trigger cell death pathways like apoptosis.
  • The precise mechanisms and protective factors involved in force-induced apoptosis remain largely unknown.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying apoptosis induced by mechanical tensile forces.
  • To identify cellular factors that protect against force-induced cell death.

Main Methods:

  • Assessed apoptosis in NIH 3T3 and HEK-293 cells subjected to tensile forces via β1-integrins.
  • Investigated the roles of Rac, p38α, p21-activated kinase 1 (Pak1), and filamin A in force-induced apoptosis.

Main Results:

  • Tensile force induced apoptosis through Rac-dependent activation of p38α.
  • Depleting Pak1, a Rac effector, blocked force-induced p38 activation and apoptosis.
  • Filamin A recruited Rac to force-transfer sites, inhibiting Rac- and p38α-mediated apoptosis.

Conclusions:

  • Filamin A acts as a mechanoprotective factor by regulating Rac-dependent signaling pathways.
  • The identified pathway (Filamin A-Rac-Pak1-p38α) is critical for cellular responses to mechanical stress and survival.

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