title: Force-induced apoptosis mediated by the Rac/Pak/p38 signalling pathway is regulated by filamin A.
abstract: Cells in mechanically challenged environments cope with high-amplitude exogenous forces that can lead to cell death, but the mechanisms that mediate force-induced apoptosis and the identity of mechanoprotective cellular factors are not defined. We assessed apoptosis in NIH 3T3 and HEK (human embryonic kidney)-293 cells exposed to tensile forces applied through β1-integrins. Apoptosis was mediated by Rac-dependent activation of p38α. Depletion of Pak1 (p21-activated kinase 1), a downstream effector of Rac, prevented force-induced p38 activation and apoptosis. Rac was recruited to sites of force transfer by filamin A, which inhibited force-induced apoptosis mediated by Rac and p38α. We conclude that, in response to tensile force, filamin A regulates Rac-dependent signals, which induce apoptosis through Pak1 and p38.
authors.affiliation: Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, ON, Canada, M5S 3E2.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Shifrin
authors.forename: Vanessa I
authors.initials: VI
authors.lastname: Pinto
authors.forename: Abbas
authors.initials: A
authors.lastname: Hassanali
authors.forename: Pamma D
authors.initials: PD
authors.lastname: Arora
authors.forename: Christopher A
authors.initials: CA
authors.lastname: McCulloch
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D003285:Contractile Proteins / Q000378:metabolism*; D064448:Filamins; D006801:Humans; D015151:Immunoblotting; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D041681:NIH 3T3 Cells; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; D054462:p21-Activated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D020830:rac1 GTP-Binding Protein