The role of FilGAP-filamin A interactions in mechanoprotection.
Cells in mechanically active environments are subjected to high-amplitude exogenous forces that can lead to cell death. Filamin A (FLNa) may protect cells from mechanically induced death by mechanisms that are not yet defined. We found that mechanical forces applied through integrins enhanced Rac-mediated lamellae formation in FLNa-null but not FLNa-expressing cells. Suppression of force-induced lamella formation was mediated by repeat 23 of FLNa, which also binds FilGAP, a recently discovered Rac GTPase-activating protein (GAP). We found that FilGAP is targeted to sites of force transfer by FLNa. This force-induced redistribution of FilGAP was essential for the suppression of Rac activity and lamellae formation in cells treated with tensile forces. Depletion of FilGAP by small interfering RNA, inhibition of FilGAP activity by dominant-negative mutation or deletion of its FLNa-binding domain, all resulted in a dramatic force-induced increase of the percentage of annexin-V-positive cells. FilGAP therefore plays a role in protecting cells against force-induced apoptosis, and this function is mediated by FLNa.
Shifrin
Yulia
Y
CIHR Group in Matrix Dynamics, University of Toronto, Toronto, Ontario, Canada. yulia.shifrin@utoronto.ca
Arora
Pamela D
PD
Ohta
Yasutaka
Y
Calderwood
David A
DA
McCulloch
Christopher A
CA
D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D001665:Binding Sites; D002460:Cell Line; D048430:Cell Shape; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D064448:Filamins; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D021381:Protein Transport; D013312:Stress, Physiological; D020744:rac GTP-Binding Proteins / Q000378:metabolism
C497033:ARHGAP24 protein, human; D017304:Annexin A5; D003285:Contractile Proteins; D064448:Filamins; D020690:GTPase-Activating Proteins; D008840:Microfilament Proteins; D020744:rac GTP-Binding Proteins