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Integrins engage mitochondrial function for signal transduction by a mechanism dependent on Rho GTPases
Erica Werner, and
Zena Werb
Department of Anatomy, University of California, San Francisco, CA 94143
Address correspondence to Erica Werner, Dept. of Cell Biology, Emory University, Whitehead Biomedical Research Bldg., 615 Michael St., Atlanta, GA 30322. Tel.: (404) 727-6277. Fax: (404) 727-6456. E-mail: ericaw{at}cellbio.emory.edu
Abstract:
We show here the transient activation of the small GTPase Rac,followed by a rise in reactive oxygen species (ROS), as necessaryearly steps in a signal transduction cascade that lead to NFBactivation and collagenase-1 (CL-1)/matrix metalloproteinase-1production after integrin-mediated cell shape changes. We showevidence indicating that this constitutes a new mechanism forROS production mediated by small GTPases. Activated RhoA alsoinduced ROS production and up-regulated CL-1 expression. A Racmutant (L37) that prevents reorganization of the actin cytoskeletonprevented integrin-induced CL-1 expression, whereas mutationsthat abrogate Rac binding to the neutrophil NADPH membrane oxidasein vitro (H26 and N130) did not. Instead, ROS were producedby integrin-induced changes in mitochondrial function, whichwere inhibited by Bcl-2 and involved transient membrane potentialloss. The cells showing this transient decrease in mitochondrialmembrane potential were already committed to CL-1 expression.These results unveil a new molecular mechanism of signal transductiontriggered by integrin engagement where a global mitochondrialmetabolic response leads to gene expression rather than apoptosis.
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B activation and collagenase-1 (CL-1)/matrix metalloproteinase-1 production after integrin-mediated cell shape changes. We show evidence indicating that this constitutes a new mechanism for ROS production mediated by small GTPases. Activated RhoA also induced ROS production and up-regulated CL-1 expression. A Rac mutant (L37) that prevents reorganization of the actin cytoskeleton prevented integrin-induced CL-1 expression, whereas mutations that abrogate Rac binding to the neutrophil NADPH membrane oxidase in vitro (H26 and N130) did not. Instead, ROS were produced by integrin-induced changes in mitochondrial function, which were inhibited by Bcl-2 and involved transient membrane potential loss. The cells showing this transient decrease in mitochondrial membrane potential were already committed to CL-1 expression. These results unveil a new molecular mechanism of signal transduction triggered by integrin engagement where a global mitochondrial metabolic response leads to gene expression rather than apoptosis. 
