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J. Cell Biol. 158 (2): 357-368

Copyright © 2002 by the Rockefeller University Press.


Article

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 necessary early steps in a signal transduction cascade that lead to NF{kappa}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.

Key Words: integrin; actin; Rac; ROS; mitochondria


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