Integrins engage mitochondrial function for signal transduction by a mechanism dependent on Rho GTPases.
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 NFkappaB 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.
Werner
Erica
E
Department of Anatomy, University of California, San Francisco, CA 94143. ericaw@cellbio.emory.edu
Werb
Zena
Z
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D002478:Cells, Cultured; D017364:Collagenases / Q000378:metabolism; D039564:Integrin alphaV; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology*; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000502:physiology*
D015703:Antigens, CD; D039564:Integrin alphaV; D017382:Reactive Oxygen Species; D017364:Collagenases; C417249:collagenase 1; D020781:Matrix Metalloproteinase 1; D020741:rho GTP-Binding Proteins