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Integrins engage mitochondrial function for signal transduction by a mechanism dependent on Rho GTPases
1Department of Anatomy, University of California, San Francisco, CA 94143. ericaw@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 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.
Insights
Integrin engagement triggers a novel signaling pathway involving Rac GTPase and reactive oxygen species (ROS) production, leading to gene expression. This mechanism utilizes mitochondrial function rather than apoptosis.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Integrin-mediated cell shape changes initiate complex signaling cascades.
- Small GTPases like Rac and RhoA play crucial roles in cellular processes.
- Reactive oxygen species (ROS) are implicated in various cellular signaling pathways.
Purpose of the Study:
- To elucidate the signaling cascade initiated by integrin engagement.
- To identify the role of small GTPases and ROS in collagenase-1 (CL-1) production.
- To investigate the mechanism of ROS generation in this context.
Main Methods:
- Utilized Rac mutants to assess the role of actin cytoskeleton reorganization and NADPH oxidase binding.
- Investigated ROS production via mitochondrial function changes.
- Employed inhibitors like Bcl-2 to study mitochondrial involvement.
Main Results:
- Transient Rac activation and subsequent ROS rise are essential for NFkappaB activation and CL-1 production.
- A novel small GTPase-mediated ROS production mechanism was identified.
- Integrin-induced ROS production involves mitochondrial membrane potential loss, not solely NADPH oxidase.
- RhoA activation also induced ROS production and CL-1 expression.
Conclusions:
- Integrin engagement triggers a novel signaling pathway involving Rac, ROS, and mitochondrial metabolism.
- This pathway leads to gene expression (CL-1 production) rather than apoptosis.
- Mitochondrial function is a key source of ROS in integrin-mediated signaling.
