| |||
|
|
|||
|
      |
|
 |
|
| |||||||||||
| |||||||||||
| |||||||||||
| | | | ||||||||
| Cytoskeletal remodeling: The Rho-le of Rac
Rac regulates cytoskeletal remodeling via inhibition of Rho GTPase activity in a redox-dependent manner. A fine balance exists between the activities of the small GTPases Rac and Rho. Rac activation is responsible for stimulating cell spreading and migration, whereas Rho activation leads to cell contractility and adhesion. The balance between these two members of the Rho family of GTPases is a critical determinant of actin cytoskeleton rearrangements, ultimately controlling cell morphology and migration.
Previous evidence has suggested that Rac negatively regulates Rho, but the molecular mechanisms behind this remain poorly understood. What is known, however, is that Rac signaling is mediated by multiple effector pathways that control actin cytoskeleton changes, transcriptional activity and the generation of reactive oxygen species (ROS). Rac signaling pathways that control cytoskeleton and transcription activity have been demonstrated to be dispensable for the inhibition of Rho. In light of this, Bar-Sagi and colleagues studied the role of ROS generation in the regulation of Rho activity. The carboxy-terminal effector-binding site known as the insert region (residues 124–135) of Rac is a requirement for ROS generation, and the authors now show that it is also needed for downregulation of Rho. To elucidate the mechanism of this pathway further, Bar-Sagi's group observed that generation of ROS by Rac can enhance the tyrosine phosphorylation of p190Rho-GAP, a Rho-specific GTPase-activation protein whose Rho-GAP activity is enhanced by Src-mediated tyrosine phosphorylation. Hence, this ROS generation by Rac through the insert region could function as a mechanism to couple Rac activity to downregulation of Rho. Before this study, p190Rho-GAP was shown to be a target of the ubiquitously expressed enzyme low-molecular-weight protein tyrosine phosphatase (LMW-PTP). Therefore, the group set out to determine if LMW-PTP could be the target for Rac-induced ROS that mediates the increase in p190Rho-GAP tyrosine phosphorylation. They found that Rac-induced generation of ROS inactivated LMW-PTP through the oxidation of an active-site cysteine residue. Thus, the pathway utilized by Rac to downregulate Rho involves the redox-dependent inactivation of LMW-PTP, in turn enhancing tyrosine phosphorylation and activation of p190Rho-GAP. Further experimentation revealed that the downregulation of LMW-PTP by ROS is a required step in integrin-mediated cell spreading. The group suggests that inactivation of LMW-PTP by Rac-mediated ROS generation and the ensuing tyrosine phosphorylation and activation of p190Rho-GAP are necessary steps in the pathway linking integrin activation to cell spreading. Therefore, the ROS-dependent downregulation of Rho might function as a mechanism to link extracellular signals and the cellular redox state to specific changes in cell morphology. The Signaling Gateway Team
References
| |
| ||||||||
| |||||||||||
 | |||||||||||
| |||||||||||
| |||||||||||
| |||||||||||
HOME | SIGNALING UPDATE | MOLECULE PAGES | DATA CENTER | ABOUT US | |||||||||||
| |||||||||||
