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Redox-dependent downregulation of Rho by Rac

Abstract

Rac and Rho GTPases function as critical regulators of actin cytoskeleton remodelling during cell spreading and migration. Here we demonstrate that Rac-mediated reactive oxygen species (ROS) production results in the downregulation of Rho activity. The redox-dependent decrease in Rho activity is required for Rac-induced formation of membrane ruffles and integrin-mediated cell spreading. The pathway linking generation of ROS to downregulation of Rho involves inhibition of the low-molecular-weight protein tyrosine phosphatase (LMW-PTP) and then an increase in the tyrosine phosphorylation and activation of its target, p190Rho-GAP. Our findings define a novel mechanism for the coupling of changes in cellular redox state to the control of actin cytoskeleton rearrangements by Rho GTPases.

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Figure 1: RacG12V downregulates Rho through a redox-dependent mechanism.
Figure 2: RacG12V results in redox-dependent phosphorylation of p190Rho-GAP.
Figure 3: RacG12V causes the oxidation and inactivation of LMW-PTP.
Figure 5: ROS are necessary for integrin-mediated Rho downregulation and cell spreading.
Figure 4: RacG12V and RacG12V-Δins induce distinct actin cytoskeleton rearrangements.

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Acknowledgements

This work was supported by a grant from the National Institutes of Health (CA55360). We thank the staff at the University Microscopy and Imaging Center for help with scanning electron microscopy and members of the laboratory for helpful discussions.

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Correspondence to Dafna Bar-Sagi.

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Figure S1 Src activity is not required for the RacG12V-mediated increase in p190Rho-GAP phosphorylation. (PDF 36 kb)

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Nimnual, A., Taylor, L. & Bar-Sagi, D. Redox-dependent downregulation of Rho by Rac. Nat Cell Biol 5, 236–241 (2003). https://doi.org/10.1038/ncb938

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