Journal
NATURE
Volume 461, Issue 7260, Pages 99-103Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature08242
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Funding
- Swiss National Science Foundation
- Novartis Foundation
- Ciba-Geigy Jubilee Foundation
- NIGMS [U54 GM064346]
- [NIH T32 GM008719]
- [NIH F30 HL094020]
- [NIH R01 GM57464]
- [NIH R01 GM71868]
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The GTPases Rac1, RhoA and Cdc42 act together to control cytoskeleton dynamics(1-3). Recent biosensor studies have shown that all three GTPases are activated at the front of migrating cells(4-7), and biochemical evidence suggests that they may regulate one another: Cdc42 can activate Rac1 (ref. 8), and Rac1 and RhoA are mutually inhibitory(9-12). However, their spatiotemporal coordination, at the seconds and single-micrometre dimensions typical of individual protrusion events, remains unknown. Here we examine GTPase coordination in mouse embryonic fibroblasts both through simultaneous visualization of two GTPase biosensors and using a 'computational multiplexing' approach capable of defining the relationships between multiple protein activities visualized in separate experiments. We found that RhoA is activated at the cell edge synchronous with edge advancement, whereas Cdc42 and Rac1 are activated 2 mm behind the edge with a delay of 40s. This indicates that Rac1 and RhoA operate antagonistically through spatial separation and precise timing, and that RhoA has a role in the initial events of protrusion, whereas Rac1 and Cdc42 activate pathways implicated in reinforcement and stabilization of newly expanded protrusions.
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