Coordination of Rho GTPase activities during cell protrusion
By M. Machacek, L. Hodgson, Christopher M. Welch, Hunter L. Elliott, O. Pertz, P. Nalbant, A. Abell, Gary L. Johnson, K. Hahn, G. Danuser. Nature, 2009
1,045 citations recorded by the source corpus.
The GTPases Rac1, RhoA and Cdc42 act together to control cytoskeleton dynamics. Recent biosensor studies have shown that all three GTPases are activated at the front of migrating cells, and biochemical evidence suggests that they may regulate one another: Cdc42 can activate Rac1 (ref. 8), and Rac1 and RhoA are mutually inhibitory. 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 μm behind the edge with a delay of 40 s. 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.
Subfields: Biomedical Engineering, Cell Biology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/1d3e8f8f18b693220bd70ab93376ad068bae6a44
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Citations in the corpus
- Rho GTPase signalling in cell migration (2015, background): “In addition to Rac, RhoA and Cdc42 are active in lamellipodial regions and contribute to lamellipodium extension [23,24].”
- Amiloride inhibits macropinocytosis by lowering submembranous pH and preventing Rac1 and Cdc42 signaling (2010, methodology): “…4 • 2010 560 CFP variant optimized for FRET (Nguyen and Daugherty, 2005), and either the CRIB domain from p21-activated kinase (PBD) published previously (Machacek et al., 2009) or the Cdc42-binding CRIB domain from WASP (CBD), amino acids 230–314, fused to the C terminus of YPet, a YFP variant…”
- Life at the leading edge. (2011, background): “This function of Rac could explain why Rac is most active slightly further back in the lamellipodium than RhoA (Machacek et al., 2009), although RhoA/ROCK can also phosphorylate and inhibit cofilin/ADF (Bernard, 2007).”