Journal
EXPERIMENTAL CELL RESEARCH
Volume 314, Issue 7, Pages 1540-1552Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2008.01.016
Keywords
RhoA; ROCK; Rac; EGF; metastasis
Categories
Funding
- NCI NIH HHS [P01 CA100324, CA 100324, P01 CA100324-05, R01 CA150344] Funding Source: Medline
- NIGMS NIH HHS [GM64346, U54 GM064346-079026, U54 GM064346-069026, R01 GM055692-10, U54 GM064346, R01 GM055692] Funding Source: Medline
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Rho GTPases are versatile regulators of cell shape that act on the actin cytoskeleton. Studies using Rho GTPase mutants have shown that, in some cells, Rac1 and Cdc42 regulate the formation of lamellipodia and filopodia, respectively at the leading edge, whereas RhoA mediates contraction at the rear of moving cells. However, recent reports have described a zone of RhoA/ROCK activation at the front of cells undergoing motility. In this study, we use a FRET-based RhoA biosensor to show that RhoA activation localizes to the leading edge of EGF-stimulated cells. Inhibition of Rho or ROCK enhanced protrusion, yet markedly inhibited cell motility; these changes correlated with a marked activation of Rac-1 at the cell edge. Surprisingly, whereas EGF-stimulated protrusion in control MTLn3 cells is Rac-independent and Cdc42-dependent, the opposite pattern is observed in MTLn3 cells after inhibition of ROCK. Thus, Rho and ROCK suppress Rac-1 activation at the leading edge, and inhibition of ROCK causes a switch between Cdc42 and Rac-1 as the dominant Rho GTPase driving protrusion in carcinoma cells. These data describe a novel role for Rho in coordinating signaling by Rac and Cdc42. (C) 2008 Elsevier Inc. All rights reserved.
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