Abstract:
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.
Citation:
El-Sibai, M., Pertz, O., Pang, H., Yip, S. C., Lorenz, M., Symons, M., ... & Backer, J. M. (2008). RhoA/ROCK-mediated switching between Cdc42-and Rac1-dependent protrusion in MTLn3 carcinoma cells. Experimental cell research, 314(7), 1540-1552.