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Vol. 12, Issue 9, 2711-2720, September 2001
Department of Cell and Developmental Biology and Lineberger
Comprehensive Cancer Center, University of North Carolina, Chapel Hill,
North Carolina 27599
The binding of extracellular matrix proteins to integrins
triggers rearrangements in the actin cytoskeleton by regulating the Rho
family of small GTPases. The signaling events that mediate changes in
the activity of Rho proteins in response to the extracellular matrix
remain largely unknown. We have demonstrated in previous studies that
integrin signaling transiently suppresses RhoA activity through
stimulation of p190RhoGAP. Here, we investigated the biological significance of adhesion-dependent RhoA inactivation by manipulating p190RhoGAP signaling in Rat1 fibroblasts. The inhibition of RhoA activity that is induced transiently by adhesion was antagonized by
expression of dominant negative p190RhoGAP. This resulted in impaired
cell spreading on a fibronectin substrate, reduced cell protrusion, and
premature assembly of stress fibers. Conversely, overexpression of
p190RhoGAP augmented cell spreading. Dominant negative p190RhoGAP
elevated RhoA activity in cells on fibronectin and inhibited migration,
whereas overexpression of the wild-type GAP decreased RhoA activity,
promoted the formation of membrane protrusions, and enhanced motility.
Cells expressing dominant negative p190RhoGAP, but not control cells or
cells overexpressing the wild-type GAP, were unable to establish
polarity in the direction of migration. Taken together, these data
demonstrate that integrin-triggered RhoA inhibition by
p190RhoGAP enhances spreading and migration by regulating cell
protrusion and polarity.
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