Cell shape-dependent control of cell-cycle progression underlies the spatial 
differentials of growth that drive tissue morphogenesis, yet little is known 
about how cell distortion impacts the biochemical signaling machinery that is 
responsible for growth control. Here we show that the Rho family GTPase, RhoA, 
conveys the "cell shape signal" to the cell-cycle machinery in human capillary 
endothelial cells. Cells accumulating p27(kip1) and arrested in mid G(1) phase 
when spreading were inhibited by restricted extracellular matrix adhesion, 
whereas constitutively active RhoA increased expression of the F-box protein 
Skp2 required for ubiquitination-dependent degradation of p27(kip1) and restored 
G(1) progression in these cells. Studies with dominant-negative and 
constitutively active forms of mDia1, a downstream effector of RhoA, and with a 
pharmacological inhibitor of ROCK, another RhoA target, revealed that RhoA 
promoted G(1) progression by altering the balance of activities between these 
two downstream effectors. These data indicate that signaling proteins such as 
mDia1 and ROCK, which are thought to be involved primarily in cytoskeletal 
remodeling, also mediate cell growth regulation by coupling cell shape to the 
cell-cycle machinery at the level of signal transduction.