Cross-talk between Ras and Rho signalling pathways in transformation favours proliferation and increased motility.
Transformation by oncogenic Ras requires the function of the Rho family GTPases. We find that Ras-transformed cells have elevated levels of RhoA-GTP, which functions to inhibit the expression of the cell cycle inhibitor p21/Waf1. These high levels of Rho-GTP are not a direct consequence of Ras signalling but are selected for in response to sustained ERK-MAP kinase signalling. While the elevated levels of Rho-GTP control the level of p21/Waf, they no longer regulate the formation of actin stress fibres in transformed cells. We show that the sustained ERK-MAP kinase signalling resulting from transformation by oncogenic Ras down-regulates ROCK1 and Rho-kinase, two Rho effectors required for actin stress fibre formation. The repression of Rho- dependent stress fibre formation by ERK-MAP kinase signalling contributes to the increased motility of Ras-transformed fibroblasts. Overexpression of the ROCK target LIM kinase restores actin stress fibres and inhibits the motility of Ras-transformed fibroblasts. We propose a model in which Ras and Rho signalling pathways cross-talk to promote signalling pathways favouring transformation.
Sahai
E
E
CRC Centre for Cell and Molecular Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
Olson
M F
MF
Marshall
C J
CJ
D000818:Animals; D002455:Cell Division; D002460:Cell Line; D002461:Cell Line, Transformed; D002465:Cell Movement; D005347:Fibroblasts / Q000201:enzymology; D005455:Fluorescent Antibody Technique; D019204:GTP-Binding Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008845:Microinjections; D020239:Receptor Cross-Talk; D018631:ras Proteins / Q000378:metabolism*
D019204:GTP-Binding Proteins; D018631:ras Proteins