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Cross-talk between Ras and Rho signalling pathways in transformation favours proliferation and increased motility
E Sahai1, M F Olson, C J Marshall
1CRC Centre for Cell and Molecular Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
Abstract:
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.
Insights
Oncogenic Ras transformation elevates RhoA-GTP, inhibiting p21/Waf1. Sustained ERK-MAP kinase signaling in Ras-transformed cells represses actin stress fiber formation, increasing cell motility.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Oncogenic Ras proteins are key drivers of cellular transformation.
- Rho family GTPases are essential for Ras-mediated transformation.
- ERK-MAP kinase signaling plays a critical role in cellular processes.
Purpose of the Study:
- To investigate the role of Rho GTPases in Ras-driven transformation.
- To elucidate the mechanisms by which Ras signaling affects cell cycle regulators and cytoskeletal dynamics.
- To understand the cross-talk between Ras, Rho, and ERK signaling pathways in cancer.
Main Methods:
- Analysis of RhoA-GTP levels in Ras-transformed cells.
- Investigation of ERK-MAP kinase signaling pathways.
- Assessment of p21/Waf1 expression.
- Evaluation of actin stress fiber formation and cell motility.
- Manipulation of ROCK1, Rho-kinase, and LIM kinase expression.
Main Results:
- Ras-transformed cells exhibit elevated RhoA-GTP, which inhibits p21/Waf1.
- Sustained ERK-MAP kinase signaling, not direct Ras signaling, leads to high Rho-GTP levels.
- ERK-MAP kinase signaling down-regulates ROCK1 and Rho-kinase, disrupting actin stress fibers.
- Repression of stress fiber formation by ERK signaling enhances Ras-transformed fibroblast motility.
- Overexpression of LIM kinase restores actin stress fibers and reduces motility.
Conclusions:
- Ras and Rho signaling pathways interact to promote transformation.
- ERK-MAP kinase signaling mediates key aspects of Ras-induced cellular changes, including cell cycle inhibition and altered motility.
- Targeting the cross-talk between these pathways may offer therapeutic strategies for Ras-driven cancers.