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MBC in Press, published online ahead of print January 9, 2002
Mol. Biol. Cell 10.1091/mbc.01-06-0302

A more recent version of this article appeared on January 1, 2002
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Submitted on June 20, 2001
Revised on October 4, 2001
Accepted on October 22, 2001

Post-transcriptional down-regulation of Rho-kinase through a MEK-dependent pathway leads to cytoskeleton disruption in ras-transformed fibroblasts

Geraldine Pawlak1 and David M. Helfman1*

1 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York

* Corresponding author. E-mail address: helfman{at}cshl.org.

Transformation by oncogenic Ras profoundly alters actin cytoskeleton organization. We investigated Ras-dependent signaling pathways involved in cytoskeleton disruption, by transfecting NRK cells with different Ras mutants. RasV12S35, a mutant known to activate specifically the Raf/MAPK pathway led to stress fiber and focal contact disruption, while the adherens junctions remained intact. Next, we found that pharmacological inhibition of MEK was sufficient to restore the cytoskeletal defects of ras-transformed NRK cells, including assembly of stress fibers and focal contacts, but did not induce reorganization of the cell-cell junctions. Investigating the mechanism underlying this phenotypic reversion, we found that the sustained MAPK signaling resulting from Ras-transformation down-regulated the expression of Rho-kinase, a Rho effector required for stress fiber formation, at the post-transcriptional level. Upon MEK inhibition, Rho-kinase expression and cofilin phosphorylation were restored, demonstrating that the Rho-kinase/LIM-kinase/cofilin pathway was functionally restored. Finally, using dominant negative or constitutively active mutants, we demonstrated that expression of Rho-kinase was both necessary and sufficient to promote cytoskeleton reorganization in NRK/ras cells. These findings further establish the Ras/MAPK pathway as the critical pathway involved in cytoskeleton disruption during Ras-transformation, and suggest a new mechanism, involving alteration in Rho-kinase expression, by which oncogenic Ras can specifically target the actin-based cytoskeleton and therefore achieve morphological transformation of the cells.




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