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MBC in Press, published online ahead of print November 28, 2007
Mol. Biol. Cell 10.1091/mbc.E07-09-0895

A more recent version of this article appeared on February 1, 2008
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Submitted on September 13, 2007
Revised on November 5, 2007
Accepted on November 19, 2007

B-RAF Regulation of Rnd3 Participates in Actin Cytoskeletal and Focal Adhesion Organization

R. Matthew Klein, Laurie S. Spofford, Ethan V. Abel, Arisa Ortiz, and Andrew E. Aplin

Center for Cell Biology and Cancer Research, Albany Medical College, Albany, NY 12208

Monitoring Editor: Jean Schwarzbauer

The actin cytoskeleton controls multiple cellular functions including cell morphology, movement and growth. Accumulating evidence indicates that oncogenic activation of the MEK/ERK1/2 pathway is accompanied by actin cytoskeletal reorganization. The signaling events contributing to actin cytoskeleton remodeling mediated by aberrant ERK1/2 activation, however, are largely unknown. Mutant B-RAF is found in a wide variety of cancers including melanoma, and enhances activation of the MEK/ERK1/2 pathway. We show that targeted knockdown of B-RAF with siRNA or pharmacological inhibition of MEK increased actin stress fiber formation and stabilized focal adhesion dynamics in human melanoma cells. These effects were due to stimulation of the Rho/ROCK/LIM kinase-2 signaling pathway cumulating in the inactivation of the actin depolymerizing/severing protein, cofilin. The expression of Rnd3, a Rho antagonist, was attenuated following B-RAF knockdown or MEK inhibition, but was enhanced in melanocytes expressing active B-RAF. Constitutive expression of Rnd3 suppressed the actin cytoskeletal and focal adhesion effects mediated by B-RAF knockdown. Depletion of Rnd3 elevated cofilin phosphorylation and stress fiber formation and reduced cell invasion. Taken together our results identify Rnd3 as a regulator of cross-talk between the RAF/MEK/ERK and Rho/ROCK signaling pathways, and a key contributor to oncogene-mediated reorganization of the actin cytoskeleton and focal adhesions.

Address correspondence to: Andrew E. Aplin (aplina{at}mail.amc.edu)






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