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Molecular and Cellular Biology, July 2004, p. 5937-5952, Vol. 24, No. 13
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.13.5937-5952.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

B-Raf Acts via the ROCKII/LIMK/Cofilin Pathway To Maintain Actin Stress Fibers in Fibroblasts

Catrin A. Pritchard,1*,{dagger} Louise Hayes,2 Leszek Wojnowski,3 Andreas Zimmer,4 Richard M. Marais,2 and Jim C. Norman1

Department of Biochemistry, University of Leicester, Leicester LE1 7RH,1 Institute of Cancer Research, London SW3 6JB, United Kingdom,2 Department of Pharmacology, Johannes Gutenberg University, D-55101 Mainz,3 Molekulare Neurobiologie, Klinik und Poliklinik für Psychiatrie und Psychotherapie, 53105 Bonn, Germany4

Received 18 July 2003/ Returned for modification 13 September 2003/ Accepted 8 March 2004

Recent data have shown that the BRAF gene is mutated at a high frequency in human malignancies. We have analyzed the migratory characteristics of B-raf–/– mouse embryonic fibroblasts (MEFs) and compared these with the organization of the actin cytoskeleton and the activity of signaling pathways that are known to influence this organization. Disruption of B-raf significantly reduced the levels of phospho-ERK1/2 and, surprisingly, induced an {approx}1.5-fold increase in cell migration. Consistent with these findings, the high level of actin stress fibers normally present in MEFs was considerably reduced following disruption of B-raf, and the F-actin content of B-raf–/– cells was less than half that of B-raf+/+ cells. Phosphorylation of the myosin light chain on Thr18/Ser19 residues was not reduced in B-raf–/– cells. Rather, reduced ROCKII expression and attenuated phosphorylation of ADF/cofilin on serine 3 occurred. Normal stress fiber and phosphocofilin levels were restored by the expression of human B-Raf and catalytically active MEK and by the overexpression of LIM kinase (LIMK). These results have important implications for the role of the B-Raf/ERK signaling pathway in regulating cell motility in normal and malignant cells. They suggest that B-Raf is involved in invasiveness by regulating the proper assembly of actin stress fibers and contractility through a ROCKII/LIMK/cofilin signaling pathway.

* Corresponding author. Mailing address: Department of Biochemistry, University of Leicester, University Rd., Leicester LE1 7RH, United Kingdom. Phone: 44 116 2523489. Fax: 44 116 2525097. E-mail: cap8{at}le.ac.uk.

{dagger} Present address: GlaxoSmithKline, Marlow, Essex CM19 5AW, United Kingdom.

Molecular and Cellular Biology, July 2004, p. 5937-5952, Vol. 24, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.13.5937-5952.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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