Differing contributions of LIMK and ROCK to TGFβ-induced transcription, motility and invasion

Morin, P., Wickman, G., Munro, J., Inman, G.J. and Olson, M.F. (2011) Differing contributions of LIMK and ROCK to TGFβ-induced transcription, motility and invasion. European Journal of Cell Biology, 90(1), pp. 13-25. (doi: 10.1016/j.ejcb.2010.09.009) (PMID:21074289)

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The ability of transforming growth factor beta (TGF beta) to induce epithelial-mesenchymal transition (EMT) is mediated by SMAD-dependent and SMAD-independent pathways such as the activation of Rho GTPase signalling. Upon activation, GTP-bound Rho stimulates the ROCK kinases, which in turn phosphorylate numerous substrates including the LIM kinases (LIMK). The net result of ROCK activation is increased actin-myosin contractile force generation, with a contribution from LIMK-induced actin filament stabilisation. In this study, we made use of siRNA-mediated knockdown and selective inhibitors to determine the contributions of ROCK and LIMK to TGF beta-induced responses. We find that both ROCK and LIMK are required for TGF beta stimulation of serum-response factor (SRF) transcriptional activity and actin stress fibre formation during EMT. In contrast, although LIMK inhibition had little effect on cell motility in scratch wound and Transwell migration assays, ROCK inhibition actually promoted TGF beta-induced cell motility by helping individual cells to break free from the epithelial sheet. Furthermore, we demonstrate that selective inhibition of LIMK, but not ROCK, effectively blocked TGF beta driven invasion through a layer of matrigel extracellular matrix protein. These results indicate that the roles of LIMK and ROCK in the Rho signalling pathway downstream of TGF beta are not identical and suggest that LIMK represents an attractive therapeutic target in TGF beta driven organ fibrosis and metastatic cancer spread.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Inman, Professor Gareth and Morin, Dr Pierre and Olson, Professor Michael
Authors: Morin, P., Wickman, G., Munro, J., Inman, G.J., and Olson, M.F.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:European Journal of Cell Biology
ISSN (Online):1618-1298

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