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TGF-β-mediated activation of RhoA signalling is required for efficient V12HaRas and V600EBRAF transformation

Oncogene volume 28, pages 983–993 (2009)Cite this article

Abstract

Transforming growth factor β-1 (TGF-β) acts as both a tumour suppressor and a tumour promoter in a context-dependent manner. The tumour-promoting activities of TGF-β are likely to result from a combination of Smad and non-Smad signalling pathways but remain poorly understood. Here we show that TGF-β-mediated activation of RhoA is dependent on the kinase activity of ALK5 and that continuous ALK5 activity maintains basal RhoA–ROCK signalling, cell morphology and actin dynamics in serum-starved rodent fibroblasts independently of Smad2, Smad3 and Smad4. In immortalized human diploid fibroblasts, we show that oncogenic rewiring by transduction of V12HaRas instigates regulation of RhoA–ROCK signalling through an autocrine TGF-β1–ALK5 pathway. Furthermore, we show that ALK5-mediated activation of RhoA is required for efficient V12HaRas, V-Raf and V600EBRAF transformation and V12HaRas-mediated anchorage-independent growth. These findings identify a new pro-oncogenic activity of TGF-β and indicate that tumours harbouring V12HaRas and V600EBRAF mutations may be susceptible to TGF-β signalling inhibitors.

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Acknowledgements

We thank P ten-Dijke, R Treisman, C Hill, T Crook, X-F Wang, R Derynck, A Hall and M Olson for valuable reagents. We thank J Wyke and M Olson for critically reading the paper and for discussions during the course of this work. This work was supported by an Association for International Cancer Research fellowship to GJI (GJI, YMF, GJF and LCS) and Cancer Research UK (YMF, GJI, GJF, LCS, and BWO).

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Author notes

  1. Y M Fleming and G J Ferguson: These authors contributed equally to this work.

Authors and Affiliations

  1. Growth Factor Signalling Laboratory, The Beatson Institute for Cancer Research, Garscube Estate, Bearsden, Glasgow, UK

    Y M Fleming, G J Ferguson, L C Spender & G J Inman

  2. Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine and The Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University Hospital, Sweden

    J Larsson & S Karlsson

  3. Invasion and Metastasis Laboratory, The Beatson Institute for Cancer Research, Garscube Estate, Bearsden, Glasgow, UK

    B W Ozanne

  4. Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, Heidelberg, Germany

    R Grosse

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  1. Y M Fleming
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Correspondence to G J Inman.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Fleming, Y., Ferguson, G., Spender, L. et al. TGF-β-mediated activation of RhoA signalling is required for efficient V12HaRas and V600EBRAF transformation. Oncogene 28, 983–993 (2009). https://doi.org/10.1038/onc.2008.449

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