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RSK regulates activated BRAF signalling to mTORC1 and promotes melanoma growth

Oncogene volume 32, pages 2917–2926 (2013)Cite this article

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Abstract

The Ras/mitogen-activated protein kinase (MAPK) signalling cascade regulates various biological functions, including cell growth, proliferation and survival. As such, this pathway is often deregulated in cancer, including melanomas, which frequently harbour activating mutations in the NRAS and BRAF oncogenes. Hyperactive MAPK signalling is known to promote protein synthesis, but the mechanisms by which this occurs remain poorly understood. Here, we show that expression of oncogenic forms of Ras and Raf promotes the constitutive activation of the mammalian target of rapamycin (mTOR). Using pharmacological inhibitors and RNA interference, we find that the MAPK-activated protein kinase RSK (p90 ribosomal S6 kinase) is partly required for these effects. Using melanoma cell lines carrying activating BRAF mutations, we show that ERK/RSK signalling regulates assembly of the translation initiation complex and polysome formation, as well as the translation of growth-related messenger RNAs containing a 5′-terminal oligopyrimidine (TOP) motif. Accordingly, we find that RSK inhibition abrogates tumour growth in mice. Our findings indicate that RSK may be a valuable therapeutic target for the treatment of tumours characterized by deregulated MAPK signalling, such as melanoma.

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Acknowledgements

This work was supported by grants from the Canadian Cancer Society Research Institute (PPR), the Cancer Research Society (PPR and SM), and the Natural Sciences and Engineering Research Council of Canada (PPR). We thank Dr Nahum Sonenberg for the phospho-4E-BP1 antibody. PP Roux holds a Canada Research Chair in Signal Transduction and Proteomics and a Career Development Award from the Human Frontier Science Programme (HFSP). K Borden and S Meloche hold Canada Research Chairs in Molecular Biology of the Cell Nucleus, and in Cellular Signalling, respectively. IRIC core facilities are supported by the FRSQ.

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Author notes

  1. P-J Zindy

    Present address: 5Current address: Laboratory of RNP Biochemistry, Department for Systems Biology, Institut de Recherches Cliniques de Montréal (IRCM), 110 Avenue des Pins Ouest, Montreal, Quebec, Canada H2W 1R7.,

  2. Y Romeo and J Moreau: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec, Canada

    Y Romeo, J Moreau, P-J Zindy, M Saba-El-Leil, G Lavoie, F Dandachi, M Baptissart, K L B Borden, S Meloche & P P Roux

  2. Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada

    K L B Borden & P P Roux

  3. Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada

    S Meloche

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Romeo, Y., Moreau, J., Zindy, PJ. et al. RSK regulates activated BRAF signalling to mTORC1 and promotes melanoma growth. Oncogene 32, 2917–2926 (2013). https://doi.org/10.1038/onc.2012.312

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