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ERK1/2-induced phosphorylation of R-Ras GTPases stimulates their oncogenic potential

Oncogene volume 35, pages 5692–5698 (2016)Cite this article

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Abstract

The Ras-related (R-Ras) isoforms TC21, R-Ras and M-Ras are members of the Ras superfamily of small GTPases. R-Ras family proteins are frequently overexpressed in human cancers, and expression of activated mutants of these GTPases is sufficient to induce cell transformation. Unlike Ras, few activating mutations of R-Ras proteins have been reported in human cancer, and very little is known about the regulation of their activity. In this study, we report that TC21 and R-Ras are phosphorylated on a conserved serine, Ser186 and Ser201, respectively, in intact cells. This residue is located in the C-terminal hypervariable region of the proteins and is not conserved in M-Ras. We show that the MAP kinases ERK1/2 phosphorylate TC21 and R-Ras on this C-terminal serine residue both in vitro and in vivo. Phosphorylation of R-Ras proteins does not affect their subcellular localization or stability but rather stimulates their activation. Phosphorylation-defective mutants of R-Ras and TC21 are compromised in their ability to promote cancer cell adhesion and migration/invasion, respectively. Importantly, we show that phosphorylation of TC21 and R-Ras potentiates their tumorigenic activity in immunodeficient mice. Our results identify a novel regulatory mechanism of the small GTPases TC21 and R-Ras that controls their oncogenic potential.

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Acknowledgements

We thank B Alarcón (CBMSO, Madrid) for pGex-4T3-TC21 and pEGFP-TC21 plasmids. CF is a recipient of fellowships from the Cole Foundation, the Association pour la Recherche contre le Cancer (ARC) and the Fonds de la recherche en santé du Québec (FRSQ). JPG is a recipient of fellowships from the Fondation pour la Recherche Médicale (FRM), the Cole Foundation and the Fonds de la recherche en santé du Québec (FRSQ). SM and GE hold the Canada Research Chairs in Cellular Signaling and Vesicle Transport and Cell Signaling, respectively. This work was supported by grants from the Canadian Institutes of Health Research to SM and GE.

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Author notes

  1. C Frémin and J-P Guégan: These authors contributed equally to this work.

Authors and Affiliations

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

    C Frémin, J-P Guégan, C Plutoni, G Emery & S Meloche

  2. Departments of Medicine, Cell Biology and Pharmacology, Perlmutter Cancer Institute, New York University, New York, NY, USA

    J Mahaffey & M R Philips

  3. Molecular Biology Program, Université de Montréal, Montreal, Quebec, Canada

    G Emery & S Meloche

  4. Department of Pathology and Cell Biology, Université de Montréal, Montreal, Quebec, Canada

    G Emery

  5. Department of Pharmacology, Université de Montréal, Montreal, Quebec, Canada

    S Meloche

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  1. C Frémin
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Correspondence to S Meloche.

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Frémin, C., Guégan, JP., Plutoni, C. et al. ERK1/2-induced phosphorylation of R-Ras GTPases stimulates their oncogenic potential. Oncogene 35, 5692–5698 (2016). https://doi.org/10.1038/onc.2016.122

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