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The ShcA adaptor activates AKT signaling to potentiate breast tumor angiogenesis by stimulating VEGF mRNA translation in a 4E-BP-dependent manner

Oncogene volume 34, pages 1729–1735 (2015)Cite this article

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Abstract

The ShcA adaptor protein is engaged by numerous receptor tyrosine kinases (RTKs) in breast cancer cells. Once activated, RTKs phosphorylate three key tyrosine phosphorylation sites (Y239, Y240 and Y317) within ShcA that creates a docking site for Grb2/SOS and Grb2/Gab-containing complexes to activate the MAPK and AKT signaling pathways, respectively. We previously demonstrated that a tyrosine to phenylalanine substitution of the ShcA tyrosine phosphorylation sites (Shc3F-Y239/240/313F) significantly impairs breast tumor growth and angiogenesis in transgenic mouse models, in part, through the regulation of vascular endothelial growth factor (VEGF) production. Despite this fact, the underlying molecular mechanisms by which ShcA transduces pro-tumorigenic signals in breast cancer cells remain poorly defined. In this study, we demonstrate that ShcA-dependent activation of AKT, but not the RAS/MAPK pathway, induces VEGF production by bolstering VEGF mRNA translation. Accordingly, ShcA drives breast tumor growth and angiogenesis in vivo in a 4E-BP-dependent manner. These findings establish ShcA as a biological bridge that links AKT activation downstream of RTKs to cap-dependent VEGF mRNA translation in order to promote mammary tumorigenesis.

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Acknowledgements

We thank Dr Peter Siegel for critical reading of the manuscript and Dr Sonia del Rincon for the VEGF antibody. This work was supported by a Canadian Institutes of Health Research (CIHR) grant (MOP-111143) to JU-S. YKI is the recipient of a TD/LDI studentship. JRH is the recipient of a McGill Integrated Research Training Program studentship. JU-S and IT are recipients of a CIHR New Investigator Salary Support award.

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Authors and Affiliations

  1. Department of Oncology, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada,

    Y K Im, R La Selva, V Gandin, J R Ha, V Sabourin, I Topisirovic & J Ursini-Siegel

  2. Goodman Cancer Research Centre, Montreal, Quebec, Canada

    N Sonenberg

  3. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

    T Pawson

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Im, Y., La Selva, R., Gandin, V. et al. The ShcA adaptor activates AKT signaling to potentiate breast tumor angiogenesis by stimulating VEGF mRNA translation in a 4E-BP-dependent manner. Oncogene 34, 1729–1735 (2015). https://doi.org/10.1038/onc.2014.110

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