Grb2 depletion under non-stimulated conditions inhibits PTEN, promotes Akt-induced tumor formation and contributes to poor prognosis in ovarian cancer

Z. Timsah, Z. Ahmed, C. Ivan, J. Berrout, M. Gagea, Y. Zhou, G. N.A. Pena, X. Hu, C. Vallien, C. V. Kingsley, Y. Lu, J. F. Hancock, J. Liu, A. B. Gladden, G. B. Mills, G. Lopez-Berestein, M. C. Hung, A. K. Sood, M. Bogdanov, J. E. Ladbury

    Research output: Contribution to journalArticle

    16 Scopus citations

    Abstract

    In the absence of extracellular stimulation the adaptor protein growth factor receptor-bound protein (Grb2) and the phospholipase Plcγ1 compete for the same binding site on fibroblast growth factor receptor 2 (FGFR2). Reducing cellular Grb2 results in upregulation of Plcγ1 and depletion of the phospholipid PI(4,5)P 2. The functional consequences of this event on signaling pathways are unknown. We show that the decrease in PI(4,5)P 2 level under non-stimulated conditions inhibits PTEN activity leading to the aberrant activation of the oncoprotein Akt. This results in excessive cell proliferation and tumor progression in a xenograft mouse model. As well as defining a novel mechanism of Akt phosphorylation with important therapeutic consequences, we also demonstrate that differential expression levels of FGFR2, Plcγ1 and Grb2 correlate with patient survival. Oncogenesis through fluctuation in the expression levels of these proteins negates extracellular stimulation or mutation and defines them as novel prognostic markers in ovarian cancer.

    Original languageEnglish (US)
    Pages (from-to)2186-2196
    Number of pages11
    JournalOncogene
    Volume35
    Issue number17
    DOIs
    StatePublished - Apr 28 2016

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Cancer Research

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  • Cite this

    Timsah, Z., Ahmed, Z., Ivan, C., Berrout, J., Gagea, M., Zhou, Y., Pena, G. N. A., Hu, X., Vallien, C., Kingsley, C. V., Lu, Y., Hancock, J. F., Liu, J., Gladden, A. B., Mills, G. B., Lopez-Berestein, G., Hung, M. C., Sood, A. K., Bogdanov, M., & Ladbury, J. E. (2016). Grb2 depletion under non-stimulated conditions inhibits PTEN, promotes Akt-induced tumor formation and contributes to poor prognosis in ovarian cancer. Oncogene, 35(17), 2186-2196. https://doi.org/10.1038/onc.2015.279