Timsah, Z, Ahmed, Z, Ivan, C et al. (17 more authors) (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). pp. 2186-2196. ISSN 0950-9232
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)P2. The functional consequences of this event on signaling pathways are unknown. We show that the decrease in PI(4,5)P2 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2015, The Author(s). This is an author produced version of a paper published in Oncogene. Uploaded in accordance with the publisher's self-archiving policy |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Mechanistic Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 18 Aug 2015 11:04 |
Last Modified: | 04 Dec 2020 15:23 |
Published Version: | http://dx.doi.org/10.1038/onc.2015.279 |
Status: | Published |
Publisher: | Nature Publishing Group |
Identification Number: | 10.1038/onc.2015.279 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:89027 |