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

Article, 0038 English OPEN
Timsah, Zahra ; Ahmed, Zamal ; Ivan, Cristina ; Berrout, Jonathan ; Gagea, Mihai ; Zhou, Yong ; Pena, Guillermo N. Armaiz ; Hu, Xin ; Vallien, Courtney ; Kingsley, Charles V. ; Lu, Yiling ; Hancock, John F. ; Liu, Jinsong ; Gladden, Andrew B. ; Mills, Gordon B. ; Lopez-Berestein, Gabriel ; Hung, Mien-Chie ; Sood, Anil K. ; Bogdanov, Mikhail ; Ladbury, John E. (2015)

In the absence of extracellular stimulation the adaptor protein Grb2 and the phospholipase Plcγ1 compete for the same binding site on FGFR2. Reducing cellular Grb2 results in up-regulation of Plcγ1 and depletion of the phospholipid PI(4,5)P2. The functional consequence 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.
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