期刊
ONCOGENE
卷 35, 期 17, 页码 2186-2196出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2015.279
关键词
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资金
- G. Harold and Leila Y. Mathers Charitable Foundation
- NIH [U54CA151668, P50 CA083639, P50 CA098258]
- RGK Foundation
- Gilder Foundation
In the absence of extracellular stimulation the adaptor protein growth factor receptor-bound protein (Grb2) and the phospholipase Plc gamma 1 compete for the same binding site on fibroblast growth factor receptor 2 (FGFR2). Reducing cellular Grb2 results in upregulation of Plc gamma 1 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, Plc gamma 1 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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