生物
PTEN公司
GRB2型
蛋白激酶B
癌症研究
癌变
信号转导衔接蛋白
信号转导
下调和上调
PI3K/AKT/mTOR通路
细胞生物学
生长因子受体
癌症
生物化学
遗传学
基因
作者
Zahra Timsah,Zamal Ahmed,Cristina Ivan,Jonathan Berrout,Mihai Gagea,Yong Zhou,Guillermo N. Armaiz-Peña,Xiaoding Hu,Courtney Vallien,Charles V. Kingsley,Yang Lü,John F. Hancock,Jie Liu,Andrew B. Gladden,J. Monroe,G. Lopez‐Berestein,Mien‐Chie Hung,Anil K. Sood,Mikhail Bogdanov,John E. Ladbury
出处
期刊:Oncogene
[Springer Nature]
日期:2015-07-27
卷期号:35 (17): 2186-2196
被引量:29
摘要
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.
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