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

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 phosp...

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Bibliographic Details
Published in:	Oncogene Vol. 35; no. 17; pp. 2186 - 2196
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 28-04-2016 Nature Publishing Group
Subjects:	13/51 14/33 631/67 64 96 96/106 96/95 Adaptor proteins AKT protein Animals Apoptosis Binding sites Carcinogenesis - genetics Cell Biology Cell proliferation Cell Proliferation - genetics Development and progression Female Fibroblast growth factor receptor 2 Gene expression Gene Expression Regulation, Neoplastic Genetic aspects GRB2 Adaptor Protein - antagonists & inhibitors GRB2 Adaptor Protein - genetics Grb2 protein Growth factors Health aspects Human Genetics Humans Internal Medicine Medical prognosis Medicine Medicine & Public Health Membrane proteins Mice Oncogene Protein v-akt - genetics Oncology original-article Ovarian cancer Ovarian Neoplasms - genetics Ovarian Neoplasms - pathology Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositols - metabolism Phospholipase C gamma - biosynthesis Phospholipase C gamma - genetics Phospholipids Phosphorylation Prognosis Properties Protein expression PTEN Phosphohydrolase - antagonists & inhibitors PTEN Phosphohydrolase - genetics PTEN protein Receptor, Fibroblast Growth Factor, Type 2 - biosynthesis Receptor, Fibroblast Growth Factor, Type 2 - genetics Signal Transduction Tumorigenesis Tumors Xenografts
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2015.279