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Title: YAP/TAZ-mediated upregulation of GAB2 leads to increased sensitivity to growth factor-induced activation of the PI3K pathway
Authors: Chao Wang
Chao Gu
Kang Jin Jeong
Dong Zhang
Wei Guo
Yiling Lu
Zhenlin Ju
Nattapon Panupinthu
Ji Yeon Yang
Mihai Mike Gagea
Patrick Kwok Shing Ng
Fan Zhang
Gordon B. Mills
Fudan University
University of Texas MD Anderson Cancer Center
Mahidol University
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 1-Jan-2017
Citation: Cancer Research. Vol.77, No.7 (2017), 1637-1648
Abstract: © 2017 American Association for Cancer Research. The transcription regulators YAP and TAZ function as effectors of the HIPPO signaling cascade, critical for organismal development, cell growth, and cellular reprogramming, and YAP/TAZ is commonly misregulated in human cancers. The precise mechanism by which aberrant YAP/TAZ promotes tumor growth remains unclear. The HIPPO tumor suppressor pathway phosphorylates YAP and TAZ, resulting in cytosolic sequestration with subsequent degradation. Here, we report that the PI3K/AKT pathway, which is critically involved in the pathophysiology of endometrial cancer, interacts with the HIPPO pathway at multiple levels. Strikingly, coordinate knockdown of YAP and TAZ, mimicking activation of the HIPPO pathway, markedly decreased both constitutive and growth factor-induced PI3K pathway activation by decreasing levels of the GAB2 linker molecule in endometrial cancer lines. Furthermore, targeting YAP/TAZ decreased endometrial cancer tumor growth in vivo. In addition, YAP and TAZ total and phosphoprotein levels correlated with clinical characteristics and outcomes in endometrial cancer. Thus, YAP and TAZ, which are inhibited by the HIPPO tumor suppressor pathway, modify PI3K/AKT pathway signaling in endometrial cancer. The cross-talk between these key pathways identifies potential new biomarkers and therapeutic targets in endometrial cancer.
ISSN: 15387445
Appears in Collections:Scopus 2016-2017

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