YAP/TAZ-mediated upregulation of GAB2 leads to increased sensitivity to growth factor-induced activation of the PI3K pathway

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

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1637-1648
Number of pages12
JournalCancer Research
Volume77
Issue number7
DOIs
StatePublished - 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Wang, C., Gu, C., Jeong, K. J., Zhang, D., Guo, W., Lu, Y., Ju, Z., Panupinthu, N., Yang, J. Y., Gagea, M. M., Ng, P. K. S., Zhang, F., & Mills, G. B. (2017). YAP/TAZ-mediated upregulation of GAB2 leads to increased sensitivity to growth factor-induced activation of the PI3K pathway. Cancer Research, 77(7), 1637-1648. https://doi.org/10.1158/0008-5472.CAN-15-3084