Regulation and function of the YAP transcription co-activator oncoprotein The yes-associated protein YAP is a potent transcription co-activator. Recent genetic studies have implicated YAP as a candidate oncogene in human chromosome 11q22 amplicon. Drosophila studies have established a novel tumor suppressor pathway Hippo that regulates both cell proliferation and apoptosis. Many components of the Hippo pathway are highly conserved. YAP is likely to be the major target inhibited by the Hippo pathway. YAP can functionally rescue yorkie (the Drosophila homolog of mammalian YAP) mutation in Drosophila. It has been suggested that the neurofibromatosis 2 (NF2) tumor suppressor is a component of the Hippo pathway acting upstream of YAP to inhibit YAP function. However, the Hippo pathway has not been investigated in mammalian cells. The long term goals of this project are to determine the function and regulation of the Hippo pathway in development of human cancers. Our preliminary data have shown that the Hippo-YAP pathway plays an essential role in cell contact inhibition and oncogenic transformation. Furthermore, YAP is highly elevated in human cancers, including prostate and liver cancers.
The specific aims of this proposal are: 1. To identify and characterize YAP target transcription factors 2. To determine the function of YAP target transcription factors in cell contact inhibition, oncogenic transformation, and epithelial-mesenchymal transition 3. To determine the function of YAP-induced micro RNA Public Health Relevance: YAP is a transcription co-activator and oncogene highly elevated in human cancers. This proposal will study the molecular mechanism of YAP in tumorigenesis by promoting cell proliferation and inhibiting cell death.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-ICI-D (01))
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Watson, Joanna M
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Yu, Fa-Xing; Luo, Jing; Mo, Jung-Soon et al. (2014) Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. Cancer Cell 25:822-30
Zhao, Bin; Guan, Kun-Liang (2014) Hippo pathway key to ploidy checkpoint. Cell 158:695-6
Mo, Jung-Soon; Park, Hyun Woo; Guan, Kun-Liang (2014) The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep 15:642-56
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Dai, Xiaoming; She, Peilu; Chi, Fangtao et al. (2013) Phosphorylation of angiomotin by Lats1/2 kinases inhibits F-actin binding, cell migration, and angiogenesis. J Biol Chem 288:34041-51
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Yu, Fa-Xing; Zhang, Yifan; Park, Hyun Woo et al. (2013) Protein kinase A activates the Hippo pathway to modulate cell proliferation and differentiation. Genes Dev 27:1223-32
Russell, Ryan C; Tian, Ye; Yuan, Haixin et al. (2013) ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat Cell Biol 15:741-50

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