Text The Hippo pathway controls cell contact inhibition, stem cell self -renewal, and tumorigenesis through phosphorylating and inactivating the downstream oncoprotein, yes-associated protein (YAP). The PI, along with others, has demonstrated that YAP promotes oncogenesis by stimulating cell proliferation and inhibiting apoptosis. YAP is overexpressed or hyperactivated in many types of cancers. Current studies involving YAP focus on determining its overall oncogenic role in various organs/tissues as well as its role in crosstalk with other signaling pathways. While these studies provide important insight into the oncogenic properties of YAP, however, the underlying molecular mechanisms through which YAP exerts its oncogenic function are poorly understood. The long-term goal of this project is to elucidate the regulatory mechanisms of the Hippo-YAP signaling pathway in mitotic cell-cycle control and oncogenic transformation, thus providing potential therapeutic targets. Our preliminary studies demonstrate that during mitosis YAP is phosphorylated on novel sites and activated in a CDK1-dependent manner. Importantly, mitotic phosphorylation is required for YAP-driven cellular transformation. We have found that YAP is required for the activation of the spindle checkpoint during mitosis. Furthermore, overexpression of YAP, but not of the non - phosphorylatable mutant, hyper-activates the spindle checkpoint and causes mitotic defects. Based on these preliminary studies, we hypothesize that CDK1-mediatd mitotic phosphorylation of YAP is biologically significant in the regulation of the spindle checkpoint activation and subsequent oncogenic transformation. Our central hypothesis will be tested through the following three specific aims:
Aim 1 : Determine the molecular mechanism of YAP regulation/activation during mitosis;
Aim 2 : Determine the role of YAP and its phosphorylation in mitotic progression, the spindle checkpoint, and aneuploidy;
Aim 3 : Determine the functional significance of YAP phosphorylation on its targets. Successful completion of these studies will not only reveal novel roles of YAP in mitosis and genome instability, but will also shed light on the mechanisms involved in YAP-driven oncogenesis.

Public Health Relevance

Aberrations of mitosis often cause chromosome instability and aneuploidy, which are major characteristics of human malignancies. Our studies provide the first evidence that YAP plays a critical role in maintaining normal cellular mitosis and that dysregulation of YAP leads to mitotic defects, thus contributing to aneuploidy/chromosome instability and subsequent oncogenic transformation. Understanding the molecular mechanisms in YAP-driven oncogenesis is key for the identification of drug targets and for future development of therapeutic strategies against cancers caused by aberrations in the Hippo-YAP signaling pathway.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Hamlet, Michelle R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Nebraska Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Wang, Zhan; Chen, Xingcheng; Zhong, Mei-Zuo et al. (2018) Cyclin-dependent kinase 1-mediated phosphorylation of YES links mitotic arrest and apoptosis during antitubulin chemotherapy. Cell Signal 52:137-146
Zhou, Jiuli; Zeng, Yongji; Cui, Lian et al. (2018) Zyxin promotes colon cancer tumorigenesis in a mitotic phosphorylation-dependent manner and through CDK8-mediated YAP activation. Proc Natl Acad Sci U S A 115:E6760-E6769
Stauffer, Seth; Zeng, Yongji; Zhou, Jiuli et al. (2017) CDK1-mediated mitotic phosphorylation of PBK is involved in cytokinesis and inhibits its oncogenic activity. Cell Signal 39:74-83
Lv, Xiangmin; He, Chunbo; Huang, Cong et al. (2017) G-1 Inhibits Breast Cancer Cell Growth via Targeting Colchicine-Binding Site of Tubulin to Interfere with Microtubule Assembly. Mol Cancer Ther 16:1080-1091
Zeng, Yongji; Stauffer, Seth; Zhou, Jiuli et al. (2017) Cyclin-dependent kinase 1 (CDK1)-mediated mitotic phosphorylation of the transcriptional co-repressor Vgll4 inhibits its tumor-suppressing activity. J Biol Chem 292:15028-15038
Pandey, Poomy; Sliker, Bailee; Peters, Haley L et al. (2016) Amyloid precursor protein and amyloid precursor-like protein 2 in cancer. Oncotarget 7:19430-44
Stauffer, Seth; Chen, Xingcheng; Zhang, Lin et al. (2016) KIBRA promotes prostate cancer cell proliferation and motility. FEBS J 283:1800-11
Chen, Xingcheng; Chen, Yuanhong; Dong, Jixin (2016) MST2 phosphorylation at serine 385 in mitosis inhibits its tumor suppressing activity. Cell Signal 28:1826-1832
Chen, Xingcheng; Stauffer, Seth; Chen, Yuanhong et al. (2016) Ajuba Phosphorylation by CDK1 Promotes Cell Proliferation and Tumorigenesis. J Biol Chem 291:14761-72
Zhang, Lin; Chen, Xingcheng; Stauffer, Seth et al. (2015) CDK1 phosphorylation of TAZ in mitosis inhibits its oncogenic activity. Oncotarget 6:31399-412

Showing the most recent 10 out of 19 publications