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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM109066-01
Application #
8614249
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Hamlet, Michelle R
Project Start
2014-01-10
Project End
2018-12-31
Budget Start
2014-01-10
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$285,950
Indirect Cost
$95,950
Name
University of Nebraska Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Jami, Mohammad-Saeid; Hou, Jinxuan; Liu, Miao et al. (2014) Functional proteomic analysis reveals the involvement of KIAA1199 in breast cancer growth, motility and invasiveness. BMC Cancer 14:194
Zhang, Lin; Yang, Shuping; Wennmann, Dirk Oliver et al. (2014) KIBRA: In the brain and beyond. Cell Signal 26:1392-9
Yang, Shuping; Ji, Ming; Zhang, Lin et al. (2014) Phosphorylation of KIBRA by the extracellular signal-regulated kinase (ERK)-ribosomal S6 kinase (RSK) cascade modulates cell proliferation and migration. Cell Signal 26:343-51
Fu, David; Lv, Xiangmin; Hua, Guohua et al. (2014) YAP regulates cell proliferation, migration, and steroidogenesis in adult granulosa cell tumors. Endocr Relat Cancer 21:297-310