Regulation of Hippo Signaling for Growth Control
Open Access
- Author:
- Deng, Yaoting
- Graduate Program:
- Biochemistry, Microbiology, and Molecular Biology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- August 04, 2014
- Committee Members:
- Zhi Chun Lai, Dissertation Advisor/Co-Advisor
Zhi Chun Lai, Committee Chair/Co-Chair
Melissa Rolls, Committee Member
Pamela Hankey Giblin, Committee Member
Richard W Ordway, Committee Member
Wendy Hanna Rose, Committee Member
Yanming Wang, Committee Member - Keywords:
- Hippo pathway
Hippo
transphosphorylation
dimerization
Merlin
Expanded
Kibra
FFA
β-cells
Yap
F-actin
apoptosis - Abstract:
- In multicellular organisms, the coordination of cell proliferation, cell death and cellular growth are crucial for the organ size control and the maintenance of organ function. The mechanisms that regulate these crucial processes provide insight into diseases, such as cancer. The Hippo (Hpo) signaling regulates cell number mainly by inhibiting cell proliferation and promoting cell apoptosis, and this signaling is highly conserved from Drosophila to mammals. Hpo is the key kinase of Hpo signaling; however, the way in which Hpo kinase activity is regulated remains less understood. In this project, I investigated how Hpo kinase is activated and regulated by upstream molecules both in vivo and in vitro. I found that Hpo dimerization could facilitate its activation by auto-phosphorylation. Moreover, membrane association appears to increase Hpo dimerization efficiency, and upstream molecules Expanded/Merlin/Kibra promote Hpo membrane association. Therefore, both dimerization and membrane association are critical for Hpo kinase to be activated. This mechanism provides essential insight to reveal the mystery that how upstream molecules transduce signal to Hpo signaling. In another project, I investigated Yap1 (a major downstream effector of mammalian Hpo signaling) activity regulation in mammalian pancreatic beta β-cells under free fatty acids (FFAs) treatment. Mammalian pancreatic β-cells are responsible for the production of insulin and therefore play a pivotal role in development and glucose homeostasis. Among many factors, high concentrations of saturated free fatty acids (FFAs) such as palmitate are known to have a negative effect on β-cell viability, which might induce type 2 diabetes. In this study, I demonstrated that Hpo signaling effector Yap1 plays a crucial role in regulating β-cell survival under FFA treatment. I found that Yap1 is activated through F-actin accumulation in a time-delayed manner to enhance β-cells viability during palmitate-induced apoptosis. Moreover, Connective Tissue Growth Factor (CTGF), one of the downstream targets of Yap1, was identified to repress palmitate-induced β-cell apoptosis. These discoveries support a model in which Yap1 could positively regulate β-cell survival under FFA treatment, and this model might lead to the development of new strategies for potential treatment of diabetes.