Exocytosis is mediated by transport, docking and fusion of secretory vesicles from trans-Golgi network and endosomes to the plasma membrane. As exocytosis is centrally involved, and tightly controlled, in a wide range of physiological processes from hormone release to embryogenesis, it is important to understand the molecular mechanisms that regulate exocytosis. Our research focuses on two separate but connected "modules" in the exocytosis pathway, the Rab GTPases and the exocyst complex, both of which are evolutionarily conserved from yeast to humans. In this proposal, we will first investigate the molecular mechanisms that control the activation of Rabin8, which is the guanine nucleotide exchange factor (GEF) for Rab8, a major regulator of exocytosis in mammalian cells. We will examine the role of phosphatidylinositides and an upstream Rab protein, Rab11, in the activation of Rabin8. In addition, we will examine the phosphorylation and regulation of Rabin8 GEF activity by Extracellular signal-regulated kinases 1/2 (ERK1/2) in response epidermal growth factor (EGF) signaling. Finally, we will determine the role of the exocyst in SNARE-mediated membrane fusion. We take a multi-disciplinary approach combining biochemistry, biophysics, yeast genetics and microscopic imaging to address key questions in the field. These studies will not only help us elucidate the regulatory mechanisms of exocytosis at the molecular level, but also contribute to our understanding of a number of diseases such as diabetes and polycystic kidney diseases (PKD).

Public Health Relevance

Exocytosis is important for many physiological processes such as embryogenesis, epithelial cell polarization, and neural transmission. Defects in the function of the Rab family of small GTPases and the exocyst have been implicated in cancer, diabetes, and Autosomal Dominant Polycystic Kidney Diseases. Studying the regulation of the Rab GTPases and exocyst is essential for the understanding of these diseases.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01GM111128-01
Application #
8737572
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ainsztein, Alexandra M
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Zhang, Chunhua; Brown, Michelle Q; van de Ven, Wilhelmina et al. (2016) Endosidin2 targets conserved exocyst complex subunit EXO70 to inhibit exocytosis. Proc Natl Acad Sci U S A 113:E41-50
Wu, Bin; Guo, Wei (2015) The Exocyst at a Glance. J Cell Sci 128:2957-64
Feng, Shanshan; Wu, Bin; Peränen, Johan et al. (2015) Kinetic activation of Rab8 guanine nucleotide exchange factor Rabin8 by Rab11. Methods Mol Biol 1298:99-106
Wu, Bin; Wang, Juanfei; Zhao, Yuting et al. (2015) Biochemical analysis of Rabin8, the guanine nucleotide exchange factor for Rab8. Methods Cell Biol 130:59-68
Wang, Juanfei; Ren, Jinqi; Wu, Bin et al. (2015) Activation of Rab8 guanine nucleotide exchange factor Rabin8 by ERK1/2 in response to EGF signaling. Proc Natl Acad Sci U S A 112:148-53
Luo, Guangzuo; Zhang, Jian; Guo, Wei (2014) The role of Sec3p in secretory vesicle targeting and exocyst complex assembly. Mol Biol Cell 25:3813-22