My goal is to understand how the Rho family of small GTPases control polarized exocytosis through the secretory vesicle docking complex, the exocyst. Spatial regulation of exocytosis is fundamental to many biological processes such as cell growth, polarity establishment, and cell-cell communication. Abnormalities in these fundamental processes may lead to pathological conditions such as cancer cell metastasis, neurological disorders, and kidney diseases. Polarized exocytosis involves directional transport, docking, and fusion of secretory vesicles with specific domains of the plasma membrane. An evolutionarily conserved multi-protein complex, the """"""""exocyst"""""""" specifically localizes to sites of active secretion and serves as the basic vesicle docking machinery at the plasma membrane. Our recent studies using the budding yeast Saccharomyces cerevisiae revealed that Rho 1, a member of the Rho family of small GTP-binding proteins, interacts with the exocyst and regulate the localization of the exocyst during each stage of the cell cycle. Here we propose to identify and characterize the proteins involved in the signal transduction from Rho 1 to the exocyst using a combination of genetic, cytological, and biochemical approaches. Furthermore, we will test our hypothesis that Rho 1 interacts with the exocyst components to facilitate their polarized assembly at the plasma membrane. Finally, we will investigate how Rho 1 coordinates exocytosis with morphogenesis and polarized cell growth. These studies are crucial to our understanding of the molecular network controlling polarized secretion in eukaryotic cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM064690-04
Application #
6942275
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Shapiro, Bert I
Project Start
2002-09-05
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
4
Fiscal Year
2007
Total Cost
$247,050
Indirect Cost
Name
University of Pennsylvania
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ren, Jinqi; Guo, Wei (2012) ERK1/2 regulate exocytosis through direct phosphorylation of the exocyst component Exo70. Dev Cell 22:967-78
Feng, Shanshan; Knödler, Andreas; Ren, Jinqi et al. (2012) A Rab8 guanine nucleotide exchange factor-effector interaction network regulates primary ciliogenesis. J Biol Chem 287:15602-9
Sakamori, Ryotaro; Das, Soumyashree; Yu, Shiyan et al. (2012) Cdc42 and Rab8a are critical for intestinal stem cell division, survival, and differentiation in mice. J Clin Invest 122:1052-65
Orlando, Kelly; Sun, Xiaoli; Zhang, Jian et al. (2011) Exo-endocytic trafficking and the septin-based diffusion barrier are required for the maintenance of Cdc42p polarization during budding yeast asymmetric growth. Mol Biol Cell 22:624-33
Das, Amlan; Guo, Wei (2011) Rabs and the exocyst in ciliogenesis, tubulogenesis and beyond. Trends Cell Biol 21:383-6
Baek, Kyuwon; Knödler, Andreas; Lee, Sung Haeng et al. (2010) Structure-function study of the N-terminal domain of exocyst subunit Sec3. J Biol Chem 285:10424-33
He, Bing; Guo, Wei (2009) The exocyst complex in polarized exocytosis. Curr Opin Cell Biol 21:537-42
Orlando, Kelly; Guo, Wei (2009) Membrane organization and dynamics in cell polarity. Cold Spring Harb Perspect Biol 1:a001321
Zuo, Xiaofeng; Guo, Wei; Lipschutz, Joshua H (2009) The exocyst protein Sec10 is necessary for primary ciliogenesis and cystogenesis in vitro. Mol Biol Cell 20:2522-9
Zhang, Xiaoyu; Orlando, Kelly; He, Bing et al. (2008) Membrane association and functional regulation of Sec3 by phospholipids and Cdc42. J Cell Biol 180:145-58

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