The overall goal of this proposal is to understand the mechanism by which eukaryotic cells direct polarized growth and secretion to specific sites on the cell surface and how this is coordinated with overall cell polarity. Previous work from our laboratory and others has implicated members of the Lgl/Sro7 and Rho/Cdc42 protein families as factors that have important roles in both membranes trafficking to the cell surface and cell polarity in a number of systems. Spatial regulation of trafficking on the cell surface in yeast requires specific patterns of Rho/Cdc42 localization as well as tight regulation of vesicle tethering and fusion functions of Lgl/Sro7 protein. In this proposal we will examine the structural elements in Cdc42 and Rho3 GTPase proteins that are critical for their distinct patterns of localization and define the specific endocytic factors and pathways utilized for recycling and trafficking of Cdc42 to the cell surface. Finally we will build on our recent discovery of a Rab-dependent vesicle docking function of Sro7 to dissect both the intra and intermolecular regulation of Sro7's dual functions in vesicle docking and fusion.

Public Health Relevance

Our investigation into the fundamental mechanisms by which Rho GTPases and Lgl tumor suppressor family members function in cell polarity is likely to be relevant to our understanding of tumor development and other diseases such as Type II diabetes as defects in these families have been associated with a number of cancers and insulin response in humans. Ultimately understanding the molecular details of these processes may allow the development of new approaches and novel therapeutics to combating cancer, or type II diabetes, as well as other diseases in which regulation of cell surface trafficking is cental to the etiology of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM054712-15A1
Application #
8295647
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Ainsztein, Alexandra M
Project Start
1998-05-01
Project End
2016-01-31
Budget Start
2012-04-01
Budget End
2013-01-31
Support Year
15
Fiscal Year
2012
Total Cost
$367,941
Indirect Cost
$117,941
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Rossi, Guendalina; Watson, Kelly; Demonch, Mallory et al. (2015) In vitro reconstitution of Rab GTPase-dependent vesicle clustering by the yeast lethal giant larvae/tomosyn homolog, Sro7. J Biol Chem 290:612-24
Watson, Leah J; Rossi, Guendalina; Brennwald, Patrick (2014) Quantitative analysis of membrane trafficking in regulation of Cdc42 polarity. Traffic 15:1330-43
Brennwald, Patrick (2013) Membrane traffic: the exocyst meets the cell cycle. Curr Biol 23:R838-40
Rossi, Guendalina; Brennwald, Patrick (2011) Yeast homologues of lethal giant larvae and type V myosin cooperate in the regulation of Rab-dependent vesicle clustering and polarized exocytosis. Mol Biol Cell 22:842-57
Boulter, Etienne; Garcia-Mata, Rafael; Guilluy, Christophe et al. (2010) Regulation of Rho GTPase crosstalk, degradation and activity by RhoGDI1. Nat Cell Biol 12:477-83
Wu, Hao; Brennwald, Patrick (2010) The function of two Rho family GTPases is determined by distinct patterns of cell surface localization. Mol Cell Biol 30:5207-17
Wu, Hao; Turner, Courtney; Gardner, Jimmy et al. (2010) The Exo70 subunit of the exocyst is an effector for both Cdc42 and Rho3 function in polarized exocytosis. Mol Biol Cell 21:430-42
Wu, Hao; Rossi, Guendalina; Brennwald, Patrick (2008) The ghost in the machine: small GTPases as spatial regulators of exocytosis. Trends Cell Biol 18:397-404
Brennwald, Patrick; Rossi, Guendalina (2007) Spatial regulation of exocytosis and cell polarity: yeast as a model for animal cells. FEBS Lett 581:2119-24
Grosshans, Bianka L; Andreeva, Anna; Gangar, Akanksha et al. (2006) The yeast lgl family member Sro7p is an effector of the secretory Rab GTPase Sec4p. J Cell Biol 172:55-66

Showing the most recent 10 out of 23 publications