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.
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.
|Watson, Kelly; Rossi, Guendalina; Temple, Brenda et al. (2015) Structural basis for recognition of the Sec4 Rab GTPase by its effector, the Lgl/tomosyn homologue, Sro7. Mol Biol Cell 26:3289-300|
|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|
|Forsmark, Annabelle; Rossi, Guendalina; Wadskog, Ingrid et al. (2011) Quantitative proteomics of yeast post-Golgi vesicles reveals a discriminating role for Sro7p in protein secretion. Traffic 12:740-53|
|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|
|Ivanov, Andrei I; Young, Cheryl; Den Beste, Kyle et al. (2010) Tumor suppressor scribble regulates assembly of tight junctions in the intestinal epithelium. Am J Pathol 176:134-45|
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