The overall goal of this proposal is to understand the mechanism by which Rho GTPases, Rab GTPases, tethering agents, and SNAREs contribute to direct polarized trafficking and growth at the cell surface. Previous work from our laboratories and others has implicated members of the Rho/Cdc42, exocyst and Sro7/Tomosyn protein families as highly conserved factors that have important roles in both polarity and membrane trafficking to the cell surface in systems as diverse as yeast and neurons. In this proposal, we will make use of new biochemical, genetic, and structural tools we have developed during the previous funding period to examine the molecular mechanisms by with Exocyst and Sro7 proteins work together as Rab effectors and vesicle tethering agents. Importantly we make use of newly identified gain-of-function alleles within the exocyst and Sro7 to understand the distinct biochemical and structural changes that occur to these tethering agents as they respond to regulatory and spatial cues.
Our investigation into the fundamental mechanisms by which cells direct growth is likely to be relevant to our understanding of a diverse set of human diseases including tumor development and Type II diabetes as defects in this process has been associated with a number of cancers and insulin responsiveness in humans. A molecular understanding of how these highly conserved processes carried by a highly conserved machinery will allow development of new approaches and novel therapeutics to combat disease.
|Jeschke, Grace R; Lou, Hua Jane; Weise, Keith et al. (2018) Substrate priming enhances phosphorylation by the budding yeast kinases Kin1 and Kin2. J Biol Chem 293:18353-18364|
|Rossi, Guendalina; Watson, Kelly; Kennedy, Wade et al. (2018) The tomosyn homologue, Sro7, is a direct effector of the Rab GTPase, Sec4, in post-Golgi vesicle tethering. Mol Biol Cell 29:1476-1486|
|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; 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|
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