NIH Reporter #11398122

Polarized Exocytosis: Rabs, Tethers, and SNAREs

This award funds research to understand the regulation and coordination of exocytosis and cell polarity, focusing on molecular mechanisms involving Rho/Cdc42 GTPases, exocyst, and Sro7/Tomosyn family members, with implications for diseases like cancer and Type II diabetes.

Description

Our investigation into the fundamental mechanisms by which cells direct polarized 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 have been found to be associated with a number of cancers and insulin responsiveness in humans. A molecular understanding of how these highly conserved processes are carried out by a highly conserved machinery will allow development of new approaches and novel therapeutics to combat disease. The overall goal of this proposal is to understand how regulation and coordination of exocytosis and cell polarity is achieved within the cell. Our laboratory has played a central role in determining how Rho/Cdc42 GTPases, the exocyst, and Sro7/Tomosyn family members act in Rab and SNARE-mediated cell surface trafficking. We will delineate the mechanism by which exocyst is allosterically regulated, model this regulation in both yeast and mammalian systems, and test the conservation of this activation using a mouse adipocyte model of regulated exocytosis. Finally, we will detail the role of specific phosphoinositide lipids in exocyst tethering, as well as deliver novel structural insights into how Sro7/tomosyn family members are regulated and act as vesicle tethers in exocytosis.

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