Professor of Cellular & Molecular Medicine
Ph.D., UC Berkeley
I. Membrane traffic is required for many essential functions, such as controlling the accessibility of cell surface receptors, the translocation of glucose transporters in response to insulin, antigen presentation, neuronal transmission and the establishment and maintenance of epithelial cell polarity. Therefore, the regulation of membrane traffic is directly relevant to a broad range of human diseases including cancer, diabetes and neural degeneration. Rab GTPases are key regulators of membrane traffic. By recruiting and activating a functionally diverse set of effectors, a single Rab can coordinate the various sub-reactions within a given stage of membrane traffic, including vesicle budding, delivery, tethering and fusion.
Work in our lab has defined three systems, conserved from yeast to man: First, vesicles are transported in a polarized fashion along cytoskeletal elements by a molecular motor. Next, the vesicles are recognized by a hetero-octomeric complex, termed the exocyst, which resides at specific sites on the plasma membrane. Finally, a SNARE complex, involving integral membrane proteins on both the vesicle and plasma membrane is formed and membrane fusion is catalyzed by Sec1, a protein that binds to the assembled SNARE complex. Each of these three systems is under regulation by Sec4p, a GTP binding protein of the rab family, and its nucleotide exchange factor, Sec2p.
Current projects are aimed at a number of key questions: How is the nucleotide exchange factor Sec2 regulated to control the activation of the rab GTPase Sec4? How does Sec4 functionally connect with a myosin to direct the polarized movement of vesicles along actin cables? How is the localization of the exocyst controlled to specify sites of new membrane incorporation? How does the exocyst recognize the secretory vesicle (and no other vesicle)? Does the exocyst undergo a cycle of assembly and disassembly in conjunction with its role in membrane traffic and does it play a role in SNARE complex assembly? We are also exploring the molecular mechanisms by which different stages of membrane traffic can be coordinated by coupling the activation and inactivation of different Rabs through cascade mechanisms. To answer these questions, we use a combination of molecular genetics, biochemistry and advanced imaging techniques.
II. In eukaryotic cells the endoplasmic reticulum forms a highly fenestrated structure that is spread throughout the cell. In collaboration with the Ferro-Novick lab we have initiated a project that focuses on the dynamics, structure and distribution of the cortical ER. Using a fluorescently tagged ER marker and a visual assay we have systematically screened the complete library of yeast gene deletion mutants for those defective in the structure or inheritance of cortical ER and have identified about a dozen genes. It is already clear that an elaborate system exists to move the ER into the daughter cell. The process starts with the formation of an ER tubule from the nuclear envelope. This tubule is extended into the daughter cell by Myo4p a type V myosin. The exocyst complex plays a key role in anchoring the ER tubule at the tip of the daughter cell. The ER is then propagated along the cortex of the daughter cell under the regulation of a MAP kinase pathway. We also recently identified several proteins, conserved throughout eukaryotic species, which are required for the formation of the reticular structure of the ER. Defects in these genes have been linked with a variety of neurological diseases in humans. Current projects are aimed at defining the roles of these components in ER structure and function, both in yeast and in mammalian cells.
I would be delighted to discuss more specifics regarding these projects. Rotation projects could be either 6 or 12 weeks in fall, winter or spring, however I will be particularly busy during the fall.
Recent Review Articles
Munson, M. and Novick, P. 2006. The Exocyst defrocked, a framework of rods revealed. Nat. Struc. Mol. Biol. 13: 577-581.
Grosshans, B., Ortiz, D. and Novick, P. 2006. Rabs and their effectors: Achieving specificity in membrane traffic. Proc. Natl. Acad. Sci. 103: 11821-11827.
Pfeffer SR, Novick PJ. 2010. Membrane traffic. Curr Opin Cell Biol. 4:419-21.
Hutagalung, A. H. and Novick, P. 2010. The Role of Rab GTPases in Membrane Traffic and Disease. 2010. Physiological Reviews (in press).
Hutagalung, A.H., Coleman, J., Pypaert, M. and Novick, P. 2009. An internal domain of Exo70p regulates an actin-independent localization pathway and exocyst assembly. Mol. Biol. Cell 20: 153-163.
Williams DC, Novick P. 2009. Analysis of SEC9 suppression reveals a relationship of SNARE function to cell physiology. PLoS One. 4:e5449.
Rivera-Molina, F.E. and Novick, P. 2009. A Rab GAP Cascade defines the boundary between two Rab GTPases on the secretory pathway. Proc. Natl. Acad. Science. 106: 14408-14413.
Sclafani, A., Chen, S., Rivera-Molina, F.E., Reinisch, K., Novick, P. and Ferro-Novick, F. 2010. Establishing a role for the GTPase Ypt1p at the late Golgi. Traffic 11:520-32.
Mizuno-Yamasaki, E., Medkova, M. , Coleman, J. and Novick, P. 2010. Phosphatidylinositol 4-phosphate controls both membrane recruitment and a regulatory switch in the Rab GEF Sec2p. Dev Cell. 18: 828-40.
Li X., Du, Y., Siegel, S., Ferro-Novick. S. and Novick, P. 2010. Activation of the MAP kinase, Slt2p, at bud tips blocks a late stage of ER inheritance in Saccharomyces cerevisiae. Mol Biol Cell. 21:1772-82.
Vasa, N., Htagalung, A., Novick, P and Reinisch, K.M. 2010. Structure of a C-terminal fragment of its Vps53 subunit suggests similarity of GARP to a family of tethering complexes. Proc Natl Acad Sci USA. 107:14176-81.