Professor of Cellular & Molecular Medicine
Ph.D., UC Berkeley
I. Membrane traffic is required for many essential cellular 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 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 are 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. 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 gene required for ER distribution. We also recently identified several conserved proteins required for the formation of the reticular structure of the ER. Defects in these genes have been linked to a variety of neurological diseases. 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
Hutagalung, A. H. and Novick, P. 2011. The Role of Rab GTPases in Membrane Traffic and Disease. Physiological Reviews 91:119-49.
Mizuno-Yamasaki E, Rivera-Molina F, Novick P. 2012. GTPase networks in membrane traffic. Annu Rev Biochem. 81:637-59.
Chen S, Novick P, Ferro-Novick S. 2013. ER structure and function. 2013. Curr Opin Cell Biol. 25:428-33.
Mizuno-Yamasaki, E., Medkova, M. , Coleman, J. and Novick, P. 2010. Phosphatidylinositol 4-phosphate controls both membrane recruitment and a regulatory switch of 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.
Chen S, Novick P, Ferro-Novick S. 2012. ER network formation requires a balance of the dynamin-like GTPase Sey1p and the Lunapark family member Lnp1p. Nat Cell Biol. 24:707-16.
Shen D, Yuan H, Hutagalung A, Verma A, Kümmel D, Wu X, Reinisch K, McNew JA, Novick P. 2013. The synaptobrevin homologue Snc2p recruits the exocyst to secretory vesicles by binding to Sec6p. J Cell Biol. 202:509-26.
Li X, Ferro-Novick S, Novick P. 2013. Different polarisome components play distinct roles in Slt2p-regulated cortical ER inheritance in Saccharomyces cerevisiae. Mol Biol Cell. 19: 3145-54
Stalder D, Mizuno-Yamasaki E, Ghassemian M, Novick P. 2013. Phosphorylation of the Rab exchange factor Sec2p directs a switch in regulatory binding partners. Proc Natl Acad Sci U S A. 110:19995-20002.
Liu D and Novick P. 2014. Bem1p contributes to secretory pathway polarization through a direct interaction with Exo70p. J Cell Biol. 207:59-72.
Ling Y, Hayano S and Novick P. 2014. Osh4p is needed to reduce the level of phosphatidylinositol-4-phosphate on secretory vesicles as they mature. Mol Biol Cell 25(21):3389-400.
Chen, S., Desai, T., McNew, J., Gerard, P. Novick, P. and Ferro-Novick, S. 2015. Lnp1 stabilizes nascent three-way junctions in the endoplasmic reticulum. Proc Natl Acad Sci U S A 112:418-23.