In virtually all tissues of every eukaryotic organism, polarized export of cell surface components is critical for a range of important cellular functions including protein secretion, assembly of the plasma membrane, cell signaling, cell polarization, cell migration, ciliogenesis, and cytokinesis. Defects in polarized export underlie or exacerbate a number of human diseases including cancer. We pioneered the genetic analysis of polarized export in yeast, identifying and characterizing a system of components that are all structurally and functionally conserved in higher eukaryotic organisms. Sec4p, the founding member of the rab GTPase family, acts as a master regulator by promoting the function of three different effectors: Myo2p a type V myosin that actively transports vesicles along polarized actin cables, the yeast homolog of the Lgl tumor suppressor Sro7p that physically links Sec4-GTP to the t-SNARE Sec9p, and the exocyst a complex of eight different gene products that interacts with components on the vesicle surface as well as polarity determinants on the cell cortex and thus tethers incoming secretory vesicles to these specialized sites. This proposal seeks to probe in greater detail the mechanism by which the exocyst acts to promote polarized export. We will define the role of the exocyst in the regulation of SNARE complex assembly and in the tethering of secretory vesicles to exocytic sites at the cell cortex. We will also critically test a model of exocyst function that requires a cycle of exocyst assembly and disassembly for ongoing vesicular traffic in vivo. These studies will shed light on one of the most poorly understood yet centrally important elements of the eukaryotic membrane traffic machinery.
In virtually all tissues of every eukaryotic organism, polarized export of cell surface components is critical for a range of important cellular functions including protein secretion, assembly of the plasma membrane, cell signaling, cell polarization, cell migration, ciliogenesis, and cytokinesis. Defects in polarized export underlie or exacerbate a number of human diseases including cancer. We will determine how the key components of the export system work together to direct efficient delivery of material to the cell surface.
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|Stalder, Danièle; Novick, Peter J (2016) The casein kinases Yck1p and Yck2p act in the secretory pathway, in part, by regulating the Rab exchange factor Sec2p. Mol Biol Cell 27:686-701|
|Novick, Peter (2016) Regulation of membrane traffic by Rab GEF and GAP cascades. Small GTPases 7:252-256|
|Casey, Amanda K; Chen, Shuliang; Novick, Peter et al. (2015) Nuclear pore complex integrity requires Lnp1, a regulator of cortical endoplasmic reticulum. Mol Biol Cell 26:2833-44|
|Stalder, Danièle; Novick, Peter J (2015) Assaying the interaction of the Rab guanine nucleotide exchange protein Sec2 with the upstream Rab, a downstream effector, and a phosphoinositide. Methods Mol Biol 1298:85-98|
|Riquelme, Meritxell; Bredeweg, Erin L; Callejas-Negrete, Olga et al. (2014) The Neurospora crassa exocyst complex tethers Spitzenkörper vesicles to the apical plasma membrane during polarized growth. Mol Biol Cell 25:1312-26|
|Novick, Peter J (2014) A pathway of a hundred genes starts with a single mutant: isolation of sec1-1. Proc Natl Acad Sci U S A 111:9019-20|
|Liu, Dongmei; Novick, Peter (2014) Bem1p contributes to secretory pathway polarization through a direct interaction with Exo70p. J Cell Biol 207:59-72|
|Ling, Yading; Hayano, Scott; Novick, Peter (2014) Osh4p is needed to reduce the level of phosphatidylinositol-4-phosphate on secretory vesicles as they mature. Mol Biol Cell 25:3389-400|
|Stalder, Danièle; Mizuno-Yamasaki, Emi; Ghassemian, Majid et al. (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|
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