Membrane traffic is required for a broad range of 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 GTPase can coordinate the various sub- reactions within a given stage of membrane traffic, including vesicle budding, delivery, tethering and fusion. Furthermore, our results indicate that adjacent stages of transport can also be coupled through coordinated rab regulation. We recently defined a rab guanine nucleotide exchange factor (GEF) cascade in which one rab, in its GTP-bound state, recruits the GEF that activates the next rab along the exocytic pathway. We also have preliminary evidence for a rab GTPase activating protein (GAP) cascade operating in a counter current fashion. Here the downstream rab recruits the GAP that inactivates the upstream rab. The net effect is rab conversion in which a given patch of membrane starts out labeled with one rab, but over time becomes labeled with another rab. Since each rab recruits and activates a distinct set of effectors, this leads to a functional maturation of the membrane. We will explore these two cascade mechanisms in further detail and test the physiological consequences of uncoupling adjacent stages of membrane traffic. We will test the role of a Sec4p effector in SNARE assembly and explore the roles of several new putative Sec4p effectors. Through these studies we will begin to define the exocytic pathway as a fully coordinated system, rather than as a collection of isolated sub-reactions. Membrane traffic is the mechanism by which material is transferred between different compartments within the cell and the regulation of membrane traffic is directly relevant to a broad range of human diseases including cancer, diabetes and neural degeneration. This study addresses the molecular mechanisms by which different stages of membrane traffic are coordinately regulated. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM082861-01
Application #
7349784
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Shapiro, Bert I
Project Start
2008-07-01
Project End
2012-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
1
Fiscal Year
2008
Total Cost
$293,550
Indirect Cost
Name
University of California San Diego
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Chen, Shuliang; Cui, Yixian; Parashar, Smriti et al. (2018) ER-phagy requires Lnp1, a protein that stabilizes rearrangements of the ER network. Proc Natl Acad Sci U S A 115:E6237-E6244
Liu, Dongmei; Li, Xia; Shen, David et al. (2018) Two subunits of the exocyst, Sec3p and Exo70p, can function exclusively on the plasma membrane. Mol Biol Cell 29:736-750
Yuan, Hua; Davis, Saralin; Ferro-Novick, Susan et al. (2017) Rewiring a Rab regulatory network reveals a possible inhibitory role for the vesicle tether, Uso1. Proc Natl Acad Sci U S A 114:E8637-E8645
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
Chen, Shuliang; Desai, Tanvi; McNew, James A et al. (2015) Lunapark stabilizes nascent three-way junctions in the endoplasmic reticulum. Proc Natl Acad Sci U S A 112:418-23
Sánchez-León, Eddy; Bowman, Barry; Seidel, Constanze et al. (2015) The Rab GTPase YPT-1 associates with Golgi cisternae and Spitzenkörper microvesicles in Neurospora crassa. Mol Microbiol 95:472-90
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
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
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

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