Microtubule (MT) properties vary within seemingly uniform MT network, and MTs with similar properties comprise functionally specialized subsets. In the current funding period, we have characterized a distinct MT subset that nucleates at the Golgi membrane (Golgi-derived MTs). In contrast to the radially organized centrosomal MTs, Golgi-derived MT array is intrinsically asymmetric and is essential for polarity of motile cells. Our previous and preliminary data indicate that Golgi-derived MTs bear unique functions. Being closely associated with the Golgi membrane, these MTs are indispensable for Golgi complex assembly, maintenance and positioning. Despite the obvious essential nature of the maintenance and reorganization of the Golgi in the life cycle and basic behavior of all cells, there is a poor understanding of the intracellular architectural mechanisms that orchestrate its dynamic, temporally regulated functions. Major gaps addressed by our study include: how vesicles are tracked to/from the Golgi, how stack alignment is ensured during Golgi complex assembly, and how they are timely relocated at mitotic onset. Our preliminary and published data indicate that Golgi-derived MTs act as the architectural basis of these precisely coordinated processes. We hypothesize that distinct location of Golgi-derived MTs with their minus ends at the Golgi membrane and their specific association with a MT-binding protein CLASP, which differentially regulates distinct molecular motors, underlies functional specificity of this MT subset. The goal of this proposal is to determine the spatial and molecular mechanisms underlying the unique functions of Golgi-derived MTs. The proposal thus targets a high- impact, fundamental area of mechanistic cell biology.
Our specific aims are: 1. Test whether vesicle delivery driven by Golgi-derived MTs is critical for Golgi homeostasis 2. Determine whether Golgi repositioning prior to cell division is accomplished by Golgi-derived MTs 3. Determine the mechanism whereby Golgi-derived MTs support efficient Golgi stack fusion

Public Health Relevance

A microtubule subset that nucleates at the Golgi membrane is indispensable for Golgi complex assembly, maintenance and positioning. In this project, we propose to determine the spatial and molecular mechanisms underlying the unique functions of Golgi-derived MTs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM078373-06A1
Application #
8630868
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Nie, Zhongzhen
Project Start
2008-04-01
Project End
2018-01-31
Budget Start
2014-02-11
Budget End
2015-01-31
Support Year
6
Fiscal Year
2014
Total Cost
$356,441
Indirect Cost
$122,914
Name
Vanderbilt University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Arnette, Christopher; Frye, Keyada; Kaverina, Irina (2016) Microtubule and Actin Interplay Drive Intracellular c-Src Trafficking. PLoS One 11:e0148996
Zhu, Xiaodong; Efimova, Nadia; Arnette, Christopher et al. (2016) Podosome dynamics and location in vascular smooth muscle cells require CLASP-dependent microtubule bending. Cytoskeleton (Hoboken) 73:300-15
Zhu, Xiaodong; Hu, Ruiying; Brissova, Marcela et al. (2015) Microtubules Negatively Regulate Insulin Secretion in Pancreatic β Cells. Dev Cell 34:656-68
Grimaldi, Ashley D; Zanic, Marija; Kaverina, Irina (2015) Encoding the microtubule structure: Allosteric interactions between the microtubule +TIP complex master regulators and TOG-domain proteins. Cell Cycle 14:1375-8
Maki, Takahisa; Grimaldi, Ashley D; Fuchigami, Sotaro et al. (2015) CLASP2 Has Two Distinct TOG Domains That Contribute Differently to Microtubule Dynamics. J Mol Biol 427:2379-95
Tonucci, Facundo M; Hidalgo, Florencia; Ferretti, Anabela et al. (2015) Centrosomal AKAP350 and CIP4 act in concert to define the polarized localization of the centrosome and Golgi in migratory cells. J Cell Sci 128:3277-89
Cleghorn, Whitney M; Branch, Kevin M; Kook, Seunghyi et al. (2015) Arrestins regulate cell spreading and motility via focal adhesion dynamics. Mol Biol Cell 26:622-35
Sanders, Anna A W M; Kaverina, Irina (2015) Nucleation and Dynamics of Golgi-derived Microtubules. Front Neurosci 9:431
Efimova, Nadia; Grimaldi, Ashley; Bachmann, Alice et al. (2014) Podosome-regulating kinesin KIF1C translocates to the cell periphery in a CLASP-dependent manner. J Cell Sci 127:5179-88
Grimaldi, Ashley D; Maki, Takahisa; Fitton, Benjamin P et al. (2014) CLASPs are required for proper microtubule localization of end-binding proteins. Dev Cell 30:343-52

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