Transport of organelles and macromolecular complexes through the cytoplasm is essential for every eukaryotic cell. This process is performed by motor proteins that use the energy of ATP hydrolysis to move many types of cargo along microtubules and actin filaments. The spatial and temporal control of motor-dependent transport is critical for cell division, organelle transport and positioning, and the movement of mRNA and protein complexes in the cytoplasm. Defects in organelle transport and motor-associated proteins contribute or cause many neurodegenerative diseases, and mistakes in motor- driven chromosome segregation can cause abnormal development and cancer. The goal of this proposal is to understand how movement of microtubule motors is regulated by accessory proteins and how movement along microtubules generates cell polarity. For analysis of proteins regulating the movement we will use cultured Drosophila S2 cells because they are highly sensitive to protein knock-down by RNAi and movement of cargo along microtubules is not perturbed by other cytoskeletal elements. For analysis of cell polarity we will use primary cultures of Drosophila neurons where microtubules and microtubule motors are key components required for growth of axons and dendrites.
The specific aims of the proposal are: (i) To establish how transport is regulated by local signals (microtubule-binding proteins). (ii) To find contribution of proteins that are not associated with microtubules to transport regulation (iii) To use neuronal model to find how microtubules and microtubule-dependent transport generate formation of cell processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM052111-15
Application #
8536818
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Gindhart, Joseph G
Project Start
1999-07-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
15
Fiscal Year
2013
Total Cost
$500,508
Indirect Cost
$169,940
Name
Northwestern University at Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Winding, Michael; Gelfand, Vladimir I (2014) Breaking up isn't easy: myosin V and its cargoes need Dma1 ubiquitin ligase's help. Dev Cell 28:479-80
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Serpinskaya, Anna S; Tuphile, Karine; Rabinow, Leonard et al. (2014) Protein kinase Darkener of apricot and its substrate EF1ýý regulate organelle transport along microtubules. J Cell Sci 127:33-9
Sakuma, Chisako; Kawauchi, Takeshi; Haraguchi, Shuka et al. (2014) Drosophila Strip serves as a platform for early endosome organization during axon elongation. Nat Commun 5:5180
Trybus, Kathleen M; Gelfand, Vladimir I (2013) Molecular motors. Mol Biol Cell 24:672
Barlan, Kari; Rossow, Molly J; Gelfand, Vladimir I (2013) The journey of the organelle: teamwork and regulation in intracellular transport. Curr Opin Cell Biol 25:483-8
Lu, Wen; Fox, Pangkong; Lakonishok, Margot et al. (2013) Initial neurite outgrowth in Drosophila neurons is driven by kinesin-powered microtubule sliding. Curr Biol 23:1018-23
Barlan, Kari; Lu, Wen; Gelfand, Vladimir I (2013) The microtubule-binding protein ensconsin is an essential cofactor of kinesin-1. Curr Biol 23:317-22
Firestone, Ari J; Weinger, Joshua S; Maldonado, Maria et al. (2012) Small-molecule inhibitors of the AAA+ ATPase motor cytoplasmic dynein. Nature 484:125-9
Bensenor, Lorena B; Barlan, Kari; Rice, Sarah E et al. (2010) Microtubule-mediated transport of the tumor-suppressor protein Merlin and its mutants. Proc Natl Acad Sci U S A 107:7311-6

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