Generation of cellular asymmetry is an unsolved problem fundamental to biology. This research seeks to develop a molecular mechanistic understanding of how yeast cells orient and assemble axes of polarity during vegetative division by budding. Yeast cells polarize, bud, and divide in two spatial patterns: the axial pattern of haploids in which buds form adjacent to the previous site of cell division, and the bipolar pattern of diploids in which buds form at either cell pole. The first focus is an investigation of the function of Bud10/Ax12, a type I transmembrane protein, which directs haploid cells to bud in axial orientations.
Aims 1 and 2 investigate the following questions: How are the localizations of axial bud-site-selection proteins (Bud3, Bud4, Bud10) temporally controlled in the cell cycle? How is Bud10 regulated to signal in haploids but not in diploids? What are the signaling targets controlled by Bud10? The second focus of this proposal is an investigation of the mechanism by which the conserved GTPase Cdc42 controls cytoskeletal polarization. Experiments are designed to identify novel Cdc42 targets or downstream pathway components, and to analyze the mechanism of action of newly described Cdc42 targets, Gic1 and Gic2. The problem of cell polarization has implications for understanding human physiology and disease. Cell polarization underlies the development of axons in the nervous system, cell-cell communication and killing in the immune response, and cell migration throughout the body. Derangements of cellular organization are strongly associated with tumor metastasis and invasiveness. Many of the molecules that control polarization in yeast are conserved in humans, therefore what is learned should guide the understanding of similar processes in human cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM049782-08
Application #
6180392
Study Section
Microbial Physiology and Genetics Subcommittee 2 (MBC)
Program Officer
Deatherage, James F
Project Start
1993-08-01
Project End
2002-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
8
Fiscal Year
2000
Total Cost
$273,730
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
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Lord, Matthew; Inose, Fumika; Hiroko, Takatoshi et al. (2002) Subcellular localization of Axl1, the cell type-specific regulator of polarity. Curr Biol 12:1347-52
Marston, A L; Chen, T; Yang, M C et al. (2001) A localized GTPase exchange factor, Bud5, determines the orientation of division axes in yeast. Curr Biol 11:803-7
Korinek, W S; Bi, E; Epp, J A et al. (2000) Cyk3, a novel SH3-domain protein, affects cytokinesis in yeast. Curr Biol 10:947-50
Korinek, W S; Copeland, M J; Chaudhuri, A et al. (2000) Molecular linkage underlying microtubule orientation toward cortical sites in yeast. Science 287:2257-9
Chen, T; Hiroko, T; Chaudhuri, A et al. (2000) Multigenerational cortical inheritance of the Rax2 protein in orienting polarity and division in yeast. Science 290:1975-8
Lord, M; Yang, M C; Mischke, M et al. (2000) Cell cycle programs of gene expression control morphogenetic protein localization. J Cell Biol 151:1501-12
Michelitch, M; Chant, J (1996) A mechanism of Bud1p GTPase action suggested by mutational analysis and immunolocalization. Curr Biol 6:446-54
Halme, A; Michelitch, M; Mitchell, E L et al. (1996) Bud10p directs axial cell polarization in budding yeast and resembles a transmembrane receptor. Curr Biol 6:570-9
Pringle, J R; Bi, E; Harkins, H A et al. (1995) Establishment of cell polarity in yeast. Cold Spring Harb Symp Quant Biol 60:729-44

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