The goal of this research is to determine how the assembly dynamics and architecture of the actin cytoskeleton are controlled by formins and the mechanisms regulating their activities in vivo. We are studying this question in budding yeast, where the formins Bni1 and Bnr1 assemble actin 'cables'that play an essential role in polarized cell growth. Our lab recently discovered four novel modes of formin regulation mediated by the polarity factors Bud6, Bud14, Smy1, and Hof1. Remarkably, each of these proteins binds to the formin-homology FH2 domain of Bnr1, but has distinct effects on Bnr1 activity in vitro and distinct Bnr1-dependent mutant actin cable phenotypes in vivo. Further, we have identified novel in vivo ligands of Bud6 and Bud14 that function with them in regulating Bnr1-mediated actin cable assembly. The proposed research will define the cellular functions and mechanisms of these proteins, and how their combined effects coordinate the proper assembly of actin cables with a characteristic length, architecture, and dynamics that is tailored to their function. This work will provide a deeper understanding of the molecular activities and interactions that underlie cell polarity and morphogenesis. The project uses a multi-disciplinary approach, combining genetics, live-cell imaging, biochemistry, and novel multi-wavelength single molecule TIRF in vitro microscopy.
The Aims are to: (1) Elucidate the specific roles and mechanisms of Bud6 in regulating Bnr1- mediated actin cable assembly;(2) Test the hypothesis that Bud14 and Smy1 provide distinct modes of formin temporal regulation required for maintaining actin cable length, dynamics, and architecture;and (3) Determine how the functions of multiple FH2-binding regulators are coordinated in vitro and in vivo.

Public Health Relevance

The proper function of human tissues and organs depends on cells within those tissues maintaining their sense of direction (or polarity), dividing properly, ad maintaining their characteristic shapes and functions. Our work addresses a family of proteins (formins) that play vital roles in controlling cell shape, polarity, and division. By determining hw formins are regulated on a molecular and cellular level, we anticipate that this research will provide new insights into the underlying mechanisms of tumorigenesis, neurodegeneration, and developmental disorders such as limb deformities and hearing loss, which result from misregulated cell shape and division.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
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Gindhart, Joseph G
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Brandeis University
Schools of Arts and Sciences
United States
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Graziano, Brian R; Yu, Hoi-Ying E; Alioto, Salvatore L et al. (2014) The F-BAR protein Hof1 tunes formin activity to sculpt actin cables during polarized growth. Mol Biol Cell 25:1730-43
Gould, Christopher J; Chesarone-Cataldo, Melissa; Alioto, Salvatore L et al. (2014) Saccharomyces cerevisiae Kelch proteins and Bud14 protein form a stable 520-kDa formin regulatory complex that controls actin cable assembly and cell morphogenesis. J Biol Chem 289:18290-301
Rosado, Michelle; Barber, Cynthia F; Berciu, Cristina et al. (2014) Critical roles for multiple formins during cardiac myofibril development and repair. Mol Biol Cell 25:811-27
Jaiswal, Richa; Breitsprecher, Dennis; Collins, Agnieszka et al. (2013) The formin Daam1 and fascin directly collaborate to promote filopodia formation. Curr Biol 23:1373-9
Jaiswal, Richa; Stepanik, Vince; Rankova, Aneliya et al. (2013) Drosophila homologues of adenomatous polyposis coli (APC) and the formin diaphanous collaborate by a conserved mechanism to stimulate actin filament assembly. J Biol Chem 288:13897-905
Breitsprecher, Dennis; Goode, Bruce L (2013) Formins at a glance. J Cell Sci 126:1-7
Chesarone-Cataldo, Melissa; Guérin, Christophe; Yu, Jerry H et al. (2011) The myosin passenger protein Smy1 controls actin cable structure and dynamics by acting as a formin damper. Dev Cell 21:217-30
Graziano, Brian R; DuPage, Amy Grace; Michelot, Alphee et al. (2011) Mechanism and cellular function of Bud6 as an actin nucleation-promoting factor. Mol Biol Cell 22:4016-28
Gould, Christopher J; Maiti, Sankar; Michelot, Alphée et al. (2011) The formin DAD domain plays dual roles in autoinhibition and actin nucleation. Curr Biol 21:384-90
Gandhi, Meghal; Smith, Benjamin A; Bovellan, Miia et al. (2010) GMF is a cofilin homolog that binds Arp2/3 complex to stimulate filament debranching and inhibit actin nucleation. Curr Biol 20:861-7

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