Department of Pediatric Oncology
tel: (617) 632-4918; fax: (617) 632-6845
Our laboratory is interested in how cell cycle signals regulate chromosome segregation and polarized morphogenesis. Our experimental approaches include a combination of biochemical, genetic and live-cell imaging.
One focus of the laboratory is on the mechanisms controlling the attachment of the mitotic spindle to the chromosomes and to polarized membrane sites. These processes require the interplay between specialized microtubule-binding proteins and microtubule-based motors. One important aspect of this project is quantitative in vivo imaging. New imaging methods may enable the modeling of processes such as the positioning of the mitotic spindle by the microtubule-based dynein motor. Another aspect of this project will be the establishment of in vitro systems to reconstitute features of these motility events.
A second area of interest is the mechanism of actin assembly by formins, a recently discovered nucleator of actin filament assembly. In yeast, linear structures called actin cables are crucial for cytokinesis and the establishment of cell polarity. We recently found that the assembly of actin cables, but not other actin structures, requires a conserved family of proteins called formins. Formins nucleate actin filaments in vitro. Formins are the only known cellular actin nucleators other than the Arp2/3 complex. Importantly, formins and the Arp2/3 complex drive the assembly of differently shaped actin filaments. This suggests a simple model of how differently shaped actin structures are formed in cells: different nucleators initiate differently shaped “building blocks” that are assembled into different structures. Based on a recently solved structure of an active formin, using both in vitro and in vivo approaches, we are characterizing the formin actin assembly mechanism.
Sheeman, B., Carvalho, P., Sagot, I., Geiser, J., Kho, D., Hoyt, M.A., and Pellman, D. Determinants ofS. cerevisiae dynein localization and activation: implications for the mechanism of spindle positioning. Curr. Biol., 2003, 13:364-72.
Lee, L., Tirnauer, J. S., Li, J., Schuyler, S. C., and Pellman, D., A cortical-microtubule capture mechanism for positioning the mitotic spindle in S. cerevisiae. Science, 2000, 287, 2260-2262.
Sagot, I., Rodal, A., Goode, B., and Pellman, D. An actin nucleation mechanism mediated by the formin Bni1 and profilin. Nature Cell Biol., 2002, 8:626-31.
Carvalho, P., Tirnauer, J., and Pellman, D. Surfing on microtubule ends. Trends Cell Biol., 2003, 13:229-37.
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