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Most work in the lab is on the organization and regulation of the microtubule cytoskeleton, and the relationship between the cell cycle and the cytoskeleton. Microtubules are polar polymers that act as directional tracks for motor proteins that move along them. Microtubules and motors move vesicles and organelles, and make up the spindle, which segregates chromosomes in mitosis and meiosis. How do cells organize microtubules into complex, dynamic structures such as the mitotic spindle? One of the keys is the centrosome (right), which nucleates microtubule polymerization from free tubulin subunits, and organizes the array of microtubules. The centrosome consists of centrioles and pericentriolar material from which microtubules grow. We're interested in understanding the centrosome, and its role in cell division and differentiation.
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There are four main projects in the lab:
4) Tubulin folding/biogenesis. Alpha-tubulin and beta-tubulin undergo a complex series of interactions with proteins termed tubulin cofactors. These interactions are thought to be involved in bringing together the two tubulins to make the tubulin heterodimer. The components of this pathway are conserved in all eukaryotes, and mutations in the yeast components cause defects in the microtubule cytoskeleton. We are interested in how these interactions help to make functional tubulin heterodimer, and whether they are involved in controlling the level of active tubulin in the cell.
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1) Cell cycle control of centrosome duplication. We have shown that duplication of the centrosome, the microtubule organizing center of animal cells, is dependent on the cell cycle kinase cdk2, and on cell cycle-specific proteolysis. We are now working to determine the molecular mechanisms of centrosome duplication and to understand how centrosome duplication is controlled so that it happens once and only once per cell cycle. Cancer cells often have aberrant centrosome numbers, and we are investigating the relationship between aberrant centrosome number and the genome instability that is common in cancer cells.
2) Microtubule nucleation and organization. Microtubules are polymers of tubulin, which is a heterodimer of alpha-tubulin and beta-tubulin. We have identified a remarkable complex of proteins associated with a third type of tubulin, gamma-tubulin. Gamma-tubulin and its associated proteins are localized to the centrosome and are critical for initiation, or nucleation, of microtubule assembly. The gamma-tubulin complex (gammaTuRC) is a very large, ring-shaped complex and contains at least 6 proteins in addition to gamma-tubulin. We are determining the role of gamma-tubulin and its associated proteins in microtubule nucleation and organization.
3) Ciliary biogenesis and function. In addition to the microtubules making up the interphase array and the mitotic spindle, many animal cells make a specialized microtubule structure, the primary cilium. This is a single, non-motile cilium that is able to act as a transducer of mechanical and chemical signals - sort of a cellular antenna. The microtubules of the ciliary axoneme grow directly from a centriole at their base, this centriole is often called a basal body. Some epithelial cells in the trachea, oviduct and brain produce hundreds of motile cilia on their surface, each with a centriole at their base. We are studying both the primary cilium and multi-ciliated cells for clues into ciliary structure and function, and centriole formation.