University of Cambridge
Tennis Court Road
Many cancer cells present numerical chromosomal abnormalities such as aneuploidy and/or polyploidy. Since the segregation of the genomic material occurs during cell division, an understanding of the mechanisms that control mitosis can unveil some of the processes that promote tumour onset and development. Moreover, one of the hallmarks of cancer is uncontrolled cell proliferation and many cell division regulators are validated targets for the isolation of novel chemotherapeutic drugs for the treatment of cancer pathologies. The goal of our research project is to understand some of the molecular mechanisms that control the last phase of cell division – cytokinesis – and to identify novel gene products that functions in this process in metazoans.
Citron kinase: a key regulator of midbody formation
Cytokinesis requires the co-ordinated action of many proteins that control sequential events. First, cells determine cleavage plane position through signals generated by the spindle microtubules, which during anaphase re-organise into an array of antiparallel and interdigitating microtubules known as the central spindle. Central spindle and astral microtubules promote ingression of the cleavage furrow that bisects the dividing cell. Furrow ingression is driven by assembly and contraction of actomyosin filaments that often organise into an annular structure known as the contractile ring. Finally, new membrane, in the form of vesicles transported along central spindle microtubules, is inserted at the cleavage site. At this late stage the central spindle forms a compact structure known as the midbody, which contains at its centre an electron-dense structure, the midbody ring or Flemming body, important for cell abscission. We have recently shown that the serine/threonine kinase Citron kinase (CIT-K) plays a key role in controlling the localisation of a network of proteins required for midbody formation in late cytokinesis. We are currently using cell biology and proteomics to dissect the role of CIT-K in midbody formation.
Regulation of cytokinesis by mitotic kinases
Mitotic serine/threonine kinases have become an intensively studied class of anti-cancer drug targets and small molecule inhibitors of mitotic kinases such as Aurora and Polo-like kinases are currently undergoing clinical trials. A comprehensive knowledge of the function of these kinases is therefore crucial to identify new pathways and biomarkers that could aid in the design of better targeted anti-cancer therapies. However, because of the multiples roles of Aurora and Polo-like kinases during cell division, their exact mechanisms of action and the identity of all their substrates are not well characterised, especially during cytokinesis. Our interest is to characterise the role of Aurora B and Polo-like kinase 1 (Plk1) specifically during cytokinesis. We are currently trying to understand how these two kinases select their specific substrates and whether they have common phosphorylation targets during cytokinesis.
- Research Associates:
- Graduate Students:
- D’Avino, P.P. and Glover D.M. (2009) Cytokinesis: mind the GAP. Nature Cell Biology, 11: 112-114.
- Montambault, E., Zhang, W., Przewloka, M.R, Archambault, V., Sevin, E.W., Laue, E.D., Glover D.M. and D’Avino, P.P. (2010) Nessun Dorma, a novel centralspindlin partner, is required for cytokinesis in Drosophila spermatocytes. Journal of Cell Biology, 191: 1351-1365.
- Bassi, I.Z., Verbrugghe, K.J., Capalbo, L., Gregory, S., Montembault, E., Glover D.M. and D’Avino PP. (2011) Sticky/Citron kinase maintains proper RhoA localization at the cleavage site during cytokinesis. Journal of Cell Biology, 195(4): 595-603.
- Capalbo, L., Montembault, E., Takeda, T., Bassi, Z.I., Glover D.M. and D’Avino PP. (2012). The Chromosomal Passenger Complex controls the function of ESCRT-III Snf7 proteins during cytokinesis. Open Biology, 2, 120070 (doi: 10.1098/rsob.120070).
- Bassi I.Z., Audusseau, M., Riparbelli, M.G., Callaini, G. and D’Avino P.P. (2013) Citron kinase controls a molecular network required for midbody formation in cytokinesis. Proceedings of the National Academy of Sciences USA, 110(24): 9782-9787.
- D'Avino P.P., Giansanti M.G., Petronczki M. (2015) Cytokinesis in animal cells. Cold Spring Harb Perspect Biol. 2015 Feb 13;7(4). pii: a015834. doi: 10.1101/cshperspect.a015834