NOTE: In October 2015 Jonathon Pines took up the position of Head of Cancer Biology at the Institute of Cancer Research in London. Many of his team will remain at the Gurdon Institute until the end of September 2017.
Jonathon Pines PhD FRS FMedSci
Head of Cancer Biology at the Institute of Cancer Research, London.
How do cells control mitosis?
How do cells regulate entry to mitosis? And, once in mitosis, how do cells coordinate chromosome segregation with cell separation to ensure that the two daughter cells receive an equal and identical copy of the genome? The answers to both questions are provided by the interplay between protein kinases, protein phosphatases, and APC/C-mediated proteolysis, and this is the focus of our research. Since mitosis is a highly dynamic process we study living cells by time-lapse fluorescence microscopy, but complement this with biochemical analyses on cells in which we have knocked-out or mutated specific mitotic regulators using somatic cell recombination.
To understand how cells trigger mitosis we are analysing the behaviour of the key mitotic kinases, the Cyclin A- and B-dependent kinases, and their regulation by phosphorylation and dephosphorylation. To understand how proteolysis regulates progress through mitosis we complement the analysis of APC/C-dependent degradation in living cells with biochemical analyses of protein complexes and ubiquitination activity. These studies are revealing how the APC/C is activated and how it is able to select a particular protein for destruction at a specific time. Moreover, the intimate coupling of the APC/C with the spindle assembly checkpoint that is essential to the control of chromosome segregation has meant that our work has begun to elucidate the key events in the checkpoint pathway.
• Di Fiore B et al. (2015) The ABBA motif binds APC/C activators and is shared by APC/C substrates and regulators. Dev Cell. 32(3):358-72.
• Grallert A et al. (2015) A PP1-PP2A phosphatase relay controls mitotic progression. Nature. 517(7532):94-8.
• Izawa D and Pines J. (2015) The mitotic checkpoint complex binds a second CDC20 to inhibit active APC/C. Nature. 517(7536):631-4.
• Matsusaka T et al. (2014) Co-activator independent differences in how the metaphase and anaphase APC/C recognise the same substrate. Biol Open. 3(10):904-12. DOI: 10.1242/bio.20149415.
• Collin P et al. (2013) The spindle assembly checkpoint works like a rheostat rather than a toggle switch. Nat Cell Biol. 15(11):1378-85.
• Izawa D and Pines J (2012) Mad2 and the APC/C compete for the same site on Cdc20 to ensure proper chromosome segregation. J Cell Biol. 199: 27-37
• Mansfeld J et al. (2011) APC15 drives the turnover of MCC-Cdc20 to make the spindle assembly checkpoint responsive to kinetochore attachment. Nature Cell Biology 13: 1234-1244.