Group Leader:
Iain Hagan
After completing my PhD studies I went to Japan on a 4-year postdoctoral fellowship with Professor Mitsuhiro Yanagida in Kyoto University. I returned to the UK in 1993 with a Cancer Research Campaign Return Fellowship to establish a group in The University of Manchester. I continued to work in what later became the Faculty of Life Sciences at The University of Manchester, with further Cancer Research Campaign Fellowship support before moving to the Paterson Institute for Cancer Research in 2001. In 1999 I was awarded the Human Frontier Science Program 10th Anniversary Medal and in 2001 was the recipient of the BSCB Hooke Medal. I am currently a Senior Group Leader at the Paterson Institute for Cancer Research.
Postdoctoral Fellows
Marisa Alonso Nuñez
Marisa Madrid
Associate Scientist
Agnes Grallert
Graduate Students
Dorota Feret
Avinash Patel
Elvan Boke
Yisu Wang
Cell Division Group - Fin1
Our spindle formation screen identified a conditional fin1 mutant with an asymmetric activation of the SPB that was strongly reminiscent of the cut12.1 phenotype (Grallert and Hagan, 2002). fin1 mutants showed strong genetic interactions with cut12, where by the cut12.s11 mutation alleviated the spindle formation defect of fin1 mutants, while double cut12.1 fin1 mutants were dead. Furthermore the severity of the fin1- spindle formation defect could be halved by mutation or deletion of wee1. This suggests that Fin1 may normally act before Wee1 in mitotic commitment to regulate it. Fin1 function was required for the premature recruitment of Plo1 to the cut12.s11 SPB and very mild induction of fin1+ expression forces Plo1 to associate with interphase SPBs of wild type cells.
These data all suggest that Fin1 acts before Cut12/Plo1 to regulate the feedback loop during mitotic commitment (Grallert and Hagan, 2002). The founder member of the NIMA related kinase (Nek or Nrk) family, A. nidulans NIMA, is required for entry into mitosis (Osmani et al., 1986). A human counterpart, Nek2, is required for spindle pole function (Fry, 2002). The spindle formation and G2 delay phenotypes of the fission yeast molecule, Fin1, therefore shares phenotypes of mutations in both systems (Grallert and Hagan, 2002; Krien et al., 1998; Krien et al., 2002). This suggests that, like Polo and aurora related kinases, the function of NIMA related kinases may be conserved across species (Nigg, 2001).
Fin1 controls mitotic exit as well as entry.
We found that the association of Fin1 with the SPB depended upon the Septum Initiation Network (SIN) The activity of the SIN is controlled through the activity of the Spg1 GTPase and the bipartite GAP complex that represses SIN activity on the old SPB of late anaphase cells by converting Spg1 into an inactive GDP bound form. Fin1 associated with Byr4 and was required to repress the SIN on the old SPB in half of the cells in the culture. Ablating Fin1 function increased septation suggesting that Fin1 function not only impinges upon SIN activity on particular SPBs, but does influence the flux through the SIN signalling pathway. Fin1 is part of a SIN negative feedback loop because the recruitment of Fin1 to the SPB is dependent upon the positive effectors of the SIN as well as the repressors and the scaffold molecules. Activation of the SIN promotes Fin1 recruitment which then keeps the SIN shut down on the old SPB. The challenge now is to work out why this only happens on the old SPB and how the SIN is shut off in the half of the population in which the SIN remains repressed on the old SPB of fin1 null cells.
references
Fry, A. M. (2002). The Nek2 protein kinase: a novel regulator of centrosome structure. Oncogene 21, 6184-6194.
Grallert, A., and Hagan, I. M. (2002). Schizosaccharomyces pombe NIMA-related kinase Fin1, regulates spindle formation and an affinity of Polo for the SPB. EMBO Journal 21, 3096-3107.
Krien, M., Bugg, S., Palatsides, M., Asouline, G., Morimyo, M., and O'Connell, M. (1998). A NIMA homologue promotes chromatin condensation in fission yeast. J Cell Sci 111, 967-76.
Krien, M. J., West, R. R., John, U. P., Koniaras, K., McIntosh, J. R., and O'Connell, M. (2002). The fission yeast NIMA kinase Fin1p is required for spindle function and nuclear envelope integrity. EMBO Journal 21, 1713-1722.
Nigg, E. A. (2001). Mitotic kinases as regulators of cell division and its checkpoints. Nature Reviews in Molecular and Cellular Biology 2, 21-32.
Osmani, S. A., Engle, D. A. B., May, G. S., Osmani, A., and Morris, N. R. (1986). Cloning and expression of NimA and BimE, 2 genes involved in the regulation of mitosis in Aspergillus-nidulans. Journal Of Cell Biology 103, A138-A138.