Abstract
Stress-activated mitogen-activated protein kinase cascades instigate a range of changes to enable eukaryotic cells to cope with particular insults. In Schizosaccharomyces pombe these responses include the transcription of specific gene sets and inhibition of entry into mitosis1,2. The S. pombe stress response pathway (SRP) also promotes commitment to mitosis in unperturbed cell cycles to allow cells to match their rate of division with nutrient availability1,3. The nature of this SRP function in cell cycle control is unknown. Entry into mitosis is controlled by mitosis-promoting factor (MPF; Cdc2/cyclin B) activity. Inhibitory phosphorylation of Cdc2 by Wee1 kinase inactivates MPF until Cdc25 removes this phosphate to promote mitosis4. The balance between Wee1 and Cdc25 activities is influenced by the recruitment of polo kinase (Plo1) to the spindle pole body (SPB)5. The SPB component Cut12 mediates this recruitment5,6. Hyper-activating mutations in either cut12 or plo1 enable Cdc25-defective cells to enter mitosis5,7. The hyperactive cut12.s11 mutation suppresses cdc25.22, as it promotes recruitment of active Plo1 to interphase SPBs6,7. Here we show that the SRP promotes phosphorylation of Plo1 on Ser 402. In unperturbed cell cycles, SRP-mediated phosphorylation of Ser 402 promotes Plo1 recruitment to SPBs and thus commitment to mitosis. Ser 402 phosphorylation also ensures efficient reinitiation of cell tip growth and cell division during recovery from particular stresses. Thus, phosphorylation of Plo1 Ser 402 not only enables SRP signalling to modulate the timing of mitotic commitment in response to nutrient status in unperturbed cycles, but also promotes the return to normal cell cycle control after stress.
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Acknowledgements
We thank A. Grallert for technical assistance in the initial stages of the project; K. Gull, P. Russell, H. Ohkura and N. Jones for reagents; Paul Nurse for support; and N. Jones and P. Nurse for discussions. This work was supported by Cancer Research UK and Rockefeller University.
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Supplementary Figures and Supplementary Table S1
Supplementary Figure S1 shows characterization of the phospho-S402 antibody and phosphorylation of serine 402 under different stress conditions. Supplementary Figure S2 shows the kinetics of S402 phosphorylation after heat shift of cdc25.22 and synchronized wild-type cells along with the kinetics of Spc1/Sty1 activation and the association between Plo1 and Spc1/Sty1 after heat stress. Supplementary Figure S3 shows that centrifugation de-polarizes the F-actin cytoskeleton. Supplementary Figure S4 shows that Plo1 does not dimerise after temperature shift because it is not possible to precipitate untagged Plo1 with epitope tagged Plo1. Supplementary Figure S5 shows a cartoon that summarizes the function of phosphorylation of S402 in cell cycle control and recovery from stress. (PPT 5761 kb)
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Petersen, J., Hagan, I. Polo kinase links the stress pathway to cell cycle control and tip growth in fission yeast. Nature 435, 507–512 (2005). https://doi.org/10.1038/nature03590
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DOI: https://doi.org/10.1038/nature03590
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