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TOR signalling regulates mitotic commitment through the stress MAP kinase pathway and the Polo and Cdc2 kinases

Abstract

The coupling of growth to cell cycle progression allows eukaryotic cells to divide at particular sizes depending on nutrient availability. In fission yeast, this coupling involves the Spc1/Sty1 mitogen-activated protein kinase (MAPK) pathway working through Polo kinase recruitment to the spindle pole bodies (SPBs). Here we report that changes in nutrients influence TOR signalling, which modulates Spc1/Sty1 activity. Rapamycin-induced inhibition of TOR signalling advanced mitotic onset, mimicking the reduction in cell size at division seen after shifts to poor nitrogen sources. Gcn2, an effector of TOR signalling and modulator of translation, regulates the Pyp2 phosphatase that in turn modulates Spc1/Sty1 activity. Rapamycin- or nutrient-induced stimulation of Spc1/Sty1 activity promotes Polo kinase SPB recruitment and Cdc2 activation to advance mitotic onset. This advanced mitotic onset is abolished in cells depleted of Gcn2, Pyp2, or Spc1/Sty1 or on blockage of Spc1/Sty1-dependent Polo SPB recruitment. Therefore, TOR signalling modulates mitotic onset through the stress MAPK pathway via the Pyp2 phosphatase.

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Figure 1: Addition of rapamycin to reduce TOR signalling advances mitotic onset, leading to reduced cell size at division.
Figure 2: Inhibition of TOR signalling after nutrient shifts or addition of rapamycin.
Figure 3: Changes in nutrients or addition of rapamycin promote mitotic commitment through stress-pathway-dependent phosphorylation of Plo1 serine 402 and Cdc2 activation.
Figure 4: Changes in Pyp2 activity regulate Spc1/Sty1 activity and cell size at commitment to mitosis.
Figure 5: Pyp2 protein is regulated by nutrient shifts and altered TOR signalling.
Figure 6: Proposed signalling pathways.

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Acknowledgements

We thank Iain Hagan, Keith Gull, Hiro Ohkura, Paul Russell, Jonathan Millar, Ronit Weissmann, Mohan Balasubramanian, Erik Boye and Nic Jones for reagents; the Rockefeller University, the Breast Cancer Research Foundation, the University of Manchester and Nic Jones/Cancer Research UK for support; Iain Hagan for technical support; and Iain Hagan, Rafael Daga, Philip Woodman and Eileithyia Swanton for stimulating discussions and valuable comments on the manuscript.

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Correspondence to Janni Petersen.

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Supplementary figures S1, S2, S3, S4, S5, S6 and Supplementary table (PDF 1302 kb)

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Petersen, J., Nurse, P. TOR signalling regulates mitotic commitment through the stress MAP kinase pathway and the Polo and Cdc2 kinases. Nat Cell Biol 9, 1263–1272 (2007). https://doi.org/10.1038/ncb1646

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