Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Polar gradients of the DYRK-family kinase Pom1 couple cell length with the cell cycle

Nature volume 459, pages 852–856 (2009)Cite this article

Abstract

Cells normally grow to a certain size before they enter mitosis and divide. Entry into mitosis depends on the activity of Cdk1, which is inhibited by the Wee1 kinase and activated by the Cdc25 phosphatase1. However, how cells sense their size for mitotic commitment remains unknown. Here we show that an intracellular gradient of the dual-specificity tyrosine-phosphorylation regulated kinase (DYRK) Pom1, which emanates from the ends of rod-shaped Schizosaccharomyces pombe cells, serves to measure cell length and control mitotic entry. Pom1 provides positional information both for polarized growth and to inhibit cell division at cell ends2,3,4,5. We discovered that Pom1 is also a dose-dependent G2–M inhibitor. Genetic analyses indicate that Pom1 negatively regulates Cdr1 and Cdr2, two previously described Wee1 inhibitors of the SAD kinase family6,7,8,9,10. This inhibition may be direct, because in vivo and in vitro evidence suggest that Pom1 phosphorylates Cdr2. Whereas Cdr1 and Cdr2 localize to a medial cortical region, Pom1 forms concentration gradients from cell tips that overlap with Cdr1 and Cdr2 in short cells, but not in long cells. Disturbing these Pom1 gradients leads to Cdr2 phosphorylation and imposes a G2 delay. In short cells, Pom1 prevents precocious M-phase entry, suggesting that the higher medial Pom1 levels inhibit Cdr2 and promote a G2 delay. Thus, gradients of Pom1 from cell ends provide a measure of cell length to regulate M-phase entry.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Pom1 is a dose-dependent inhibitor of entry into mitosis and phosphorylates Cdr2.
Figure 2: Ectopic localization of Pom1 to the cell middle imposes a G2 delay.
Figure 3: Pom1 overlaps with Cdr2 and prevents mitosis in small cells.

References

  1. Nurse, P. Universal control mechanism regulating onset of M-phase. Nature 344, 503–508 (1990)

    Article  ADS  CAS  Google Scholar 

  2. Bähler, J. & Pringle, J. R. Pom1p, a fission yeast protein kinase that provides positional information for both polarized growth and cytokinesis. Genes Dev. 12, 1356–1370 (1998)

    Article  Google Scholar 

  3. Celton-Morizur, S., Racine, V., Sibarita, J. B. & Paoletti, A. Pom1 kinase links division plane position to cell polarity by regulating Mid1p cortical distribution. J. Cell Sci. 119, 4710–4718 (2006)

    Article  CAS  Google Scholar 

  4. Huang, Y., Chew, T. G., Ge, W. & Balasubramanian, M. K. Polarity determinants Tea1p, Tea4p, and Pom1p inhibit division-septum assembly at cell ends in fission yeast. Dev. Cell 12, 987–996 (2007)

    Article  CAS  Google Scholar 

  5. Padte, N. N., Martin, S. G., Howard, M. & Chang, F. The cell-end factor Pom1p inhibits Mid1p in specification of the cell division plane in fission yeast. Curr. Biol. 16, 2480–2487 (2006)

    Article  CAS  Google Scholar 

  6. Coleman, T. R., Tang, Z. & Dunphy, W. G. Negative regulation of the wee1 protein kinase by direct action of the nim1/cdr1 mitotic inducer. Cell 72, 919–929 (1993)

    Article  CAS  Google Scholar 

  7. Parker, L. L., Walter, S. A., Young, P. G. & Piwnica-Worms, H. Phosphorylation and inactivation of the mitotic inhibitor Wee1 by the nim1/cdr1 kinase. Nature 363, 736–738 (1993)

    Article  ADS  CAS  Google Scholar 

  8. Wu, L. & Russell, P. Nim1 kinase promotes mitosis by inactivating Wee1 tyrosine kinase. Nature 363, 738–741 (1993)

    Article  ADS  CAS  Google Scholar 

  9. Breeding, C. S. et al. The cdr2+ gene encodes a regulator of G2/M progression and cytokinesis in Schizosaccharomyces pombe . Mol. Biol. Cell 9, 3399–3415 (1998)

    Article  CAS  Google Scholar 

  10. Kanoh, J. & Russell, P. The protein kinase Cdr2, related to Nim1/Cdr1 mitotic inducer, regulates the onset of mitosis in fission yeast. Mol. Biol. Cell 9, 3321–3334 (1998)

    Article  CAS  Google Scholar 

  11. Petersen, J. & Hagan, I. M. Polo kinase links the stress pathway to cell cycle control and tip growth in fission yeast. Nature 435, 507–512 (2005)

    Article  ADS  CAS  Google Scholar 

  12. Shiozaki, K. & Russell, P. Cell-cycle control linked to extracellular environment by MAP kinase pathway in fission yeast. Nature 378, 739–743 (1995)

    Article  ADS  CAS  Google Scholar 

  13. Wu, L. & Russell, P. Nif1, a novel mitotic inhibitor in Schizosaccharomyces pombe . EMBO J. 16, 1342–1350 (1997)

    Article  CAS  Google Scholar 

  14. Bähler, J. & Nurse, P. Fission yeast Pom1p kinase activity is cell cycle regulated and essential for cellular symmetry during growth and division. EMBO J. 20, 1064–1073 (2001)

    Article  Google Scholar 

  15. Lundgren, K. et al. mik1 and wee1 cooperate in the inhibitory tyrosine phosphorylation of cdc2. Cell 64, 1111–1122 (1991)

    Article  CAS  Google Scholar 

  16. Parker, L. L., Atherton-Fessler, S. & Piwnica-Worms, H. p107wee1 is a dual-specificity kinase that phosphorylates p34cdc2 on tyrosine 15. Proc. Natl Acad. Sci. USA 89, 2917–2921 (1992)

    Article  ADS  CAS  Google Scholar 

  17. Morrell, J. L., Nichols, C. B. & Gould, K. L. The GIN4 family kinase, Cdr2p, acts independently of septins in fission yeast. J. Cell Sci. 117, 5293–5302 (2004)

    Article  CAS  Google Scholar 

  18. Tatebe, H., Shimada, K., Uzawa, S., Morigasaki, S. & Shiozaki, K. Wsh3/Tea4 is a novel cell-end factor essential for bipolar distribution of Tea1 and protects cell polarity under environmental stress in S. pombe . Curr. Biol. 15, 1006–1015 (2005)

    Article  CAS  Google Scholar 

  19. Martin, S. G., McDonald, W. H., Yates, J. R. & Chang, F. Tea4p links microtubule plus ends with the formin for3p in the establishment of cell polarity. Dev. Cell 8, 479–491 (2005)

    Article  CAS  Google Scholar 

  20. Mata, J. & Nurse, P. tea1 and the microtubular cytoskeleton are important for generating global spatial order within the fission yeast cell. Cell 89, 939–949 (1997)

    Article  CAS  Google Scholar 

  21. Russell, P. & Nurse, P. Negative regulation of mitosis by wee1+, a gene encoding a protein kinase homolog. Cell 49, 559–567 (1987)

    Article  CAS  Google Scholar 

  22. Tapon, N., Moberg, K. H. & Hariharan, I. K. The coupling of cell growth to the cell cycle. Curr. Opin. Cell Biol. 13, 731–737 (2001)

    Article  CAS  Google Scholar 

  23. Kalab, P., Pralle, A., Isacoff, E. Y., Heald, R. & Weis, K. Analysis of a RanGTP-regulated gradient in mitotic somatic cells. Nature 440, 697–701 (2006)

    Article  ADS  CAS  Google Scholar 

  24. Fuller, B. G. et al. Midzone activation of aurora B in anaphase produces an intracellular phosphorylation gradient. Nature 453, 1132–1136 (2008)

    Article  ADS  CAS  Google Scholar 

  25. Souza, G. M., Lu, S. & Kuspa, A. YakA, a protein kinase required for the transition from growth to development in Dictyostelium . Development 125, 2291–2302 (1998)

    CAS  PubMed  Google Scholar 

  26. Pellettieri, J., Reinke, V., Kim, S. K. & Seydoux, G. Coordinate activation of maternal protein degradation during the egg-to-embryo transition in C. elegans . Dev. Cell 5, 451–462 (2003)

    Article  CAS  Google Scholar 

  27. Mercer, S. E. & Friedman, E. Mirk/Dyrk1B: a multifunctional dual-specificity kinase involved in growth arrest, differentiation, and cell survival. Cell Biochem. Biophys. 45, 303–315 (2006)

    Article  CAS  Google Scholar 

  28. Kishi, M., Pan, Y. A., Crump, J. G. & Sanes, J. R. Mammalian SAD kinases are required for neuronal polarization. Science 307, 929–932 (2005)

    Article  ADS  CAS  Google Scholar 

  29. Lew, D. J. The morphogenesis checkpoint: how yeast cells watch their figures. Curr. Opin. Cell Biol. 15, 648–653 (2003)

    Article  CAS  Google Scholar 

  30. Bähler, J. et al. Heterologous modules for efficient and versatile PCR-based gene targeting in Schizosaccharomyces pombe . Yeast 14, 943–951 (1998)

    Article  Google Scholar 

  31. Snaith, H. A., Samejima, I. & Sawin, K. E. Multistep and multimode cortical anchoring of tea1p at cell tips in fission yeast. EMBO J. 24, 3690–3699 (2005)

    Article  CAS  Google Scholar 

  32. Wu, J. Q. et al. Assembly of the cytokinetic contractile ring from a broad band of nodes in fission yeast. J. Cell Biol. 174, 391–402 (2006)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We wish to thank J. Bähler, F. Chang, P. Cruz, K. Gull, I. Hagan, P. Russell, K. Shiozaki and V. Simanis for strains and reagents. We thank R. Benton, F. Chang, C. Fankhauser, N. Hernandez and F. Bendezu for critical reading of the manuscript. We also wish to thank J. Moseley and P. Nurse for open discussion before publication. Research in the laboratory of S.G.M. is supported by a Swiss National Science Foundation Professorship grant (PP00A–114936) and a Human Frontiers Science Program Career Development Award (CDA0016/2008).

Author Contributions S.G.M. conceived the project, and designed and analysed the experiments. S.G.M. and M.B.G. performed the experiments. The manuscript was written by S.G.M. with input from M.B.G.

Author information

Authors and Affiliations

  1. Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Génopode Building, 1015 Lausanne, Switzerland ,

    Sophie G. Martin & Martine Berthelot-Grosjean

Authors
  1. Sophie G. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martine Berthelot-Grosjean
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sophie G. Martin.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-9 with Legends and Supplementary Table 1. (PDF 6051 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Martin, S., Berthelot-Grosjean, M. Polar gradients of the DYRK-family kinase Pom1 couple cell length with the cell cycle. Nature 459, 852–856 (2009). https://doi.org/10.1038/nature08054

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature08054

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing