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


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.

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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.

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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.

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Correspondence to Sophie G. Martin.

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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).

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