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Cdk and APC activities limit the spindle-stabilizing function of Fin1 to anaphase

Nature Cell Biology volume 9, pages 106–112 (2007)Cite this article

Abstract

The fidelity of chromosome segregation depends on proper regulation of mitotic spindle behaviour. In anaphase, spindle stability is promoted by the dephosphorylation of cyclin-dependent kinase (Cdk) substrates, which results from Cdk inactivation and phosphatase activation1,2,3,4. Few of the critical Cdk targets have been identified3,5,6. Here, we identify the budding-yeast protein Fin1 (ref. 7) as a spindle-stabilizing protein whose activity is strictly limited to anaphase by changes in its phosphorylation state and rate of degradation. Phosphorylation of Fin1 from S phase to metaphase, by the cyclin-dependent kinase Clb5–Cdk1, inhibits Fin1 association with the spindle. In anaphase, when Clb5–Cdk1 is inactivated, Fin1 is dephosphorylated by the phosphatase Cdc14. Fin1 dephosphorylation targets it to the poles and microtubules of the elongating spindle, where it contributes to spindle integrity. A non-phosphorylatable Fin1 mutant localizes to the spindle before anaphase and impairs efficient chromosome segregation. As cells complete mitosis and disassemble the spindle, the ubiqutin ligase APCCdh1 targets Fin1 for destruction. Our studies illustrate how phosphorylation-dependent changes in the behaviour of Cdk1 substrates influence complex mitotic processes.

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Figure 1: Fin1 phosphorylation and spindle association are cell-cycle regulated and depend on Cdc14.
Figure 2: Mutation of Cdk1 sites on Fin1 creates a non-phosphorylated dominant-lethal mutant that localizes prematurely to spindles.
Figure 3: Non-phosphorylated Fin1 promotes spindle stability.
Figure 4: Fin1 binds and stabilizes microtubules.
Figure 5: Fin1 proteolysis depends on APCCdh1 and a destruction box.

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Acknowledgements

We thank P. Heiter and F. Uhlmann for yeast strains, S. Reck-Peterson and the Ron Vale lab for reagents and technical assistance with microtubule-binding assays, and the Peter Walter lab for the use of their microscope. We thank members of the Morgan lab for thoughtful discussions and critical reading of the manuscript. This work was supported by funding from the National Institute of General Medical Sciences (GM50684).

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  1. Departments of Physiology and Biochemistry & Biophysics, University of California, UCSF Mailcode 2200, Genentech Hall Room N312B, 600 16th Street, San Francisco, 94158-2517, CA, USA

    Erika L. Woodbury & David O. Morgan

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  1. Erika L. Woodbury
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  2. David O. Morgan
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E.L.W. performed all experiments and wrote the manuscript under the guidance of D.O.M.

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Correspondence to David O. Morgan.

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Woodbury, E., Morgan, D. Cdk and APC activities limit the spindle-stabilizing function of Fin1 to anaphase. Nat Cell Biol 9, 106–112 (2007). https://doi.org/10.1038/ncb1523

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