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PP1-mediated dephosphorylation of phosphoproteins at mitotic exit is controlled by inhibitor-1 and PP1 phosphorylation

Nature Cell Biology volume 11, pages 644651 (2009) | Download Citation

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Abstract

Loss of cell division cycle 2 (Cdc2, also known as Cdk1) activity after cyclin B degradation is necessary, but not sufficient, for mitotic exit. Proteins phosphorylated by Cdc2 and downstream mitotic kinases must be dephosphorylated. We report here that protein phosphatase-1 (PP1) is the main catalyst of mitotic phosphoprotein dephosphorylation. Suppression of PP1 during early mitosis is maintained through dual inhibition by Cdc2 phosphorylation and the binding of inhibitor-1. Protein kinase A (PKA) phosphorylates inhibitor-1, mediating binding to PP1. As Cdc2 levels drop after cyclin B degradation, auto-dephosphorylation of PP1 at its Cdc2 phosphorylation site (Thr 320) allows partial PP1 activation. This promotes PP1-regulated dephosphorylation at the activating site of inhibitor-1 (Thr 35) followed by dissociation of the inhibitor-1–PP1 complex and then full PP1 activation to promote mitotic exit. Thus, Cdc2 both phosphorylates multiple mitotic substrates and inhibits their PP1-mediated dephosphorylation.

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Acknowledgements

This work was supported by NIH grants to S.K. (RO1 GM67225) and A.C.N. (DA10044).

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Author notes

    • Judy Qiju Wu
    • , Jessie Yanxiang Guo
    •  & Wanli Tang

    These authors contributed equally to this work.

Affiliations

  1. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.

    • Judy Qiju Wu
    • , Jessie Yanxiang Guo
    • , Wanli Tang
    • , Chih-Sheng Yang
    • , Christopher D. Freel
    • , Chen Chen
    •  & Sally Kornbluth
  2. Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508, USA.

    • Angus C. Nairn

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Contributions

J.Q.W., J.Y.G., WT., A.C.N. and S.K. designed the experiments; J.Q.W., J.Y.G., W.T., C.Y. and C.C. performed experiments; A.C.N. contributed reagents; C.D.F. analysed data; J.Q.W. and S.K. wrote and J.Y.G., W.T. and A.C.N. edited the manuscript.

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Sally Kornbluth.

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DOI

https://doi.org/10.1038/ncb1871

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