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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 644–651 (2009)Cite this article

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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Figure 1: Dephosphorylation of mitotic phosphoproteins by okadaic acid-sensitive phosphatase activity.
Figure 2: PP1 is required for the dephosphorylation of substrates at mitotic, but not meiotic, exit.
Figure 3: Cdc2 regulation of PP1 prevents premature substrate dephosphorylation in mitosis.
Figure 4: PP1 auto-dephosphorylation and inhibitor-1 dephosphorylation control PP1-regulated Cdc2 substrate dephosphorylation.
Figure 5: Cell-cycle regulation of inhibitor-1.

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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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  1. Judy Qiju Wu, Jessie Yanxiang Guo and Wanli Tang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, 27710, NC, 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, 06508, CT, 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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Correspondence to Sally Kornbluth.

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Wu, J., Guo, J., Tang, W. et al. PP1-mediated dephosphorylation of phosphoproteins at mitotic exit is controlled by inhibitor-1 and PP1 phosphorylation. Nat Cell Biol 11, 644–651 (2009). https://doi.org/10.1038/ncb1871

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