Nothing Special   »   [go: up one dir, main page]
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.

  • Letter
  • Published:

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.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

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.

Similar content being viewed by others

References

  1. Lew, D. J. & Kornbluth, S. Regulatory roles of cyclin dependent kinase phosphorylation in cell cycle control. Curr. Opin. Cell Biol. 8, 795–804 (1996).

    Article  CAS  Google Scholar 

  2. Azzam, R. et al. Phosphorylation by cyclin B-Cdk underlies release of mitotic exit activator Cdc14 from the nucleolus. Science 305, 516–519 (2004).

    Article  CAS  Google Scholar 

  3. Amon, A. A decade of Cdc14—a personal perspective. FEBS J. 275, 5774–5784 (2008).

    Article  CAS  Google Scholar 

  4. Queralt, E. & Uhlmann, F. Cdk-counteracting phosphatases unlock mitotic exit. Curr. Opin. Cell Biol. 20, 661–668 (2008).

    Article  CAS  Google Scholar 

  5. Trautmann, S. & McCollum, D. Cell cycle: new functions for Cdc14 family phosphatases. Curr. Biol. 12, R733–735 (2002).

    Article  CAS  Google Scholar 

  6. Axton, J. M., Dombradi, V., Cohen, P. T. & Glover, D. M. One of the protein phosphatase 1 isoenzymes in Drosophila is essential for mitosis. Cell 63, 33–46 (1990).

    Article  CAS  Google Scholar 

  7. Bailis, J. M. & Roeder, G. S. Pachytene exit controlled by reversal of Mek1-dependent phosphorylation. Cell 101, 211–221 (2000).

    Article  CAS  Google Scholar 

  8. Chen, F. et al. Multiple protein phosphatases are required for mitosis in Drosophila. Curr. Biol. 17, 293–303 (2007).

    Article  Google Scholar 

  9. Doonan, J. H. & Morris, N. R. The bimG gene of Aspergillus nidulans, required for completion of anaphase, encodes a homolog of mammalian phosphoprotein phosphatase 1. Cell 57, 987–996 (1989).

    Article  CAS  Google Scholar 

  10. Che, S. et al. A phosphatase activity in Xenopus oocyte extracts preferentially dephosphorylates the MPM-2 epitope. FEBS Lett. 424, 225–233 (1998).

    Article  CAS  Google Scholar 

  11. Skoufias, D. A., Indorato, R. L., Lacroix, F., Panopoulos, A. & Margolis, R. L. Mitosis persists in the absence of Cdk1 activity when proteolysis or protein phosphatase activity is suppressed. J. Cell Biol. 179, 671–685 (2007).

    Article  CAS  Google Scholar 

  12. Mochida, S. & Hunt, T. Calcineurin is required to release Xenopus egg extracts from meiotic M phase. Nature 449, 336–340 (2007).

    Article  CAS  Google Scholar 

  13. Nishiyama, T., Yoshizaki, N., Kishimoto, T. & Ohsumi, K. Transient activation of calcineurin is essential to initiate embryonic development in Xenopus laevis. Nature 449, 341–345 (2007).

    Article  CAS  Google Scholar 

  14. Kwon, Y. G., Lee, S. Y., Choi, Y., Greengard, P. & Nairn, A. C. Cell cycle-dependent phosphorylation of mammalian protein phosphatase 1 by cdc2 kinase. Proc. Natl Acad. Sci. USA 94, 2168–2173 (1997).

    Article  CAS  Google Scholar 

  15. Dohadwala, M. et al. Phosphorylation and inactivation of protein phosphatase 1 by cyclin-dependent kinases. Proc. Natl Acad. Sci. USA 91, 6408–6412 (1994).

    Article  CAS  Google Scholar 

  16. Wu, Q. et al. A role for Cdc2- and PP2A-mediated regulation of Emi2 in the maintenance of CSF arrest. Curr. Biol. 17, 213–224 (2007).

    Article  CAS  Google Scholar 

  17. Margolis, S. S. et al. A role for PP1 in the Cdc2/Cyclin B-mediated positive feedback activation of Cdc25. Mol. Biol. Cell 17, 1779–1789 (2006).

    Article  CAS  Google Scholar 

  18. Margolis, S.S. et al. PP1 control of M phase entry exerted through 14-3-3-regulated Cdc25 dephosphorylation. EMBO J. 22, 5734–5745 (2003).

    Article  CAS  Google Scholar 

  19. Snyder, G. L. et al. Phosphorylation of DARPP-32 and protein phosphatase inhibitor-1 in rat choroid plexus: regulation by factors other than dopamine. J. Neurosci. 12, 3071–3083 (1992).

    Article  CAS  Google Scholar 

  20. Ceulemans, H. & Bollen, M. Functional diversity of protein phosphatase-1, a cellular economizer and reset button. Physiol. Rev. 84, 1–39 (2004).

    Article  CAS  Google Scholar 

  21. Kotani, S. et al. PKA and MPF-activated polo-like kinase regulate anaphase-promoting complex activity and mitosis progression. Mol. Cell 1, 371–380 (1998).

    Article  CAS  Google Scholar 

  22. Stegmeier, F. & Amon, A. Closing mitosis: the functions of the Cdc14 phosphatase and its regulation. Annu. Rev. Genet. 38, 203–232 (2004).

    Article  CAS  Google Scholar 

  23. El-Armouche, A. et al. Role of calcineurin and protein phosphatase-2A in the regulation of phosphatase inhibitor-1 in cardiac myocytes. Biochem. Biophys. Res. Commun. 346, 700–706 (2006).

    Article  CAS  Google Scholar 

  24. Higuchi, E., Nishi, A., Higashi, H., Ito, Y. & Kato, H. Phosphorylation of protein phosphatase-1 inhibitors, inhibitor-1 and DARPP-32, in renal medulla. Eur. J. Pharmacol. 408, 107–116 (2000).

    Article  CAS  Google Scholar 

  25. Bibb, J. A. et al. Phosphorylation of protein phosphatase inhibitor-1 by Cdk5. J. Biol. Chem. 276, 14490–14497 (2001).

    Article  CAS  Google Scholar 

  26. Bianchi, M. & Villa-Moruzzi, E. Binding of phosphatase-1 delta to the retinoblastoma protein pRb involves domains that include substrate recognition residues and a pRB binding motif. Biochem. Biophys. Res. Commun. 280, 1–3 (2001).

    Article  CAS  Google Scholar 

  27. Wolfe, B. A., McDonald, W. H., Yates, J. R., 3rd & Gould, K. L. Phospho-regulation of the Cdc14/Clp1 phosphatase delays late mitotic events in S. pombe. Dev. Cell 11, 423–430 (2006).

    Article  CAS  Google Scholar 

  28. Casaletto, J. B. et al. Inhibition of the anaphase-promoting complex by the Xnf7 ubiquitin ligase. J. Cell Biol. 169, 61–71 (2005).

    Article  CAS  Google Scholar 

  29. Murray, A. W. Cell cycle extracts. Methods Cell Biol. 36, 581–605 (1991).

    Article  CAS  Google Scholar 

  30. Gustafson, E. L. et al. Immunocytochemical localization of phophatase inhibitor-1 in rat brain. J. Comp. Neurol. 310, 170–188 (1991).

    Article  CAS  Google Scholar 

  31. Snyder, G. L. et al. Phosphorylation of DARPP-32 and protein phosphatase inhibitor-1 in rat choroid plexus: regulation by factors other than dopamine. J. Neurosci. 12, 3071–3083 (1992).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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

Author information

Author notes

  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

Authors
  1. Judy Qiju Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jessie Yanxiang Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wanli Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chih-Sheng Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christopher D. Freel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Angus C. Nairn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sally Kornbluth
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Sally Kornbluth.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 395 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1871

This article is cited by

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