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.

  • Article
  • Published:

Chronophin, a novel HAD-type serine protein phosphatase, regulates cofilin-dependent actin dynamics

Nature Cell Biology volume 7, pages 21–29 (2005)Cite this article

Abstract

Cofilin is a key regulator of actin cytoskeletal dynamics whose activity is controlled by phosphorylation of a single serine residue. We report the biochemical isolation of chronophin (CIN), a unique cofilin-activating phosphatase of the haloacid dehalogenase (HAD) superfamily. CIN directly dephosphorylates cofilin with high specificity and colocalizes with cofilin in motile and dividing cells. Loss of CIN activity blocks phosphocycling of cofilin, stabilizes F-actin structures and causes massive cell division defects. Our findings identify a physiological phospho-serine protein substrate for a mammalian HAD-type phosphatase and demonstrate that CIN is an important novel regulator of cofilin-mediated actin reorganization.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: CIN is a cofilin phosphatase.
Figure 2: Effects of CIN on the actin cytoskeleton.
Figure 3: Subcellular localization of endogenous CIN.
Figure 4: CIN is targeted to sites of cofilin-dependent actin dynamics during mitosis.
Figure 5: CIN regulates cofilin-dependent cell division.
Figure 6: CIN induces cofilin-dependent multinucleation.
Figure 7: CIN controls cofilin phosphorylation during mitosis.
Figure 8: CIN regulates mitotic progression.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Bamburg, J. R. Proteins of the ADF/Cofilin family: Essential regulators of actin dynamics. Annu. Rev. Cell Dev. Biol. 15, 185–230 (1999).

    Article  CAS  Google Scholar 

  2. Carlier, M. -F. et al. Actin depolymerizing factor (ADF/Cofilin) enhances the rate of filament turnover: Implication in actin-based motility. J. Cell Biol. 136, 1307–1323 (1997).

    Article  CAS  Google Scholar 

  3. Lappalainen, P. & Drubin, D. G. Cofilin promotes rapid actin filament turnover in vivo. Nature 388, 78–82 (1997).

    Article  CAS  Google Scholar 

  4. Pollard, T. D. & Borisy, G. G. Cellular motility driven by assembly and disassembly of actin filaments. Cell 112, 453–465 (2003).

    Article  CAS  Google Scholar 

  5. Bamburg, J. R. & Wiggan, O'N. P. ADF/cofilin and actin dynamics in disease. Trends Cell Biol. 12, 598–605 (2002).

    Article  CAS  Google Scholar 

  6. Arber, S. et al. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature 393, 805–809 (1998).

    Article  CAS  Google Scholar 

  7. Yang, N. et al. Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature 393, 809–812 (1998).

    Article  CAS  Google Scholar 

  8. Toshima, J. et al. Cofilin phosphorylation by testicular protein kinase 1 and its role in integrin-mediated actin reorganization and focal adhesion formation. Mol. Biol. Cell 12, 1131–1145 (2001).

    Article  CAS  Google Scholar 

  9. Edwards, D. C., Sander, L. C., Bokoch, G. M. & Gill, G. N. Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nature Cell Biol. 1, 253–259 (1999).

    Article  CAS  Google Scholar 

  10. Maekawa, M. et al. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 285, 895–898 (1999).

    Article  CAS  Google Scholar 

  11. Niwa, R., Nagata-Ohashi, K., Takeichi, M., Mizuno, K. & Uemura, T. Control of actin reorganization by Slingshot, a family of phosphatases that dephosphorylate ADF/Cofilin. Cell 108, 233–246 (2002).

    Article  CAS  Google Scholar 

  12. Rogers, S. L., Wiedemann, U., Stuurman, N. & Vale, R. D. Molecular requirements for actin-based lamella formation in Drosophila S2 cells. J. Cell Biol. 162, 1079–1088 (2003).

    Article  CAS  Google Scholar 

  13. Zhan, Q., Bamburg, J. R. & Badwey, J. A. Products of phosphoinositide specific phospholipase C can trigger dephosphorylation of cofilin in chemoattractant stimulated neutrophils. Cell Motil. Cytoskeleton 54, 1–15 (2003).

    Article  CAS  Google Scholar 

  14. Aravind, L., Galperin, M. Y. & Koonin, E. V. The catalytic domain of the P-type ATPase has the haloacid dehalogenase fold. Trends Biochem. Sci. 23, 127–129 (1998).

    Article  CAS  Google Scholar 

  15. Collet, J. F., Stroobant, V. & Van Schaftingen, E. Mechanistic studies of phosphoserine phosphatase, an enzyme related to P-type ATPases. J. Biol. Chem. 274, 33985–33990 (1999).

    Article  CAS  Google Scholar 

  16. Li, X. et al. Eya protein phosphatase activity regulates Six1–Dach–Eya transcriptional effects in mammalian organogenesis. Nature 426, 247–254 (2003).

    Article  CAS  Google Scholar 

  17. Rayapureddi, J. P. et al. Eyes absent represents a class of protein tyrosine phosphatases. Nature 426, 295–298 (2003).

    Article  CAS  Google Scholar 

  18. Tootle, T. L. et al. The transcription factor Eyes absent is a protein tyrosine phosphatase. Nature 426, 299–302 (2003).

    Article  CAS  Google Scholar 

  19. Collet, J. F., Stroobant, V., Pirard, M., Delpierre, G. & Van Schaftingen, E. A new class of phosphotransferases phosphorylated on an aspartate residue in an amino-terminal DXDX(T/V) motif. J. Biol. Chem. 273, 14107–14112 (1998).

    Article  CAS  Google Scholar 

  20. Selengut, J. D. MDP-1 is a new and distinct member of the haloacid dehalogenase family of aspartate-dependent phosphohydrolases. Biochemistry 40, 12704–12711 (2001).

    Article  CAS  Google Scholar 

  21. Amano, T., Kaji, N., Ohashi, K. & Mizuno, K. Mitosis-specific activation of LIM motif-containing protein kinase and roles of cofilin phosphorylation and dephosphorylation in mitosis. J. Biol. Chem. 277, 22093–22102 (2002).

    Article  CAS  Google Scholar 

  22. Kaji, N. et al. Cell cycle-associated changes in Slingshot phosphatase activity and roles in cytokinesis in animal cells. J. Biol. Chem. 278, 33450–33455 (2003).

    Article  CAS  Google Scholar 

  23. Nagata-Ohashi, K. et al. A pathway of neuregulin-induced activation of cofilin-phosphatase Slingshot and cofilin in lamellipodia. J. Cell Biol. 165, 465–471 (2004).

    Article  Google Scholar 

  24. Nagaoka, R., Abe, H., Kusano, K. & Obinata, T. Concentration of cofilin, a small actin-binding protein, at the cleavage furrow during cytokinesis. Cell Motil. Cytoskeleton 30, 1–7 (1995).

    Article  CAS  Google Scholar 

  25. Gunsalus, K. C. et al. Mutations in twinstar, a Drosophila gene encoding a cofilin/ADF homologue, result in defects in centrosome migration and cytokinesis. J. Cell Biol. 131, 1243–1259 (1995).

    Article  CAS  Google Scholar 

  26. Clute, P. & Pines, J. Temporal and spatial control of cyclin B1 destruction in metaphase. Nature Cell Biol. 1, 82–87 (1999).

    Article  CAS  Google Scholar 

  27. Brodeur, G. M. Neuroblastoma: Biological insights into a clinical enigma. Nature Rev. Cancer 3, 203–216 (2003).

    Article  CAS  Google Scholar 

  28. Hittmair, A., Rogatsch, H., Feichtinger, H., Hobisch, A. & Mikuz, G. Testicular seminomas are aneuploid tumors. Lab. Invest. 72, 70–74 (1995).

    CAS  PubMed  Google Scholar 

  29. Gohla, A. & Bokoch, G. M. 14–3-3 regulates actin dynamics by stabilizing phosphorylated cofilin. Curr. Biol. 12, 1704–1710 (2002).

    Article  CAS  Google Scholar 

  30. Ambach, A. et al. The serine phosphatases PP1 and PP2A associate with and activate the actin-binding protein cofilin in human T lymphocytes. Eur. J. Immunol. 30, 3422–3431 (2000).

    Article  CAS  Google Scholar 

  31. Jang, Y. M. et al. Human pyridoxal phosphatase. Molecular cloning, functional expression, and tissue distribution. J. Biol. Chem. 278, 50040–50046 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by US Public Health Service grants GM39434 and GM44428 to G.M.B., by the Deutsche Forschungsgemeinschaft with an Emmy-Noether Postdoctoral Fellowship (GO 966) to A.G and by a postdoctoral fellowship (BI 814) to J.B. This is publication number 16968-IMM from The Scripps Research Institute.

Author information

Authors and Affiliations

  1. Departments of Immunology and Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, CA, USA

    Antje Gohla, Jörg Birkenfeld & Gary M. Bokoch

Authors
  1. Antje Gohla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jörg Birkenfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gary M. Bokoch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gary M. Bokoch.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Fig S1, Fig S2, Fig S3, Fig S4, Table S1 (PDF 1459 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gohla, A., Birkenfeld, J. & Bokoch, G. Chronophin, a novel HAD-type serine protein phosphatase, regulates cofilin-dependent actin dynamics. Nat Cell Biol 7, 21–29 (2005). https://doi.org/10.1038/ncb1201

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1201

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