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.

Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase

Abstract

Cell division, cell motility and the formation and maintenance of specialized structures in differentiated cells depend directly on the regulated dynamics of the actin cytoskeleton1,2. To understand the mechanisms of these basic cellular processes, the signalling pathways that link external signals to the regulation of the actin cytoskeleton need to be characterized2,3. Here we identify a pathway for the regulation of cofilin, a ubiquitous actin-binding protein that is essential for effective depolymerization of actin filaments4,5,6,7,8. LIM-kinase 1, also known as KIZ, is a protein kinase with two amino-terminal LIM motifs9,10,11 that induces stabilization of F-actin structures in transfected cells. Dominant-negative LIM-kinase1 inhibits the accumulation of the F-actin. Phosphorylation experiments in vivo and in vitro provide evidence that cofilin is a physiological substrate of LIM-kinase 1. Phosphorylation by LIM-kinase 1 inactivates cofilin, leading to accumulation of actin filaments. Constitutively active Rac augmented cofilin phosphorylation and LIM-kinase 1 autophosphorylation whereas phorbol ester inhibited these processes. Our results define a mechanism for the regulation of cofilin and hence of actin dynamics in vivo. By modulating the stability of actin cytoskeletal structures, this pathway should play a central role in regulating cell motility and morphogenesis.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: LIMK-1 induces accumulation of the actin cytoskeleton in transfected cells.
Figure 2: LIMK-1 promotes phosphorylation of cofilin in vivo and in vitro, and inactivation of cofilin in situ.
Figure 3: LIM-kinases stabilize the actin cytoskeleton through inactivation of cofilin.
Figure 4: PMA and activated Rac affect LIMK-1 activity and cofilin phosphorylation.

Similar content being viewed by others

References

  1. Michison, T. J. & Cramer, L. P. Actin-based cell motility and cell locomotion. Cell 84, 371–379 (1996).

    Article  Google Scholar 

  2. Welch, M. D., Mallavarapu, A., Rosenblatt, J. & Mitchison, T. J. Actin dynamics in vivo. Curr. Opin. Cell Biol. 9, 54–61 (1997).

    Article  CAS  Google Scholar 

  3. Tapon, N. & Hall, A. Rho, Rac and cdc42 GTPases regulate the organization of the actin cytoskeleton. Curr. Opin. Cell Biol. 9, 86–92 (1997).

    Article  CAS  Google Scholar 

  4. Moon, A. & Drubin, D. G. The ADF/cofilin proteins: stimulus-responsive modulators of actin dynamics. Mol. Biol. Cell 6, 1423–1431 (1995).

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  6. Rosenblatt, J., Agnew, B. J., Abe, H., Bamburg, J. R. & Mitchison, T. J. Xenopus actin depolymerizing factor/cofilin (XAC) is responsible for the turnover of actin filaments in Listeria monocytogenes tails. J. Cell Biol. 136, 1323–1332 (1997).

    Article  CAS  Google Scholar 

  7. 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 

  8. Theriot, J. A. Accelerating on a treadmill: ADF/cofilin promotes rapid actin filament turnover in the dynamic cytoskeleton. J. Cell Biol. 136, 1165–1168 (1997).

    Article  CAS  Google Scholar 

  9. Bernard, O., Ganiatsas, S., Kannourakis, G. & Dringen, R. Kiz-1, a protein with LIM zinc finger and kinase domains, is expressed mainly in neurons. Cell Growth Differ. 5, 1159–1171 (1994).

    CAS  PubMed  Google Scholar 

  10. Mizuno, K. et al. Identification of a human cDNA encoding a novel protein kinase with two repeats of the LIM/double zinc finger motif. Oncogene 9, 1605–1612 (1994).

    CAS  PubMed  Google Scholar 

  11. David, I. B., Toyama, R. & Taira, M. LIM domain proteins. C.R. Acad. Sci. 318, 295–306 (1995).

    Google Scholar 

  12. Okano, I. et al. Identification and characterization of a novel family of serine/threonine kinases containing two N-terminal LIM motifs. J. Biol. Chem. 270, 31321–31330 (1995).

    Article  CAS  Google Scholar 

  13. Arber, S. & Caroni, P. Specificity of single LIM motifs in targeting and LIM/LIM interactions in situ. Genes Dev. 10, 289–300 (1996).

    Article  CAS  Google Scholar 

  14. Arber, S. et al. MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure. Cell 88, 393–403 (1997).

    Article  CAS  Google Scholar 

  15. Tanaka, E. & Sabry, J. Making the connection: cytoskeletal rearrangements during growth cone guidance. Cell 83, 171–176 (1995).

    Article  CAS  Google Scholar 

  16. 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 

  17. Morgan, T. E., Lockerbie, R. O., Minamide, L. S., Browning, M. D. & Bamburg, J. R. Isolation and characterization of a regulated form of actin depolymerizing factor. J. Cell Biol. 122, 623–633 (1993).

    Article  CAS  Google Scholar 

  18. Abe, H., Obinata, T., Minamide, L. S. & Bamburg, J. R. Xenopus laevis actin-depolymerizing factor/cofilin: a phosphorylation-regulated protein essential for development. J. Cell Biol. 132, 871–885 (1996).

    Article  CAS  Google Scholar 

  19. Agnew, B. J., Minamide, L. S. & Bamburg, J. R. Reactivation of phosphorylated actin depolymerizing factor and identification of the regulatory site. J. Biol. Chem. 270, 17582–17587 (1995).

    Article  CAS  Google Scholar 

  20. Nagoaka, R., Abe, H., Kusano, K. & Obinata, T. Effects of cofilin on actin filamentous structures in cultured muscle cells. J. Cell Sci. 108, 581–593 (1995).

    Google Scholar 

  21. Nebl, G., Meuer, S. C. & Samstag, Y. Dephosphorylation of serine 3 regulates nuclear translocation of cofilin. J. Biol. Chem. 271, 26276–26280 (1996).

    Article  CAS  Google Scholar 

  22. vonArx, P., Bantle, S., Soldati, T. & Perriard, J.-C. Dominant negative effect of cytoplasmic actin isoproteins on cardiomyocyte cytoarchitecture and function. J. Cell Biol. 131, 1759–1773 (1995).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Adams, T. Jessell, W. Krek, U. Müller and G. Thomas for comments on the manuscript. S.A. and H.H. were supported by grants from the Swiss Foundation for Research on Muscle Diseases. O.B. was supported by the Australian NH-MRC, and the Australian Cooperative Research Centre Scheme, and O.B. and C.A.S. were supported by the National Multiple Sclerosis Society of Australia.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Pico Caroni.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arber, S., Barbayannis, F., Hanser, H. et al. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature 393, 805–809 (1998). https://doi.org/10.1038/31729

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/31729

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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