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:

p53-cofactor JMY is a multifunctional actin nucleation factor

Abstract

Many cellular structures are assembled from networks of actin filaments, and the architecture of these networks depends on the mechanism by which the filaments are formed. Several classes of proteins are known to assemble new filaments, including the Arp2/3 complex, which creates branched filament networks, and Spire, which creates unbranched filaments1,2. We find that JMY, a vertebrate protein first identified as a transcriptional co-activator of p53, combines these two nucleating activities by both activating Arp2/3 and assembling filaments directly using a Spire-like mechanism. Increased levels of JMY expression enhance motility, whereas loss of JMY slows cell migration. When slowly migrating HL-60 cells are differentiated into highly motile neutrophil-like cells, JMY moves from the nucleus to the cytoplasm and is concentrated at the leading edge. Thus, JMY represents a new class of multifunctional actin assembly factor whose activity is regulated, at least in part, by sequestration in the nucleus.

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: JMY nucleates actin filaments and activates the Arp2/3 complex.
Figure 2: Mechanistic dissection of JMY.
Figure 3: JMY nucleates actin by the same mechanism as Spire.
Figure 4: JMY localizes to the leading edge of motile cells.
Figure 5: JMY contributes to cell motility.

Similar content being viewed by others

References

  1. Welch, M. & Mullins, R. Cellular control of actin nucleation. Annu. Rev. Cell Dev. Biol. 18, 247–288 (2002).

    Article  CAS  Google Scholar 

  2. Quinlan, M. E., Heuser, J. E., Kerkhoff, E. & Mullins, R. D. Drosophila Spire is an actin nucleation factor. Nature 433, 382–388 (2005).

    Article  CAS  Google Scholar 

  3. Marchand, J. B., Kaiser, D. A., Pollard, T. D. & Higgs, H. N. Interaction of WASP/Scar proteins with actin and vertebrate Arp2/3 complex. Nature Cell Biol. 3, 76–82 (2001).

    Article  CAS  Google Scholar 

  4. Shikama, N. et al. A novel cofactor for p300 that regulates the p53 response. Mol. Cell 4, 365–376 (1999).

    Article  CAS  Google Scholar 

  5. Coutts, A., Boulahbel, H., Graham, A. & La Thangue, N. Mdm2 targets the p53 transcription cofactor JMY for degradation. EMBO Rep. 8, 84–90 (2006).

    Article  Google Scholar 

  6. Symons, M. et al. Wiskott–Aldrich syndrome protein, a novel effector for the GTPase CDC42Hs, is implicated in actin polymerization. Cell 84, 723–734 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Cooper, J. & Pollard, T. Effect of capping protein on the kinetics of actin polymerization. Biochemistry 24, 793–799 (1985).

    Article  CAS  Google Scholar 

  9. Pan, F., Egile, C., Lipkin, T. & Li, R. ARPC1/Arc40 mediates the interaction of the actin-related protein 2 and 3 complex with Wiskott–Aldrich syndrome protein family activators. J. Biol. Chem. 279, 54629–54636 (2004).

    Article  CAS  Google Scholar 

  10. Ahuja, R. et al. Cordon-Bleu is an actin nucleation factor and controls neuronal morphology. Cell 131, 337–350 (2007).

    Article  CAS  Google Scholar 

  11. Collins, S., Ruscetti, F., Gallagher, R. & Gallo, R. Normal functional characteristics of cultured human promyelocytic leukemia cells (HL-60) after induction of differentiation by dimethylsulfoxide. J. Exp. Med. 149, 969–974 (1979).

    Article  CAS  Google Scholar 

  12. Kowalski, J. R. et al. Cortactin regulates cell migration through activation of N-WASP. J. Cell Sci. 118, 79–87 (2005).

    Article  CAS  Google Scholar 

  13. Sablina, A., Chumakov, P. & Kopnin, B. Tumor suppressor p53 and its homologue p73α affect cell migration. J. Biol. Chem. 278, 27362–27371 (2003).

    Article  CAS  Google Scholar 

  14. Gadea, G., de Toledo, M., Anguille, C. & Roux, P. Loss of p53 promotes RhoA-ROCK-dependent cell migration and invasion in 3D matrices. J. Cell Biol. 178, 23–30 (2007).

    Article  CAS  Google Scholar 

  15. Krubasik, D. et al. Absence of p300 induces cellular phenotypic changes characteristic of epithelial to mesenchyme transition. Br. J. Cancer 94, 1326–1332 (2006).

    Article  CAS  Google Scholar 

  16. Southwick, F. S., Dabiri, G. A., Paschetto, M. & Zigmond, S. H. Polymorphonuclear leukocyte adherence induces actin polymerization by a transduction pathway which differs from that used by chemoattractants. J. Cell Biol. 109, 1561–1569 (1989).

    Article  CAS  Google Scholar 

  17. Mullins, R., Heuser, J. & Pollard, T. The interaction of Arp2/3 complex with actin: nucleation, high affinity pointed end capping, and formation of branching networks of filaments. Proc. Natl Acad. Sci. USA 95, 6181–6186 (1998).

    Article  CAS  Google Scholar 

  18. Blanchoin, L. et al. Direct observation of dendritic actin filament networks nucleated by Arp2/3 complex and WASP/Scar proteins. Nature 404, 1007–1011 (2000).

    Article  CAS  Google Scholar 

  19. Blanchoin, L., Pollard, T. D. & Hitchcock-DeGregori, S. E. Inhibition of the Arp2/3 complex-nucleated actin polymerization and branch formation by tropomyosin. Curr. Biol. 11, 1300–1304 (2001).

    Article  CAS  Google Scholar 

  20. Shao, D., Forge, A., Munro, P. & Bailly, M. Arp2/3 complex-mediated actin polymerisation occurs on specific pre-existing networks in cells and requires spatial restriction to sustain functional lamellipod extension. Cell Motil. Cytoskel. 63, 395–414 (2006).

    Article  CAS  Google Scholar 

  21. Gordon, D. J., Eisenberg, E. & Korn, E. D. Characterization of cytoplasmic actin isolated from Acanthamoeba castellanii by a new method. J. Biol. Chem. 251, 4778–4786 (1976).

    CAS  PubMed  Google Scholar 

  22. Cooper, J. A., Walker, S. B. & Pollard, T. D. Pyrene actin: documentation of the validity of a sensitive assay for actin polymerization. J. Muscle Res. Cell Motil. 4, 253–262 (1983).

    Article  CAS  Google Scholar 

  23. Dayel, M. J., Holleran, E. A. & Mullins, R. D. Arp2/3 complex requires hydrolyzable ATP for nucleation of new actin filaments. Proc. Natl Acad. Sci. USA 98, 14871–14876 (2001).

    Article  CAS  Google Scholar 

  24. Akin, O. & Mullins, R. D. Capping protein increases the rate of actin-based motility by promoting filament nucleation by the Arp2/3 complex. Cell 133, 841–851 (2008).

    Article  CAS  Google Scholar 

  25. Weiner, O. et al. Hem-1 complexes are essential for Rac activation, actin polymerization, and myosin regulation during neutrophil chemotaxis. PLoS Biol. 4, e38 (2006).

    Article  Google Scholar 

  26. Cassimeris, L., McNeill, H. & Zigmond, S. Chemoattractant-stimulated polymorphonuclear leukocytes contain two populations of actin filaments that differ in their spatial distributions and relative stabilities. J. Cell Biol. 110, 1067–1075 (1990).

    Article  CAS  Google Scholar 

  27. Stuurman, N., Amodaj N., Vale, R. D. Micro-Manager: open source software for light microscope imaging. Microsc. Today 15, 42–43 (2007).

    Article  Google Scholar 

  28. Petrella, E., Machesky, L., Kaiser, D. & Pollard, T. Structural requirements and thermodynamics of the interaction of proline peptides with profilin. Biochemistry 35, 16535–16543 (1996).

    Article  CAS  Google Scholar 

  29. Kelly, A., Kranitz, H., Dötsch, V. & Mullins, R. Actin binding to the central domain of WASP/Scar proteins plays a critical role in the activation of the Arp2/3 complex. J. Biol. Chem. 281, 10589–10597 (2006).

    Article  CAS  Google Scholar 

  30. Kreishman-Deitrick, M. et al. NMR analyses of the activation of the Arp2/3 complex by neuronal Wiskott–Aldrich syndrome protein. Biochemistry 44, 15247–15256 (2005).

    Article  CAS  Google Scholar 

  31. Campellone, K. G., Webb, N. J., Znameroski, E. A. & Welch, M. D. WHAMM is an Arp2/3 complex activator that binds microtubules and functions in ER to Golgi transport. Cell 134, 148–161 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Kelly and R. Manlove for sequence analysis; O. Akin for help with Matlab scripts and advice; C. Campbell and H. Bourne for critical reading of the manuscript; and O. Weiner, S. Wilson, P. Temkin, E. Oh, C. Vizcarra, S. Cai, M. D'Ambrosio, K. Campellone, and members of the Mullins laboratory for reagents and helpful discussions. This work was supported by grants from the National Institutes of Health, the American Heart Association Predoctoral Fellowship (J.B.Z.), Medical Research Council funding (A.S.C.), and the Burroughs-Wellcome Fund Career Award in the Biomedical Sciences Fellowship (M.E.Q.).

Author information

Authors and Affiliations

Authors

Contributions

J.B.Z., A.S.C. and M.E.Q. conducted the experiments and analysed the results. J.B.Z., A.S.C., M.E.Q., N.B.T. and R.D.M. conceived the experiments and wrote the manuscript.

Corresponding author

Correspondence to R. Dyche Mullins.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 2442 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zuchero, J., Coutts, A., Quinlan, M. et al. p53-cofactor JMY is a multifunctional actin nucleation factor. Nat Cell Biol 11, 451–459 (2009). https://doi.org/10.1038/ncb1852

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1852

This article is cited by

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