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.

  • Review Article
  • Published:

A nucleator arms race: cellular control of actin assembly

Key Points

  • The actin cytoskeleton has key roles in many dynamic cellular processes, such as cell shape changes, cell movement, cell division and membrane dynamics.

  • Mammalian cells express numerous factors that nucleate actin filaments de novo, including the actin-related protein 2/3 (ARP2/3) complex and multiple nucleation-promoting factors (NPFs), 15 formins and several members of the Spire, Cordon-bleu and leiomodin families.

  • Actin nucleators are regulated by distinct autoinhibitory and trans-inhibitory mechanisms and are directed to reorganize the cytoskeleton by their numerous protein and phospholipid binding partners.

  • ARP2/3 generates branched filament networks at plasma membrane invaginations or protrusions in concert with NPFs from the Wiskott–Aldrich syndrome protein (WASP) and WASP-family verprolin homologue (WAVE; also known as SCAR) families, but also assembles actin at endosomes, along the endoplasmic reticulum–Golgi secretory pathway, and perhaps in the nucleus by cooperating with the recently identified NPFs: WASP and SCAR homologue (WASH), WASP homologue associated with actin, membranes and microtubules (WHAMM) and junction-mediating regulatory protein (JMY), respectively.

  • Formins nucleate unbranched actin structures, facilitate filament elongation and sometimes bundle actin during plasma membrane protrusion, stress fibre formation and cell division.

  • Nucleators from the Spire, Cordon-bleu and leiomodin families use multiple actin monomer-binding sequences to nucleate actin, and influence membrane transport, neuronal morphology and muscle cell organization, respectively.

Abstract

For over a decade, the actin-related protein 2/3 (ARP2/3) complex, a handful of nucleation-promoting factors and formins were the only molecules known to directly nucleate actin filament formation de novo. However, the past several years have seen a surge in the discovery of mammalian proteins with roles in actin nucleation and dynamics. Newly recognized nucleation-promoting factors, such as WASP and SCAR homologue (WASH), WASP homologue associated with actin, membranes and microtubules (WHAMM), and junction-mediating regulatory protein (JMY), stimulate ARP2/3 activity at distinct cellular locations. Formin nucleators with additional biochemical and cellular activities have also been uncovered. Finally, the Spire, cordon-bleu and leiomodin nucleators have revealed new ways of overcoming the kinetic barriers to actin polymerization.

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: Localization and function of actin nucleation factors in mammalian cells.
Figure 2: The structure of ARP2/3 in Y-branches and a model for nucleation and branching.
Figure 3: Different groups of NPFs possess distinct modes of regulation.
Figure 4: FH2 domain structure and an elongation model of formin-mediated actin polymerization.
Figure 5: Different formins have distinct domain organizations.
Figure 6: WH2 domain-containing actin nucleators and models for polymerization.

Similar content being viewed by others

References

  1. Goley, E. D. & Welch, M. D. The ARP2/3 complex: an actin nucleator comes of age. Nature Rev. Mol. Cell Biol. 7, 713–726 (2006).

    Article  CAS  Google Scholar 

  2. Chesarone, M. A., DuPage, A. G. & Goode, B. L. Unleashing formins to remodel the actin and microtubule cytoskeletons. Nature Rev. Mol. Cell Biol. 11, 62–74 (2010).

    Article  CAS  Google Scholar 

  3. Stradal, T. E. & Scita, G. Protein complexes regulating Arp2/3-mediated actin assembly. Curr. Opin. Cell Biol. 18, 4–10 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Goley, E. D., Rodenbusch, S. E., Martin, A. C. & Welch, M. D. Critical conformational changes in the Arp2/3 complex are induced by nucleotide and nucleation promoting factor. Mol. Cell 16, 269–279 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Zencheck, W. D. et al. Nucleotide- and activator-dependent structural and dynamic changes of Arp2/3 complex monitored by hydrogen/deuterium exchange and mass spectrometry. J. Mol. Biol. 390, 414–427 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nolen, B. J., Littlefield, R. S. & Pollard, T. D. Crystal structures of actin-related protein 2/3 complex with bound ATP or ADP. Proc. Natl Acad. Sci. USA 101, 15627–15632 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Martin, A. C. et al. Effects of Arp2 and Arp3 nucleotide-binding pocket mutations on Arp2/3 complex function. J. Cell Biol. 168, 315–328 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dayel, M. J. & Mullins, R. D. Activation of Arp2/3 complex: addition of the first subunit of the new filament by a WASP protein triggers rapid ATP hydrolysis on Arp2. PLoS Biol. 2, E91 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Le Clainche, C., Pantaloni, D. & Carlier, M. F. ATP hydrolysis on actin-related protein 2/3 complex causes debranching of dendritic actin arrays. Proc. Natl Acad. Sci. USA 100, 6337–6342 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Martin, A. C., Welch, M. D. & Drubin, D. G. Arp2/3 ATP hydrolysis-catalysed branch dissociation is critical for endocytic force generation. Nature Cell Biol. 8, 826–833 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Nolen, B. J. & Pollard, T. D. Insights into the influence of nucleotides on actin family proteins from seven structures of Arp2/3 complex. Mol. Cell 26, 449–457 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Beltzner, C. C. & Pollard, T. D. Identification of functionally important residues of Arp2/3 complex by analysis of homology models from diverse species. J. Mol. Biol. 336, 551–565 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Rouiller, I. et al. The structural basis of actin filament branching by the Arp2/3 complex. J. Cell Biol. 180, 887–895 (2008). This paper provides the highest resolution model of ARP2/3 in filament branches.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. LeClaire, L. L., 3rd, Baumgartner, M., Iwasa, J. H., Mullins, R. D. & Barber, D. L. Phosphorylation of the Arp2/3 complex is necessary to nucleate actin filaments. J. Cell Biol. 182, 647–654 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rodal, A. A. et al. Conformational changes in the Arp2/3 complex leading to actin nucleation. Nature Struct. Mol. Biol. 12, 26–31 (2005).

    Article  CAS  Google Scholar 

  16. 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  PubMed  Google Scholar 

  17. Kelly, A. E., Kranitz, H., Dotsch, V. & Mullins, R. D. 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  PubMed  Google Scholar 

  18. Boczkowska, M. et al. X-Ray scattering study of activated Arp2/3 complex with bound actin-WCA. Structure 16, 695–704 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hertzog, M. et al. The β-thymosin/WH2 domain; structural basis for the switch from inhibition to promotion of actin assembly. Cell 117, 611–623 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Chereau, D. et al. Actin-bound structures of Wiskott-Aldrich syndrome protein (WASP)-homology domain 2 and the implications for filament assembly. Proc. Natl Acad. Sci. USA 102, 16644–16649 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bosticardo, M., Marangoni, F., Aiuti, A., Villa, A. & Grazia Roncarolo, M. Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome. Blood 113, 6288–6295 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Snapper, S. B. et al. N.-WASP deficiency reveals distinct pathways for cell surface projections and microbial actin-based motility. Nature Cell Biol. 3, 897–904 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Lommel, S. et al. Actin pedestal formation by enteropathogenic Escherichia coli and intracellular motility of Shigella flexneri are abolished in N-WASP-defective cells. EMBO Rep. 2, 850–857 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Anton, I. M., Jones, G. E., Wandosell, F., Geha, R. & Ramesh, N. WASP-interacting protein (WIP): working in polymerisation and much more. Trends Cell Biol. 17, 555–562 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Ho, H. Y. et al. Toca-1 mediates Cdc42-dependent actin nucleation by activating the N-WASP–WIP complex. Cell 118, 203–216 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Campellone, K. G. et al. Repetitive N-WASP-binding elements of the enterohemorrhagic Escherichia coli effector EspF(U) synergistically activate actin assembly. PLoS Pathog. 4, e1000191 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Takano, K., Toyooka, K. & Suetsugu, S. EFC/F-BAR proteins and the N-WASP–WIP complex induce membrane curvature-dependent actin polymerization. EMBO J. 27, 2817–2828 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tomasevic, N. et al. Differential regulation of WASP and N-WASP by Cdc42, Rac1, Nck, and PI(4,5)P2 . Biochemistry 46, 3494–3502 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Innocenti, M. et al. ABI1 regulates the activity of N-WASP and WAVE in distinct actin-based processes. Nature Cell Biol. 7, 969–976 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Torres, E. & Rosen, M. K. Protein-tyrosine kinase and GTPase signals cooperate to phosphorylate and activate Wiskott-Aldrich syndrome protein (WASP)/neuronal WASP. J. Biol. Chem. 281, 3513–3520 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Padrick, S. B. et al. Hierarchical regulation of WASP/WAVE proteins. Mol. Cell 32, 426–438 (2008). This paper describes allosteric- and new multimerization-based mechanisms for activating NPFs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sallee, N. A. et al. The pathogen protein EspF(U) hijacks actin polymerization using mimicry and multivalency. Nature 454, 1005–1008 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bu, W., Chou, A. M., Lim, K. B., Sudhaharan, T. & Ahmed, S. The Toca-1-N-WASP complex links filopodial formation to endocytosis. J. Biol. Chem. 284, 11622–11636 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Legg, J. A. et al. N.-WASP involvement in dorsal ruffle formation in mouse embryonic fibroblasts. Mol. Biol. Cell 18, 678–687 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tsujita, K. et al. Coordination between the actin cytoskeleton and membrane deformation by a novel membrane tubulation domain of PCH proteins is involved in endocytosis. J. Cell Biol. 172, 269–279 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Benesch, S. et al. N-WASP deficiency impairs EGF internalization and actin assembly at clathrin-coated pits. J. Cell Sci. 118, 3103–3115 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Dahl, J. P. et al. Characterization of the WAVE1 knock-out mouse: implications for CNS development. J. Neurosci. 23, 3343–3352 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Soderling, S. H. et al. Loss of WAVE-1 causes sensorimotor retardation and reduced learning and memory in mice. Proc. Natl Acad. Sci. USA 100, 1723–1728 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yamazaki, D. et al. WAVE2 is required for directed cell migration and cardiovascular development. Nature 424, 452–456 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Yan, C. et al. WAVE2 deficiency reveals distinct roles in embryogenesis and Rac-mediated actin-based motility. EMBO J. 22, 3602–3612 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Eden, S., Rohatgi, R., Podtelejnikov, A. V., Mann, M. & Kirschner, M. W. Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck. Nature 418, 790–793 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Gautreau, A. et al. Purification and architecture of the ubiquitous WAVE complex. Proc. Natl Acad. Sci. USA 101, 4379–4383 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ismail, A. M., Padrick, S. B., Chen, B., Umetani, J. & Rosen, M. K. The WAVE regulatory complex is inhibited. Nature Struct. Mol. Biol. 16, 561–563 (2009).

    CAS  Google Scholar 

  44. Derivery, E., Lombard, B., Loew, D. & Gautreau, A. The WAVE complex is intrinsically inactive. Cell. Motil. Cytoskeleton 66, 777–790 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Innocenti, M. et al. ABI1 is essential for the formation and activation of a WAVE2 signalling complex. Nature Cell Biol. 6, 319–327 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Steffen, A. et al. Sra-1 and Nap1 link Rac to actin assembly driving lamellipodia formation. EMBO J. 23, 749–759 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Suetsugu, S. et al. Optimization of WAVE2 complex-induced actin polymerization by membrane-bound IRSp53, PIP3, and Rac. J. Cell Biol. 173, 571–585 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Oikawa, T. et al. PtdIns(3,4,5)P3 binding is necessary for WAVE2-induced formation of lamellipodia. Nature Cell Biol. 6, 420–426 (2004).

    CAS  PubMed  Google Scholar 

  49. Leng, Y. et al. Abelson-interactor-1 promotes WAVE2 membrane translocation and Abelson-mediated tyrosine phosphorylation required for WAVE2 activation. Proc. Natl Acad. Sci. USA 102, 1098–1103 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Suetsugu, S., Yamazaki, D., Kurisu, S. & Takenawa, T. Differential roles of WAVE1 and WAVE2 in dorsal and peripheral ruffle formation for fibroblast cell migration. Dev. Cell 5, 595–609 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Lebensohn, A. M. & Kirschner, M. W. Activation of the WAVE complex by coincident signals controls actin assembly. Mol. Cell 36, 512–524 (2009). This paper shows that Rac, PtdIns(3,4,5)P 3 and phosphorylation cooperate during activation of the WAVE complex.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Steffen, A. et al. Filopodia formation in the absence of functional WAVE- and Arp2/3-complexes. Mol. Biol. Cell 17, 2581–2591 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yamazaki, D., Oikawa, T. & Takenawa, T. Rac-WAVE-mediated actin reorganization is required for organization and maintenance of cell-cell adhesion. J. Cell Sci. 120, 86–100 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Linardopoulou, E. V. et al. Human subtelomeric WASH genes encode a new subclass of the WASP family. PLoS Genet. 3, e237 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Derivery, E. et al. The Arp2/3 activator WASH controls the fission of endosomes through a large multiprotein complex. Dev. Cell 17, 712–723 (2009). This paper shows that WASH has a role in the recycling of endosomes to the plasma membrane.

    Article  CAS  PubMed  Google Scholar 

  56. Gomez, T. S. & Billadeau, D. D. A FAM21-containing WASH complex regulates retromer-dependent sorting. Dev. Cell 17, 699–711 (2009). This paper indicates that WASH functions in the trafficking of endosomes to the trans -Golgi network.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Duleh, S. N. & Welch, M. D. WASH and the Arp2/3 complex regulate endosome shape and trafficking. Cytoskeleton. 67, 193–206 (2010).

    CAS  PubMed  Google Scholar 

  58. Liu, R. et al. Wash functions downstream of Rho and links linear and branched actin nucleation factors. Development 136, 2849–2860 (2009). This paper begins to characterize the biochemical activities and cellular roles of

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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). This paper identifies WHAMM as an NPF that interacts with actin and microtubules to modulate membrane dynamics and transport.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zuchero, J. B., Coutts, A. S., Quinlan, M. E., Thangue, N. B. & Mullins, R. D. p53-cofactor JMY is a multifunctional actin nucleation factor. Nature Cell Biol. 11, 451–459 (2009). This paper identifies JMY as both an NPF and an actin nucleator that shuttles between the nucleus and plasma membrane.

    Article  CAS  PubMed  Google Scholar 

  61. Coutts, A. S., Weston, L. & La Thangue, N. B. A transcription co-factor integrates cell adhesion and motility with the p53 response. Proc. Natl Acad. Sci. USA 106, 19872–19877 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Ammer, A. G. & Weed, S. A. Cortactin branches out: roles in regulating protrusive actin dynamics. Cell. Motil. Cytoskeleton 65, 687–707 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Martinez-Quiles, N., Ho, H. Y., Kirschner, M. W., Ramesh, N. & Geha, R. S. Erk/Src phosphorylation of cortactin acts as a switch on-switch off mechanism that controls its ability to activate N-WASP. Mol. Cell Biol. 24, 5269–5280 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  65. Tehrani, S., Tomasevic, N., Weed, S., Sakowicz, R. & Cooper, J. A. Src phosphorylation of cortactin enhances actin assembly. Proc. Natl Acad. Sci. USA 104, 11933–11938 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cao, H. et al. Actin and Arf1-dependent recruitment of a cortactin-dynamin complex to the Golgi regulates post-Golgi transport. Nature Cell Biol. 7, 483–492 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Merrifield, C. J., Perrais, D. & Zenisek, D. Coupling between clathrin-coated-pit invagination, cortactin recruitment, and membrane scission observed in live cells. Cell 121, 593–606 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Zhu, J. et al. Regulation of cortactin/dynamin interaction by actin polymerization during the fission of clathrin-coated pits. J. Cell Sci. 118, 807–817 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Helwani, F. M. et al. Cortactin is necessary for E-cadherin-mediated contact formation and actin reorganization. J. Cell Biol. 164, 899–910 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Boguslavsky, S. et al. p120 catenin regulates lamellipodial dynamics and cell adhesion in cooperation with cortactin. Proc. Natl Acad. Sci. USA 104, 10882–10887 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bryce, N. S. et al. Cortactin promotes cell motility by enhancing lamellipodial persistence. Curr. Biol. 15, 1276–1285 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Kempiak, S. J. et al. A neural Wiskott-Aldrich Syndrome protein-mediated pathway for localized activation of actin polymerization that is regulated by cortactin. J. Biol. Chem. 280, 5836–5842 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Lai, F. P. et al. Cortactin promotes migration and platelet-derived growth factor-induced actin reorganization by signaling to Rho-GTPases. Mol. Biol. Cell 20, 3209–3223 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Humphries, C. L. et al. Direct regulation of Arp2/3 complex activity and function by the actin binding protein coronin. J. Cell Biol. 159, 993–1004 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Cai, L., Marshall, T. W., Uetrecht, A. C., Schafer, D. A. & Bear, J. E. Coronin 1B coordinates Arp2/3 complex and cofilin activities at the leading edge. Cell 128, 915–929 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Brieher, W. M., Kueh, H. Y., Ballif, B. A. & Mitchison, T. J. Rapid actin monomer-insensitive depolymerization of Listeria actin comet tails by cofilin, coronin, and Aip1. J. Cell Biol. 175, 315–324 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kueh, H. Y., Charras, G. T., Mitchison, T. J. & Brieher, W. M. Actin disassembly by cofilin, coronin, and Aip1 occurs in bursts and is inhibited by barbed-end cappers. J. Cell Biol. 182, 341–353 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Gandhi, M., Achard, V., Blanchoin, L. & Goode, B. L. Coronin switches roles in actin disassembly depending on the nucleotide state of actin. Mol. Cell 34, 364–374 (2009). This paper explains the paradoxical ability of coronin to both antagonize and synergize with cofilin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Chan, C., Beltzner, C. C. & Pollard, T. D. Cofilin dissociates Arp2/3 complex and branches from actin filaments. Curr. Biol. 19, 537–545 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Cai, L., Makhov, A. M., Schafer, D. A. & Bear, J. E. Coronin 1B antagonizes cortactin and remodels Arp2/3-containing actin branches in lamellipodia. Cell 134, 828–842 (2008). This paper describes the competing activities of cortactin and coronin during the dynamics of ARP2/3-containing F-actin branches.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Higgs, H. N. & Peterson, K. J. Phylogenetic analysis of the formin homology 2 domain. Mol. Biol. Cell 16, 1–13 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Harris, E. S., Li, F. & Higgs, H. N. The mouse formin, FRLα, slows actin filament barbed end elongation, competes with capping protein, accelerates polymerization from monomers, and severs filaments. J. Biol. Chem. 279, 20076–20087 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Moseley, J. B. et al. A conserved mechanism for Bni1- and mDia1-induced actin assembly and dual regulation of Bni1 by Bud6 and profilin. Mol. Biol. Cell 15, 896–907 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Romero, S. et al. Formin is a processive motor that requires profilin to accelerate actin assembly and associated ATP hydrolysis. Cell 119, 419–429 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Chesarone, M., Gould, C. J., Moseley, J. B. & Goode, B. L. Displacement of formins from growing barbed ends by Bud14 is critical for actin cable architecture and function. Dev. Cell 16, 292–302 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Harris, E. S., Rouiller, I., Hanein, D. & Higgs, H. N. Mechanistic differences in actin bundling activity of two mammalian formins, FRL1 and mDia2. J. Biol. Chem. 281, 14383–14392 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Li, F. & Higgs, H. N. Dissecting requirements for auto-inhibition of actin nucleation by the formin, mDia1. J. Biol. Chem. 280, 6986–6992 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Copeland, J. W., Copeland, S. J. & Treisman, R. Homo-oligomerization is essential for F-actin assembly by the formin family FH2 domain. J. Biol. Chem. 279, 50250–50256 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Xu, Y. et al. Crystal structures of a formin homology-2 domain reveal a tethered dimer architecture. Cell 116, 711–723 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Lu, J. et al. Structure of the FH2 domain of Daam1: implications for formin regulation of actin assembly. J. Mol. Biol. 369, 1258–1269 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Shimada, A. et al. The core FH2 domain of diaphanous-related formins is an elongated actin binding protein that inhibits polymerization. Mol. Cell 13, 511–522 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Otomo, T. et al. Structural basis of actin filament nucleation and processive capping by a formin homology 2 domain. Nature 433, 488–494 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Paul, A. S. & Pollard, T. D. The role of the FH1 domain and profilin in formin-mediated actin-filament elongation and nucleation. Curr. Biol. 18, 9–19 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Kovar, D. R., Harris, E. S., Mahaffy, R., Higgs, H. N. & Pollard, T. D. Control of the assembly of ATP- and ADP-actin by formins and profilin. Cell 124, 423–435 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Vavylonis, D., Kovar, D. R., O'Shaughnessy, B. & Pollard, T. D. Model of formin-associated actin filament elongation. Mol. Cell 21, 455–466 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Eisenmann, K. M. et al. T cell responses in mammalian diaphanous-related formin mDia1 knock-out mice. J. Biol. Chem. 282, 25152–25158 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Sakata, D. et al. Impaired T lymphocyte trafficking in mice deficient in an actin-nucleating protein, mDia1. J. Exp. Med. 204, 2031–2038 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Shi, Y. et al. The mDial formin is required for neutrophil polarization, migration, and activation of the LARG/RhoA/ROCK signaling axis during chemotaxis. J. Immunol. 182, 3837–3845 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Peng, J. et al. Myeloproliferative defects following targeting of the Drf1 gene encoding the mammalian diaphanous related formin mDia1. Cancer Res. 67, 7565–7571 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Li, F. & Higgs, H. N. The mouse formin mDia1 is a potent actin nucleation factor regulated by autoinhibition. Curr. Biol. 13, 1335–1340 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Wallar, B. J. et al. The basic region of the diaphanous-autoregulatory domain (DAD) is required for autoregulatory interactions with the diaphanous-related formin inhibitory domain. J. Biol. Chem. 281, 4300–4307 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Lammers, M., Rose, R., Scrima, A. & Wittinghofer, A. The regulation of mDia1 by autoinhibition and its release by Rho•GTP. EMBO J. 24, 4176–4187 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Nezami, A. G., Poy, F. & Eck, M. J. Structure of the autoinhibitory switch in formin mDia1. Structure 14, 257–263 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Otomo, T., Otomo, C., Tomchick, D. R., Machius, M. & Rosen, M. K. Structural basis of Rho GTPase-mediated activation of the formin mDia1. Mol. Cell 18, 273–281 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Rose, R. et al. Structural and mechanistic insights into the interaction between Rho and mammalian Dia. Nature 435, 513–518 (2005).

    Article  CAS  PubMed  Google Scholar 

  106. Seth, A., Otomo, C. & Rosen, M. K. Autoinhibition regulates cellular localization and actin assembly activity of the diaphanous-related formins FRLα and mDia1. J. Cell Biol. 174, 701–713 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Peng, J., Wallar, B. J., Flanders, A., Swiatek, P. J. & Alberts, A. S. Disruption of the Diaphanous-related formin Drf1 gene encoding mDia1 reveals a role for Drf3 as an effector for Cdc42. Curr. Biol. 13, 534–545 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Pellegrin, S. & Mellor, H. The Rho family GTPase Rif induces filopodia through mDia2. Curr. Biol. 15, 129–133 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Lammers, M., Meyer, S., Kuhlmann, D. & Wittinghofer, A. Specificity of interactions between mDia isoforms and Rho proteins. J. Biol. Chem. 283, 35236–35246 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kitzing, T. M. et al. Positive feedback between Dia1, LARG, and RhoA regulates cell morphology and invasion. Genes Dev. 21, 1478–1483 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Young, K. G. & Copeland, J. W. Formins in cell signaling. Biochim. Biophys. Acta. 14 Oct 2008 (doi: 10.1016/j.bbamcr.2008.09.017).

  112. Hotulainen, P. & Lappalainen, P. Stress fibers are generated by two distinct actin assembly mechanisms in motile cells. J. Cell Biol. 173, 383–394 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Watanabe, S. et al. mDia2 induces the actin scaffold for the contractile ring and stabilizes its position during cytokinesis in NIH 3T3 cells. Mol. Biol. Cell 19, 2328–2338 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Sarmiento, C. et al. WASP family members and formin proteins coordinate regulation of cell protrusions in carcinoma cells. J. Cell Biol. 180, 1245–1260 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Yang, C. et al. Novel roles of formin mDia2 in lamellipodia and filopodia formation in motile cells. PLoS Biol. 5, e317 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Brandt, D. T. et al. Dia1 and IQGAP1 interact in cell migration and phagocytic cup formation. J. Cell Biol. 178, 193–200 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gupton, S. L., Eisenmann, K., Alberts, A. S. & Waterman-Storer, C. M. mDia2 regulates actin and focal adhesion dynamics and organization in the lamella for efficient epithelial cell migration. J. Cell Sci. 120, 3475–3487 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. Colucci-Guyon, E. et al. A role for mammalian diaphanous-related formins in complement receptor (CR3)-mediated phagocytosis in macrophages. Curr. Biol. 15, 2007–2012 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Carramusa, L., Ballestrem, C., Zilberman, Y. & Bershadsky, A. D. Mammalian diaphanous-related formin Dia1 controls the organization of E-cadherin-mediated cell-cell junctions. J. Cell Sci. 120, 3870–3882 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Ryu, J. R., Echarri, A., Li, R. & Pendergast, A. M. Regulation of cell-cell adhesion by Abi/Diaphanous complexes. Mol. Cell Biol. 29, 1735–1748 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Gasman, S., Kalaidzidis, Y. & Zerial, M. RhoD regulates endosome dynamics through Diaphanous-related formin and Src tyrosine kinase. Nature Cell Biol. 5, 195–204 (2003).

    Article  CAS  PubMed  Google Scholar 

  122. Bartolini, F. et al. The formin mDia2 stabilizes microtubules independently of its actin nucleation activity. J. Cell Biol. 181, 523–536 (2008). This paper shows that the formin mDia2 can directly stabilize microtubules.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Wen, Y. et al. EB1 and APC bind to mDia to stabilize microtubules downstream of Rho and promote cell migration. Nature Cell Biol. 6, 820–830 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. Lewkowicz, E. et al. The microtubule-binding protein CLIP-170 coordinates mDia1 and actin reorganization during CR3-mediated phagocytosis. J. Cell Biol. 183, 1287–1298 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Liu, W. et al. Mechanism of activation of the Formin protein Daam1. Proc. Natl Acad. Sci. USA 105, 210–215 (2008). This paper describes the importance of Dishevelled in regulating DAAM1 activity.

    Article  PubMed  Google Scholar 

  126. Esue, O., Harris, E. S., Higgs, H. N. & Wirtz, D. The filamentous actin cross-linking/bundling activity of mammalian formins. J. Mol. Biol. 384, 324–334 (2008).

    Article  CAS  PubMed  Google Scholar 

  127. Vaillant, D. C. et al. Interaction of the N- and C-terminal autoregulatory domains of FRL2 does not inhibit FRL2 activity. J. Biol. Chem. 283, 33750–33762 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Higashi, T. et al. Biochemical characterization of the Rho GTPase-regulated actin assembly by diaphanous-related formins, mDia1 and Daam1, in platelets. J. Biol. Chem. 283, 8746–8755 (2008).

    Article  CAS  PubMed  Google Scholar 

  129. Habas, R., Kato, Y. & He, X. Wnt/Frizzled activation of Rho regulates vertebrate gastrulation and requires a novel formin homology protein Daam1. Cell 107, 843–854 (2001).

    Article  CAS  PubMed  Google Scholar 

  130. Sato, A. et al. Profilin is an effector for Daam1 in non-canonical Wnt signaling and is required for vertebrate gastrulation. Development 133, 4219–4231 (2006).

    Article  CAS  PubMed  Google Scholar 

  131. Koka, S. et al. The formin-homology-domain-containing protein FHOD1 enhances cell migration. J. Cell Sci. 116, 1745–1755 (2003).

    Article  CAS  PubMed  Google Scholar 

  132. Schonichen, A. et al. Biochemical characterization of the diaphanous autoregulatory interaction in the formin homology protein FHOD1. J. Biol. Chem. 281, 5084–5093 (2006).

    Article  CAS  PubMed  Google Scholar 

  133. Schulte, A. et al. The human formin FHOD1 contains a bipartite structure of FH3 and GTPase-binding domains required for activation. Structure 16, 1313–1323 (2008).

    Article  CAS  PubMed  Google Scholar 

  134. Hannemann, S. et al. The Diaphanous-related Formin FHOD1 associates with ROCK1 and promotes Src-dependent plasma membrane blebbing. J. Biol. Chem. 283, 27891–27903 (2008).

    Article  CAS  PubMed  Google Scholar 

  135. Takeya, R., Taniguchi, K., Narumiya, S. & Sumimoto, H. The mammalian formin FHOD1 is activated through phosphorylation by ROCK and mediates thrombin-induced stress fibre formation in endothelial cells. EMBO J. 27, 618–628 (2008). This paper defines a ROCK-mediated mechanism of FHOD1 regulation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Kobielak, A., Pasolli, H. A. & Fuchs, E. Mammalian formin-1 participates in adherens junctions and polymerization of linear actin cables. Nature Cell Biol. 6, 21–30 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. Dettenhofer, M., Zhou, F. & Leder, P. Formin 1-isoform IV deficient cells exhibit defects in cell spreading and focal adhesion formation. PLoS One 3, e2497 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Leader, B. et al. Formin-2, polyploidy, hypofertility and positioning of the meiotic spindle in mouse oocytes. Nature Cell Biol. 4, 921–928 (2002).

    Article  CAS  PubMed  Google Scholar 

  139. Dumont, J. et al. Formin-2 is required for spindle migration and for the late steps of cytokinesis in mouse oocytes. Dev. Biol. 301, 254–265 (2007).

    Article  CAS  PubMed  Google Scholar 

  140. Li, H., Guo, F., Rubinstein, B. & Li, R. Actin-driven chromosomal motility leads to symmetry breaking in mammalian meiotic oocytes. Nature Cell Biol. 10, 1301–1308 (2008).

    Article  CAS  PubMed  Google Scholar 

  141. Schuh, M. & Ellenberg, J. A new model for asymmetric spindle positioning in mouse oocytes. Curr. Biol. 18, 1986–1992 (2008). References 140 and 141 implicate FMN2 in the control of spindle movements in mammalian oocytes.

    Article  CAS  PubMed  Google Scholar 

  142. Miyagi, Y. et al. Delphilin: a novel PDZ and formin homology domain-containing protein that synaptically colocalizes and interacts with glutamate receptor δ2 subunit. J. Neurosci. 22, 803–814 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Matsuda, K., Matsuda, S., Gladding, C. M. & Yuzaki, M. Characterization of the δ2 glutamate receptor-binding protein delphilin: Splicing variants with differential palmitoylation and an additional PDZ domain. J. Biol. Chem. 281, 25577–25587 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. Takeuchi, T. et al. Enhancement of both long-term depression induction and optokinetic response adaptation in mice lacking delphilin. PLoS One 3, e2297 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Young, K. G., Thurston, S. F., Copeland, S., Smallwood, C. & Copeland, J. W. INF1 is a novel microtubule-associated formin. Mol. Biol. Cell 19, 5168–5180 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Chhabra, E. S. & Higgs, H. N. INF2 Is a WASP homology 2 motif-containing formin that severs actin filaments and accelerates both polymerization and depolymerization. J. Biol. Chem. 281, 26754–26767 (2006).

    Article  CAS  PubMed  Google Scholar 

  147. Chhabra, E. S., Ramabhadran, V., Gerber, S. A. & Higgs, H. N. INF2 is an endoplasmic reticulum-associated formin protein. J. Cell Sci. 122, 1430–1440 (2009). This paper suggests that the formin INF2 can associate with the ER and influence its morphology.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Dominguez, R. Actin filament nucleation and elongation factors — structure-function relationships. Crit. Rev. Biochem. Mol. Biol. 44, 351–366 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. 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  PubMed  Google Scholar 

  150. Bosch, M. et al. Analysis of the function of Spire in actin assembly and its synergy with formin and profilin. Mol. Cell 28, 555–568 (2007). This paper provides a detailed biochemical analysis of the numerous effects of Spire on actin dynamics.

    Article  CAS  PubMed  Google Scholar 

  151. Rebowski, G. et al. X-ray scattering study of actin polymerization nuclei assembled by tandem W domains. Proc. Natl Acad. Sci. USA 105, 10785–10790 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Rosales-Nieves, A. E. et al. Coordination of microtubule and microfilament dynamics by Drosophila Rho1, Spire and Cappuccino. Nature Cell Biol. 8, 367–376 (2006).

    Article  CAS  PubMed  Google Scholar 

  153. Quinlan, M. E., Hilgert, S., Bedrossian, A., Mullins, R. D. & Kerkhoff, E. Regulatory interactions between two actin nucleators, Spire and Cappuccino. J. Cell Biol. 179, 117–128 (2007). This paper demonstrates that Spire binds directly to and influences the actin nucleating activity of the formin Cappuccino.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Pechlivanis, M., Samol, A. & Kerkhoff, E. Identification of a short Spir interaction sequence at the C-terminal end of formin subgroup proteins. J. Biol. Chem. 284, 25324–25333 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Kerkhoff, E. et al. The Spir actin organizers are involved in vesicle transport processes. Curr. Biol. 11, 1963–1968 (2001).

    Article  CAS  PubMed  Google Scholar 

  156. Ahuja, R. et al. Cordon-bleu is an actin nucleation factor and controls neuronal morphology. Cell 131, 337–350 (2007). This paper identifies COBL as a nucleator that regulates actin dynamics and dendrite branching in neurons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Chereau, D. et al. Leiomodin is an actin filament nucleator in muscle cells. Science 320, 239–243 (2008). This paper identifies LMOD2 as a potent actin nucleator that influences sarcomere assembly in muscle cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Conley, C. A., Fritz-Six, K. L., Almenar-Queralt, A. & Fowler, V. M. Leiomodins: larger members of the tropomodulin (Tmod) gene family. Genomics 73, 127–139 (2001).

    Article  CAS  PubMed  Google Scholar 

  159. Thanbichler, M. & Shapiro, L. Getting organized — how bacterial cells move proteins and DNA. Nature Rev. Microbiol. 6, 28–40 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. Dominguez, D. Hanein, M. Rosen and N. Volkmann for providing structural images, and members of the Welch laboratory for comments on this manuscript. We also thank investigators whose earlier work laid the foundation for the studies noted in this Review but who could not be cited owing to space restrictions. K.G.C is supported by a Leukemia and Lymphoma Society special fellowship. M.D.W is supported by grants NIH/NIGMS RO1-GM059609 and NIH/NIAID RO1-AI074760.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Matthew D. Welch's homepage

Glossary

WCA domain

The minimal sequence element required for potent activation of ARP2/3-mediated actin nucleation and the formation of dendritic networks.

Lamellipodium

A sheet-like cellular protrusion that contains a dynamic Y-branched and cross-linked F-actin meshwork, which elongates to drive membrane protrusion.

WASP homology 1 (WH1) domain

A regulatory domain found in WASP-like NPFs that binds Pro-rich actin-binding proteins such as WIP.

GTPase-binding domain

A crucial regulatory element found in some ARP2/3 activators and formin nucleators that promotes autoinhibitory interactions under resting conditions, but can bind to small GTPases such as Cdc42, Rac or Rho to relieve autoinhibition.

Pro-rich domain

A domain commonly found in ARP2/3 activators that contains binding sites for SH3 domains and the actin monomer-associated protein profilin.

Filopodium

A finger-like cellular extension composed of unbranched actin filaments that elongate to drive membrane protrusion.

Membrane ruffle

A dynamic cell surface protrusion containing a network of newly assembled actin filaments. It can appear as a dorsal circular wave or in peripheral cellular extensions.

SCAR homology domain

A regulatory element found in WAVE NPFs that bind multiple components of the WAVE complex.

WASH homology domain 1

One of two subdomains — WAHD1 and WAHD2 (also known as TBR) — that comprise a putative regulatory element found in WASH NPFs.

Retromer

A protein complex that is important for recycling transmembrane receptors from endosomes to the trans-Golgi.

Coiled coil

A structural motif in proteins that consists of two or more helices that twist around each other to form a stable, rod-like structure.

Cadherin

A calcium-dependent adhesion transmembrane protein that has important roles in cell–cell contacts.

Formin homology (FH) domain

A domain found in formin proteins. Examples include the conserved dimeric FH2 domain that nucleates actin and the Pro-rich FH1 domain that associates with the actin-binding protein profilin and SH3 and WW domains.

Diaphanous inhibitory domain

A regulatory region near the N terminus of many formins that partially overlaps with a GBD and is involved in inhibiting actin nucleation activity by binding to a C-terminal DAD.

Diaphanous autoregulatory domain

A short ( 20 residue) peptide located near the C terminus of many formins that can bind to an N-terminal DID to inhibit actin nucleation activity.

Focal adhesion

A large transmembrane structure consisting of a cluster of integrins and associated proteins that binds to extracellular matrix molecules and intracellular actin stress fibres.

Wnt signalling

(Wingless and Int signalling). A complex network of proteins with important roles in embryogenesis and signal transduction cascades involving intracellular responses to extracellular cues.

Adherens junction

A specialized intercellular junction of the plasma membrane, in which cadherin molecules of adjacent cells interact with each other extracellularly in a calcium-dependent manner, and associate with actin filaments inside cells.

PDZ domain

(Postsynaptic density protein, Discs large and Zona occludens 1 domain). A domain present in many scaffolding proteins that binds to specific short amino-acid sequences.

FYVE domain

(Fab1, YOTB, Vac1 and EEA1 domain). A type of zinc-finger domain that binds PtdIns3P and is found in many proteins involved in membrane trafficking.

Neurite

A projection (for example, an axon or dendrite) from the cell body of a neuron.

Leu-rich repeat

A structural motif that participates in protein–protein interactions and is comprised of repeating 20–30 residue peptides that are rich in Leu residues.

Sarcomere

A specialized structure in striated muscle composed of actin, myosin and other proteins that serves as the smallest unit that generates contractile force.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Campellone, K., Welch, M. A nucleator arms race: cellular control of actin assembly. Nat Rev Mol Cell Biol 11, 237–251 (2010). https://doi.org/10.1038/nrm2867

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm2867

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