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New insights into the regulation and cellular functions of the ARP2/3 complex

Abstract

The actin-related protein 2/3 (ARP2/3) complex nucleates branched actin filament networks, but requires nucleation promoting factors (NPFs) to stimulate this activity. NPFs include proteins such as Wiskott–Aldrich syndrome protein (WASP), neural WASP (NWASP), WASP family verprolin-homologous protein (WAVE; also known as SCAR) and the recently identified WASP and SCAR homologue (WASH) complex. The mechanisms underlying NPF-dependent regulation and the cellular functions of ARP2/3 are being unravelled using new chemical and genetic approaches. Of particular interest is the role of the ARP2/3 complex in vesicular trafficking and directional cell motility.

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Figure 1: Activation of NPFs by various stimuli.
Figure 2: Cellular functions of ARP2/3.

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References

  1. Pollard, T. Regulation of actin filament assembly by Arp2/3 complex and formins. Annu. Rev. Biophys. Biomol. Struct. 36, 451–477 (2007).

    Article  CAS  Google Scholar 

  2. Machesky, L. M., Atkinson, S. J., Ampe, C., Vandekerckhove, J. & Pollard, T. D. Purification of a cortical complex containing two unconventional actins from Acanthamoeba by affinity chromatography on profilin-agarose. J. Cell Biol. 127, 107–115 (1994).

    Article  CAS  Google Scholar 

  3. Welch, M. D., Iwamatsu, A. & Mitchison, T. J. Actin polymerization is induced by Arp2/3 protein complex at the surface of Listeria monocytogenes. Nature 385, 265–269 (1997).

    CAS  PubMed  Google Scholar 

  4. 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 

  5. Campellone, K. G. & Welch, M. D. A nucleator arms race: cellular control of actin assembly. Nature Rev. Mol. Cell Biol. 11, 237–251 (2010).

    Article  CAS  Google Scholar 

  6. Gandhi, M. et al. GMF is a cofilin homolog that binds Arp2/3 complex to stimulate filament debranching and inhibit actin nucleation. Curr. Biol. 20, 861–867 (2010).

    Article  CAS  Google Scholar 

  7. 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).

    Article  CAS  Google Scholar 

  8. Maritzen, T. et al. Gadkin negatively regulates cell spreading and motility via sequestration of the actin-nucleating ARP2/3 complex. Proc. Natl Acad. Sci. USA 109, 10382–10387 (2012).

    Article  CAS  Google Scholar 

  9. Rocca, D. L., Martin, S., Jenkins, E. L. & Hanley, J. G. Inhibition of Arp2/3-mediated actin polymerization by PICK1 regulates neuronal morphology and AMPA receptor endocytosis. Nature Cell Biol. 10, 259–271 (2008).

    Article  CAS  Google Scholar 

  10. Akin, O. & Mullins, R. 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 

  11. Higgs, H. N. & Pollard, T. D. Regulation of actin polymerization by Arp2/3 complex and WASp/Scar proteins. J. Biol. Chem. 274, 32531–32534 (1999).

    Article  CAS  Google Scholar 

  12. Weaver, A. M. et al. Cortactin promotes and stabilizes Arp2/3-induced actin filament network formation. Curr. Biol. 11, 370–374 (2001).

    Article  CAS  Google Scholar 

  13. Kim, A. S., Kakalis, L. T., Abdul-Manan, N., Liu, G. A. & Rosen, M. K. Autoinhibition and activation mechanisms of the Wiskott–Aldrich syndrome protein. Nature 404, 151–158 (2000).

    Article  CAS  Google Scholar 

  14. Bear, J. E., Rawls, J. F. & Saxe, C. L. SCAR, a WASP-related protein, isolated as a suppressor of receptor defects in late Dictyostelium development. J. Cell Biol. 142, 1325–1335 (1998).

    Article  CAS  Google Scholar 

  15. 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  Google Scholar 

  16. 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).

    Article  CAS  Google Scholar 

  17. Chen, Z. et al. Structure and control of the actin regulatory WAVE complex. Nature 468, 533–538 (2010).

    Article  CAS  Google Scholar 

  18. Ura, S. et al. Pseudopod growth and evolution during cell movement is controlled through SCAR/WAVE dephosphorylation. Curr. Biol. 22, 553–561 (2012).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  20. Gomez, T. S. & Billadeau, D. D. A FAM21-containing WASH complex regulates retromer-dependent sorting. Dev. Cell 17, 699–711 (2009).

    Article  CAS  Google Scholar 

  21. 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).

    Article  CAS  Google Scholar 

  22. Derivery, E. & Gautreau, A. Evolutionary conservation of the WASH complex, an actin polymerization machine involved in endosomal fission. Commun. Integr. Biol. 3, 227–230 (2010).

    Article  Google Scholar 

  23. Gomez, T. S., Gorman, J. A., Artal-Martinez de Narvajas, A., Koenig, A. O. & Billadeau, D. D. Trafficking defects in WASH-knockout fibroblasts originate from collapsed endosomal and lysosomal networks. Mol. Biol. Cell 23, 3215–3228 (2012).

    Article  CAS  Google Scholar 

  24. Zech, T. et al. The Arp2/3 activator WASH regulates α5β1-integrin-mediated invasive migration. J. Cell Sci. 124, 3753–3759 (2011).

    Article  CAS  Google Scholar 

  25. Carnell, M. et al. Actin polymerization driven by WASH causes V-ATPase retrieval and vesicle neutralization before exocytosis. J. Cell Biol. 193, 831–839 (2011).

    Article  CAS  Google Scholar 

  26. Jia, D. et al. WASH and WAVE actin regulators of the Wiskott–Aldrich syndrome protein (WASP) family are controlled by analogous structurally related complexes. Proc. Natl Acad. Sci. USA 107, 10442–10447 (2010).

    Article  CAS  Google Scholar 

  27. Kirkbride, K. C. et al. Regulation of late endosomal/lysosomal maturation and trafficking by cortactin affects Golgi morphology. Cytoskeleton (Hoboken) 69, 625–643 (2012).

    Article  CAS  Google Scholar 

  28. 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 

  29. Ti, S. C., Jurgenson, C. T., Nolen, B. J. & Pollard, T. D. Structural and biochemical characterization of two binding sites for nucleation-promoting factor WASp-VCA on Arp2/3 complex. Proc. Natl Acad. Sci. USA 108, E463–E471 (2011).

    Article  CAS  Google Scholar 

  30. Padrick, S. B., Doolittle, L. K., Brautigam, C. A., King, D. S. & Rosen, M. K. Arp2/3 complex is bound and activated by two WASP proteins. Proc. Natl Acad. Sci. USA 108, E472–E479 (2011).

    Article  CAS  Google Scholar 

  31. Gaucher, J. F. et al. Interactions of isolated C-terminal fragments of neural Wiskott–Aldrich syndrome protein (N-WASP) with actin and Arp2/3 complex. J. Biol. Chem. 287, 34646–34659 (2012).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  33. 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).

    Article  CAS  Google Scholar 

  34. Zuchero, J. B., Belin, B. & Mullins, R. D. Actin binding to WH2 domains regulates nuclear import of the multifunctional actin regulator JMY. Mol. Biol. Cell 23, 853–863 (2012).

    Article  CAS  Google Scholar 

  35. Kovacs, E. M. et al. N-WASP regulates the epithelial junctional actin cytoskeleton through a non-canonical post-nucleation pathway. Nature Cell Biol. 13, 934–943 (2011).

    Article  CAS  Google Scholar 

  36. Schwob, E. & Martin, R. P. New yeast actin-like gene required late in the cell cycle. Nature 355, 179–182 (1992).

    Article  CAS  Google Scholar 

  37. Yae, K. et al. Sleeping beauty transposon-based phenotypic analysis of mice: lack of Arpc3 results in defective trophoblast outgrowth. Mol. Cell. Biol. 26, 6185–6196 (2006).

    Article  CAS  Google Scholar 

  38. Nolen, B. J. et al. Characterization of two classes of small molecule inhibitors of Arp2/3 complex. Nature 460, 1031–1034 (2009).

    Article  CAS  Google Scholar 

  39. Sun, S. C. et al. Arp2/3 complex regulates asymmetric division and cytokinesis in mouse oocytes. PLoS ONE 6, e18392 (2011).

    Article  CAS  Google Scholar 

  40. Yi, K. et al. Dynamic maintenance of asymmetric meiotic spindle position through Arp2/3-complex-driven cytoplasmic streaming in mouse oocytes. Nature Cell Biol. 13, 1252–1258 (2011).

    Article  CAS  Google Scholar 

  41. Yang, Q., Zhang, X. F., Pollard, T. D. & Forscher, P. Arp2/3 complex-dependent actin networks constrain myosin II function in driving retrograde actin flow. J. Cell Biol. 197, 939–956 (2012).

    Article  CAS  Google Scholar 

  42. Wu, C. et al. Arp2/3 is critical for lamellipodia and response to extracellular matrix cues but is dispensable for chemotaxis. Cell 148, 973–987 (2012).

    Article  CAS  Google Scholar 

  43. Baggett, A. W. et al. Structural characterization and computer-aided optimization of a small-molecule inhibitor of the Arp2/3 complex, a key regulator of the actin cytoskeleton. ChemMedChem 7, 1286–1294 (2012).

    Article  CAS  Google Scholar 

  44. Suraneni, P. et al. The Arp2/3 complex is required for lamellipodia extension and directional fibroblast cell migration. J. Cell Biol. 197, 239–251 (2012).

    Article  CAS  Google Scholar 

  45. Block, J. et al. FMNL2 drives actin-based protrusion and migration downstream of Cdc42. Curr. Biol. 22, 1005–1012 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors apologize to their colleagues whose work could not be cited owing to space limitations. They thank E. Haynes for assistance with figure conception and illustration. Work in the laboratory of J.E.B was supported by funds from the Howard Hughes Medical Institute (HHMI) and the US National Institutes of Health (NIH) (GM083035).

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Correspondence to James E. Bear.

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Rotty, J., Wu, C. & Bear, J. New insights into the regulation and cellular functions of the ARP2/3 complex. Nat Rev Mol Cell Biol 14, 7–12 (2013). https://doi.org/10.1038/nrm3492

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