Initiation and Nucleation

Lamellipodia and Lamella

Step 1: Initiation and Nucleation

Lamellipodia are primarily composed of a dense network of actin filaments. The initial step in the formation of lamellipodia is therefore the nucleation of these filaments, which is generally accepted to be mediated by the Arp2/3 complex. For further information on this process of nucleation see Functional Module: Arp2/3 complex. The mechanism of Arp2/3-mediated nucleation has become known as the ‘dendritic nucleation model’ [1] and is based on Arp2/3 binding to the sides of existing actin filaments and subsequently nucleating new filaments as ‘branches’.

The cytoskeleton of lamellipodia is highly dynamic compared to that of the lamella [2] and as a result actin filaments are constantly cycling through phases of assembly and disassembly. The continued nucleation and polymerization of new filaments requires a number of additional factors that either regulate or supplement the activity of the Arp2/3 complex.

Current evidence suggests multiple nucleators may function alongside the Arp2/3 complex [2], although their full influence on the growth of the actin filament network and its ability to exert a protrusive force on the cell membrane remains unclear. Members of the formin (mDia1) family of nucleators have been found to localize to lamellipodia where they are implicated in the nucleation of unbranched filaments [3]. Similar reports suggest spire and other proteins possessing multiple WH2 domains (e.g. JMY [4]; cordon bleu [5]) are involved in unbranched actin filament nucleation within lamellipodia .

WH2 (Wiskott-Aldrich homology 2) domains are highly evolutionarily conserved domains of approximately 35 amino acids in length and serve as actin binding sites [6]. A mechanism by which WH2 domain-containing proteins promote filament nucleation has been proposed [7], however recent studies have indicated a greater level of complexity surrounds the biological function of the WH2 domains. For example, it has been shown that Cordon bleu functions with similar characteristics to profilin, being a weak nucleator, but also readily severs filaments and sequesters ADP-actin [8]. Nevertheless, proteins possessing WH2 domains are likely to have an influence on actin filament nucleation in lamellipodia, albeit at a regulatory level or supplementary to the influence of Arp2/3 itself.

In recent years the branched model of filament nucleation within lamellipodia has been brought into question, with one study reporting a lack of branched filaments in lamellipodia of 3T3 fibroblasts and another study suggesting branches are an experimental artifact [9]. Despite these claims, the dendritic nucleation model remains widely accepted and subsequent re-analysis of previous results, which suggested a predominantnly unbranched array, revealed the existence of over 200 branched filaments [10].

Other factors that facilitate and enhance actin nucleation include various Nucleation Promoting Factors (NPF) and NPF accessory proteins. In general these proteins bring together actin monomers and/or actin filaments to promote nucleation and branching. For specific examples and more information on their roles in nucleation see Nucleation Promoting Factors.

References

  1. Svitkina TM., Bulanova EA., Chaga OY., Vignjevic DM., Kojima S., Vasiliev JM. & Borisy GG. Mechanism of filopodia initiation by reorganization of a dendritic network. J. Cell Biol. 2003; 160(3):409-21. [PMID: 12566431]
  2. Ridley AJ. Life at the leading edge. Cell 2011; 145(7):1012-22. [PMID: 21703446]
  3. Chesarone MA., DuPage AG. & Goode BL. Unleashing formins to remodel the actin and microtubule cytoskeletons. Nat. Rev. Mol. Cell Biol. 2010; 11(1):62-74. [PMID: 19997130]
  4. Zuchero JB., Coutts AS., Quinlan ME., Thangue NB. & Mullins RD. p53-cofactor JMY is a multifunctional actin nucleation factor. Nat. Cell Biol. 2009; 11(4):451-9. [PMID: 19287377]
  5. Campellone KG. & Welch MD. A nucleator arms race: cellular control of actin assembly. Nat. Rev. Mol. Cell Biol. 2010; 11(4):237-51. [PMID: 20237478]
  6. Paunola E., Mattila PK. & Lappalainen P. WH2 domain: a small, versatile adapter for actin monomers. FEBS Lett. 2002; 513(1):92-7. [PMID: 11911886]
  7. Ahuja R., Pinyol R., Reichenbach N., Custer L., Klingensmith J., Kessels MM. & Qualmann B. Cordon-bleu is an actin nucleation factor and controls neuronal morphology. Cell 2007; 131(2):337-50. [PMID: 17956734]
  8. Husson C., Renault L., Didry D., Pantaloni D. & Carlier MF. Cordon-Bleu uses WH2 domains as multifunctional dynamizers of actin filament assembly. Mol. Cell 2011; 43(3):464-77. [PMID: 21816349]
  9. Urban E., Jacob S., Nemethova M., Resch GP. & Small JV. Electron tomography reveals unbranched networks of actin filaments in lamellipodia. Nat. Cell Biol. 2010; 12(5):429-35. [PMID: 20418872]
  10. Yang C. & Svitkina T. Visualizing branched actin filaments in lamellipodia by electron tomography. Nat. Cell Biol. 2011; 13(9):1012-3; author reply 1013-4. [PMID: 21892140]
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