Trends in Cell Biology
ReviewThe lamellipodium: where motility begins
Section snippets
Lamellipodium tip engages protein complexes to drive actin polymerization
Pathogens that usurp the machinery of the cell to move in cytoplasm do so by recruiting to their surface the complexes involved in driving actin polymerization [6] (Table 1). A growing body of evidence indicates that the tips of lamellipodia and filopodia serve an analogous function of localizing and harnessing actin polymerization for cell motility. This was highlighted by studies of the dynamics of GFP-tagged vasodilator-stimulated phosphoprotein (VASP; a member of the Ena/VASP family of
Signaling at the tip through Rho GTPases
The assembly of actin-based membrane projections is regulated by small GTPases of the Rho family 23, 24. Two members of this family, Rac1 and Cdc42, signal the formation of lamellipodia and filopodia, respectively [25]. The activation of Rac and Cdc42 can be mediated by stimulation of both growth factor [23] and integrin [26] receptors and requires GDP–GTP exchange factors (GEFs), many of which have been described 27, 28. Rho GTPases are synthesized as cytosolic proteins but can be targeted to
Forming and stabilizing the actin network
Actin polymerization at the lamellipodium tip must be tightly coupled to the establishment of molecular linkages that constrain the generated actin filaments within a membrane sheet, through filament–filament and filament–membrane interactions. Emphasis has recently been placed on the possible role of the Arp2/3 complex in initiating and structuring actin networks. In vitro experiments have shown that Arp2/3 can promote the branching of actin filaments, but conflicting models have been proposed
Microspikes and filopodia
According to antibody labeling [43], Arp2/3 is excluded from filopodia and microspikes. This situation might reflect the elongation of pre-existing filaments in filopodia during protrusion [63] with no new filament generation, as in lamellipodia. Microspikes and filopodia are probably generated by bundling of lamellipodium filaments; fascin and fimbrin (plastin), which both bundle actin filaments in vitro, have been implicated in this process [64]. Fascin is a ubiquitous protein involved in
Lamellipodium disassembly
In a steadily migrating lamellipodium, the actin meshwork remains essentially constant in breadth (Fig. 1 and supplementary video at: http://archive.bmn.com/supp/tcb/small.avi), indicating a balance between assembly at the front and disassembly at the rear. Protrusion and retraction rates can be regulated at the level of actin assembly, apparently through the recruitment or dissociation of regulatory scaffolds 10, 15, 18. Disassembly is thought to be achieved by proteins of the ADF/cofilin
Shunting to the front with myosin motors
Several non-filament-forming members of the myosin family have been localized in lamellipodia and filopodia, following the first observation of myosin I in Dictyostelium [79]. Myosin is not required for Listeria motility in vitro [11], suggesting a specific need for myosin-linked processes in the membrane leaflet environment of the lamellipodium. In addition to myosin I, myosins V and VI [80], VII [81], and X [82] localize to lamellipodia and membrane ruffles. Myosin I proteins in both budding
Concluding remarks
Resolving the mechanism of protrusion of the lamellipodium leaflet is central to reaching an understanding of actin-based cell motility. Already, studies of isolated proteins, in vitro and in vivo models, and pathogen systems 6, 94, as well as theoretical treatments [95], have brought us a long way towards this aim. Nevertheless, because lamellipodia and filopodia do not exhibit the structural regularity found in more stable bundled arrays of actin [64], future advances in unveiling
Acknowledgements
Our work was supported by funds from the Austrian Science Research Council (to J.V.S.). K.R. is the holder of an EMBO postdoctoral fellowship, and K.R. and T.S. thank J. Wehland for allowing time to contribute to this article. We thank H. Nakagawa and P. Hahne for allowing us to cite unpublished work.
References (99)
Assembling an actin cytoskeleton for cell attachment and movement
Biochim. Biophys. Acta
(1998)- et al.
Surfing pathogens and the lessons learned for actin polymerization
Trends Cell Biol.
(2001) - et al.
Scar1 and the related Wiskott–Aldrich syndrome protein, WASP, regulate the actin cytoskeleton through the Arp2/3 complex
Curr. Biol.
(1998) The actin cytoskeleton
Electron Microsc. Rev.
(1988)Negative regulation of fibroblast motility by Ena/VASP proteins
Cell
(2000)Scar/WAVE is localised at the tips of protruding lamellipodia in living cells
FEBS Lett.
(2001)The Abl interactor proteins localize to sites of actin polymerization at the tips of lamellipodia and filopodia
Curr. Biol.
(2001)- et al.
Inhibition of cell migration by Abl family tyrosine kinases through uncoupling of Crk–CAS complexes
J. Biol. Chem.
(2001) Regulating cellular actin assembly
Curr. Opin. Cell Biol.
(2001)Rho family proteins: coordinating cell responses
Trends Cell Biol.
(2001)