Trends in Cell Biology
Volume 12, Issue 3, 1 March 2002, Pages 112-120
Journal home page for Trends in Cell Biology

Review
The lamellipodium: where motility begins

https://doi.org/10.1016/S0962-8924(01)02237-1Get rights and content

Abstract

Lamellipodia, filopodia and membrane ruffles are essential for cell motility, the organization of membrane domains, phagocytosis and the development of substrate adhesions. Their formation relies on the regulated recruitment of molecular scaffolds to their tips (to harness and localize actin polymerization), coupled to the coordinated organization of actin filaments into lamella networks and bundled arrays. Their turnover requires further molecular complexes for the disassembly and recycling of lamellipodium components. Here, we give a spatial inventory of the many molecular players in this dynamic domain of the actin cytoskeleton in order to highlight the open questions and the challenges ahead.

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)

  • C.D. Nobes et al.

    Rho, Rac, and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia

    Cell

    (1995)
  • P. Rodriguez-Viciana

    Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras

    Cell

    (1997)
  • P. Rickert

    Leukocytes navigate by compass: roles of PI3Kγ and its lipid products

    Trends Cell Biol.

    (2000)
  • S. Krugmann

    Cdc42 induces filopodia by promoting the formation of an IRSp53:Mena complex

    Curr. Biol.

    (2001)
  • R.H. Daniels et al.

    p21-activated protein kinase: a crucial component of morphological signaling?

    Trends Biochem. Sci.

    (1999)
  • S. Bagrodia et al.

    Pak to the future

    Trends Cell Biol.

    (1999)
  • G.G. Borisy et al.

    Actin machinery: pushing the envelope

    Curr. Opin. Cell Biol.

    (2000)
  • A.M. Weaver

    Cortactin promotes and stabilizes Arp2/3-induced actin filament network formation

    Curr. Biol.

    (2001)
  • W.K. Peitsch

    Drebrin particles: components in the ensemble of proteins regulating actin dynamics of lamellipodia and filopodia

    Eur. J. Cell Biol.

    (2001)
  • A. van der Flier et al.

    Structural and functional aspects of filamins

    Biochim. Biophys. Acta

    (2001)
  • E.L. de Hostos

    The coronin family of actin-associated proteins

    Trends Cell Biol.

    (1999)
  • J.R. Bartles

    Parallel actin bundles and their multiple actin-bundling proteins

    Curr. Opin. Cell Biol.

    (2000)
  • Y. Yamakita

    Phosphorylation of human fascin inhibits its actin binding and bundling activities

    J. Biol. Chem.

    (1996)
  • J.V. Small

    Lamellipodia architecture: actin filament turnover and the lateral flow of actin filaments during motility

    Semin. Cell Biol.

    (1994)
  • R. Oldenbourg

    Mechanism of lateral movement of filopodia and radial actin bundles across neuronal growth cones

    Biophys. J.

    (2000)
  • J.R. Bamburg

    Putting a new twist on actin: ADF/cofilins modulate actin dynamics

    Trends Cell Biol.

    (1999)
  • R.I. Tuxworth

    A role for myosin VII in dynamic cell adhesion

    Curr. Biol.

    (2001)
  • C.H. Lin

    Myosin drives retrograde F-actin flow in neuronal growth cones

    Neuron

    (1996)
  • M.A. Titus

    Getting to the point with myosin VI

    Curr. Biol.

    (2000)
  • A. Mogilner et al.

    Cell motility driven by actin polymerization

    Biophys. J.

    (1996)
  • M. Abercrombie

    The crawling movement of metazoan cells

    Proc. R. Soc. London B Biol. Sci.

    (1980)
  • J.P. Heath et al.

    On the mechanisms of cortical actin flow and its role in cytoskeletal organization of fibroblasts

    Symp. Soc. Exp. Biol.

    (1993)
  • S.D. Glacy

    Subcellular distribution of rhodamine–actin microinjected into living fibroblastic cells

    J. Cell Biol.

    (1983)
  • D. Pantaloni

    Mechanism of actin-based motility

    Science

    (2001)
  • M.D. Welch

    The human Arp2/3 complex is composed of evolutionarily conserved subunits and is localized to cellular regions of dynamic actin filament assembly

    J. Cell Biol.

    (1997)
  • K. Rottner

    VASP dynamics during lamellipodia protrusion

    Nat. Cell Biol.

    (1999)
  • T.P. Loisel

    Reconstitution of actin-based motility of Listeria and Shigella using pure proteins

    Nature

    (1999)
  • F. Castellano

    A WASp–VASP complex regulates actin polymerization at the plasma membrane

    Embo J.

    (2001)
  • H. Miki

    WAVE, a novel WASP-family protein involved in actin reorganization induced by Rac

    Embo J.

    (1998)
  • H. Nakagawa

    N-WASP, WAVE and Mena play different roles in the organization of actin cytoskeleton in lamellipodia

    J. Cell Sci.

    (2001)
  • R.S. Westphal

    Scar/WAVE-1, a Wiskott–Aldrich syndrome protein, assembles an actin-associated multi-kinase scaffold

    Embo J.

    (2000)
  • M. Geese

    Accumulation of profilin II at the surface of Listeria is concomitant with the onset of motility and correlates with bacterial speed

    J. Cell Sci.

    (2000)
  • Y.L. Wang

    Exchange of actin subunits at the leading edge of living fibroblasts: possible role of treadmilling

    J. Cell Biol.

    (1985)
  • A. Hall

    Rho GTPases and the actin cytoskeleton

    Science

    (1998)
  • L.S. Price

    Activation of Rac and Cdc42 by integrins mediates cell spreading

    Mol. Biol. Cell

    (1998)
  • L. Van Aelst et al.

    Rho GTPases and signaling networks

    Genes Dev.

    (1997)
  • G. Scita

    Signaling from Ras to Rac and beyond: not just a matter of GEFs

    Embo J.

    (2000)
  • D. Michaelson

    Differential localization of Rho GTPases in live cells: regulation by hypervariable regions and RhoGDI binding

    J. Cell Biol.

    (2001)
  • V.S. Kraynov

    Localized Rac activation dynamics visualized in living cells

    Science

    (2000)
  • Cited by (0)

    View full text