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  • Review Article
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Steering cell migration: lamellipodium dynamics and the regulation of directional persistence

Nature Reviews Molecular Cell Biology volume 15, pages 577–590 (2014)Cite this article

Subjects

Key Points

  • Lamellipodial protrusion depends on the force generated by actin polymerization. Actin polymerization is the sum of the activities of nucleators — for example, the actin-related protein 2/3 (ARP2/3) complex — and elongators — formins and ENA/VASP proteins.

  • Small GTPases, such as RAC and CDC42, control both actin nucleators and actin elongators; RAC activates the WASP family verprolin-homologous protein (WAVE) complex upstream of the ARP2/3 complex independently of the activation of the formin FMNL2 by CDC42, but RAC may coordinate ARP2/3 with ENA/VASP proteins by inducing a complex between WAVE and lamellipodin.

  • The speed of cell migration depends on the turnover of actin branched junctions and on the elongation of actin networks.

  • An intrinsic instability of lamellipodia is due to ARP2/3 inhibitory proteins, such as Arpin, which is also activated downstream of RAC.

  • The persistence of lamellipodia is the major controller of cell directionality.

  • Directional persistence (that is, the characteristic time during which a cell sustains its migration in the same direction) is the combinatory result of several intertwined positive- and negative-feedback loops that sustain or stop actin polymerization at the leading edge.

Abstract

Membrane protrusions at the leading edge of cells, known as lamellipodia, drive cell migration in many normal and pathological situations. Lamellipodial protrusion is powered by actin polymerization, which is mediated by the actin-related protein 2/3 (ARP2/3)-induced nucleation of branched actin networks and the elongation of actin filaments. Recently, advances have been made in our understanding of positive and negative ARP2/3 regulators (such as the SCAR/WAVE (SCAR/WASP family verprolin-homologous protein) complex and Arpin, respectively) and of proteins that control actin branch stability (such as glial maturation factor (GMF)) or actin filament elongation (such as ENA/VASP proteins) in lamellipodium dynamics and cell migration. This Review highlights how the balance between actin filament branching and elongation, and between the positive and negative feedback loops that regulate these activities, determines lamellipodial persistence. Importantly, directional persistence, which results from lamellipodial persistence, emerges as a critical factor in steering cell migration.

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Figure 1: Growth factor receptor signalling regulates lamellipodin and the WAVE complex.
Figure 2: Regulation of WAVE complex activity by phosphorylation.
Figure 3: Priming of the ARP2/3 complex.
Figure 4: Direct effectors of actin polymerization.
Figure 5: Balance of actin branching versus elongation regulates lamellipodial persistence and protrusion speed.
Figure 6: Positive- and negative-feedback loops between RAC and actin polymerization govern cell migration.

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Acknowledgements

Work in the authors' laboratories is supported by grants from BBSRC (BB/G00319X/1; BB/F011431/1; BB/J000590/1) (M.K.), Wellcome Trust (077429/Z/05/Z; 082907/Z/07/Z) (M.K.), Agence Nationale de la Recherche (A.G.), Institut National du Cancer (A.G.) and Association pour la Recherche sur le Cancer (A.G.).

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Authors and Affiliations

  1. Randall Division of Cell & Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London, SE1 1UL, UK

    Matthias Krause

  2. Laboratoire d'Enzymologie et Biochimie Structurales, CNRS UPR3082, Gif-sur-Yvette, 91190, France

    Alexis Gautreau

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  1. Matthias Krause
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Correspondence to Matthias Krause or Alexis Gautreau.

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Cell Migration Gateway

Glossary

Integrin

A member of a large family of transmembrane proteins, which exist in the plasma membrane as heterodimers of α- and β-subunits and mediate the interaction of cells with the extracellular matrix.

Invadopodia

Invasive protrusions of tumour cells that locally secrete proteases to degrade the extracellular matrix, which thereby enables them to penetrate the basement membrane.

Blebs

Outward membrane bulges that form owing to weakening of the actin cortex and high intracellular pressure.

Lamellipodium persistence

Characteristic time during which a lamellipodium persists.

WCA domain

The carboxy-terminal domain of nucleation-promoting factors that activate the actin-related protein 2/3 (ARP2/3) complex and delivers the first actin molecule of the branched junction.

Liposomes

Artificial lipid membranes that form vesicles.

Prenylated

When a protein is conjugated to a fatty acid (prenyl group) that anchors proteins to membranes.

BAR domain

A conserved protein domain that forms a banana-shaped dimer, which senses curved membranes or induces curvature corresponding to its shape.

Trans-Golgi network

(TGN). A compartment of the Golgi apparatus from which various post-Golgi vesicles are generated.

Guanine nucleotide exchange factor

(GEF). A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a small GTP-binding protein.

Exocyst complex

A dynamic complex of proteins that permit the polarized tethering of post-Golgi vesicles to the plasma membrane.

PH domain

(Pleckstrin homology domain). A small signal transduction domain that binds to phosphoinositide lipids in membranes.

Barbed end

The most dynamic end of an actin filament, which is usually elongated.

Guided migration

Migration that is biased by external cues.

FH1 and FH2 domains

The two characteristic formin homology domains of formins. FH1 associates with, and delivers profilin–actin to, FH2 dimers that promote elongation of actin filaments by staying associated with barbed ends.

Random migration

Migration that is not biased by external cues.

Cell translocation

Active displacement of cells.

Fluorescence recovery after photobleaching

(FRAP). A method by which one localized pool of fluorescent proteins is rendered non-fluorescent by high-energy illumination. The way in which fluorescence recovers gives an indication of the exchange rates (flow) of the remaining fluorescent molecules. This flow cannot be seen in the steady-state distribution of fluorescent proteins.

WD40 repeat

A protein motif composed of a 40-amino-acid repeat that forms a blade of a characteristic β-propeller structure.

Directional persistence

Characteristic time during which cells sustain their migration in one direction. Directional persistence is a descriptor, like cell speed, of all kinds of cell migration, even random migration.

Directionality

The orientation of cell migration. This parameter is important in guided migration but not in random migration. Directionality should not be confused with directional persistence.

Microtubule-organizing centre

A large macromolecular assembly that nucleates and tethers microtubules.

GTPase-activating proteins

(GAPs). Proteins that inactivate small GTP-binding proteins by increasing their rate of GTP hydrolysis.

F-BAR domain

A special type of BAR domain that is located at the amino terminus of proteins and which usually senses or induces invaginations of the plasma membrane.

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Krause, M., Gautreau, A. Steering cell migration: lamellipodium dynamics and the regulation of directional persistence. Nat Rev Mol Cell Biol 15, 577–590 (2014). https://doi.org/10.1038/nrm3861

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