Review Article | Published:

Functions of cofilin in cell locomotion and invasion

Nature Reviews Molecular Cell Biology volume 14, pages 405415 (2013) | Download Citation

Abstract

Recently, a consensus has emerged that cofilin severing activity can generate free actin filament ends that are accessible for F-actin polymerization and depolymerization without changing the rate of G-actin association and dissociation at either filament end. The structural basis of actin filament severing by cofilin is now better understood. These results have been integrated with recently discovered mechanisms for cofilin activation in migrating cells, which led to new models for cofilin function that provide insights into how cofilin regulation determines the temporal and spatial control of cell behaviour.

Key points

  • Cofilin is an actin-binding protein that can influence actin dynamics to regulate the initiation and shape of cell protrusions.

  • Cofilin severing activity can generate free filament ends that are accessible to G-actin, thus triggering actin polymerization and actin depolymerization without changing the rate constants for actin monomer association and dissociation at either filament end.

  • The cofilin activity cycle includes several activation–inactivation steps that need to be spatially and temporally regulated by different proteins in order to achieve efficient cell motility.

  • Several molecules are involved in the activation of cofilin at protrusions, including Na+–H+ exchanger 1 (NHE1), phospholipase C (PLC) and cortactin, which contribute to the first activation step of cofilin. Cofilin can also be activated upon dephosphorylation by phosphatases such as Slingshot (SSH) and chronophin (CIN).

  • Cofilin is inactivated by LIM-domain kinase (LIMK)- and TES kinase (TESK)-mediated phosphorylation at Ser3.

  • Visualization of cofilin activity in live cells is crucial to understand its biological function. Cofilin activity can be studied in vivo using different techniques such as FRAP (fluorescence recovery after photobleaching), FRET (fluorescence resonance energy transfer), FLIP (fluorescence loss in photobleaching), BiFC (bimolecular fluorescence complementation), barbed end assays, PLA (proximity ligation assay) and cofilin uncaging.

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Acknowledgements

The authors would like to thank members of the Condeelis and Hodgson laboratories for helpful discussions. They apologize to those whose work could not be cited owing to space limitations. The authors' research is funded by grants GM093121 (to L.H. and J.J.B.-C.) and CA150344 (to J.C., R.E. and J.J.B.-C.).

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Author notes

    • Marco A. O. Magalhaes

    Present address: Oral Pathology and Oral Medicine Department, Faculty of Dentistry, University of Toronto, 511-124 Edward Street, Toronto, Ontario, Canada L8T5A8.

Affiliations

  1. Department of Anatomy and Structural Biology, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, New York 10461, USA.

    • Jose Javier Bravo-Cordero
    • , Marco A. O. Magalhaes
    • , Robert J. Eddy
    • , Louis Hodgson
    •  & John Condeelis
  2. Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine of Yeshiva University, 1301 Morris Park Avenue, Bronx, New York 10461, USA.

    • Jose Javier Bravo-Cordero
    • , Marco A. O. Magalhaes
    • , Louis Hodgson
    •  & John Condeelis

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Competing interests

John Condeelis acknowledges a financial interest in MetaStat, Inc. Jose Javier Bravo-Cordero, Marco A. O. Magalhaes, Robert J. Eddy and Louis Hodgson declare no competing financial interests.

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Supplementary information

Glossary

Motility cycle

A series of steps that enables cell movement. The first step is the formation of a directional protrusion driven by actin polymerization, followed by adhesion, contractile tension and tail retraction.

Amoeboid cell migration

A common type of motility whereby cells extend actin polymerization-dependent protrusions in the direction of migration.

Chemotaxis

Polarized cell migration in response to extracellular, soluble cues. Chemotaxis is characterized by the directional extension of a locomotory protrusion towards the source of a chemoattractant.

Pointed end

The end of the actin filament that is characterized by a slow growing rate.

Barbed ends

The fast growing ends of actin filaments that are characterized by a fast 'on rate' and high affinity for ATP•G-actin.

Invadopodium

Invasive protrusion that is extended by actin polymerization and is involved in extracellular matrix degradation.

Lamellipodium

A common locomotory protrusion that is extended by actin polymerization.

Histamine degranulation

Release of the pro-inflammatory molecule histamine from intracellular granules.

Crawling cells

Cells that use the motility cycle for locomotion.

Focal adhesion

Macromolecular complexes involved in cell–extracellular matrix interactions.

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https://doi.org/10.1038/nrm3609

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