Polarized cell motility induces hydrogen peroxide to inhibit cofilin via cysteine oxidation

Cameron, J. M., Gabrielsen, M., Chim, Y. H., Munro, J., McGhee, E. J., Sumpton, D., Eaton, P., Anderson, K. I., Yin, H. and Olson, M. F. (2015) Polarized cell motility induces hydrogen peroxide to inhibit cofilin via cysteine oxidation. Current Biology, 25(11), pp. 1520-1525. (doi:10.1016/j.cub.2015.04.020)

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Abstract

Mesenchymal cell motility is driven by polarized actin polymerization [1]. Signals at the leading edge recruit actin polymerization machinery to promote membrane protrusion, while matrix adhesion generates tractive force to propel forward movement. To work effectively, cell motility is regulated by a complex network of signaling events that affect protein activity and localization. H2O2 has an important role as a diffusible second messenger [2], and mediates its effects through oxidation of cysteine thiols. One cell activity influenced by H2O2 is motility [3]. However, a lack of sensitive and H2O2-specific probes for measurements in live cells has not allowed for direct observation of H2O2 accumulation in migrating cells or protrusions. In addition, the identities of proteins oxidized by H2O2 that contribute to actin dynamics and cell motility have not been characterized. We now show, as determined by fluorescence lifetime imaging microscopy, that motile cells generate H2O2 at membranes and cell protrusions and that H2O2 inhibits cofilin activity through oxidation of cysteines 139 (C139) and 147 (C147). Molecular modeling suggests that C139 oxidation would sterically hinder actin association, while the increased negative charge of oxidized C147 would lead to electrostatic repulsion of the opposite negatively charged surface. Expression of oxidation-resistant cofilin impairs cell spreading, adhesion, and directional migration. These findings indicate that H2O2 production contributes to polarized cell motility through localized cofilin inhibition and that there are additional proteins oxidized during cell migration that might have similar roles.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Munro, Dr June and Yin, Professor Huabing and Sumpton, Mr David and Anderson, Professor Kurt and McGhee, Dr Ewan and Gabrielsen, Dr Mads and Cameron, Mrs Jenifer and Olson, Professor Michael
Authors: Cameron, J. M., Gabrielsen, M., Chim, Y. H., Munro, J., McGhee, E. J., Sumpton, D., Eaton, P., Anderson, K. I., Yin, H., and Olson, M. F.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:Current Biology
Publisher:Cell Press
ISSN:0960-9822
ISSN (Online):1879-0445
Published Online:14 May 2015
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Current Biology 25(11):1520-1525
Publisher Policy:Reproduced under a Creative Commons License

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