Reactive oxygen species and hydrogen peroxide generation in cell migration

Abstract

Directional cell migration is a complex process that requires spatially and temporally co-ordinated regulation of actin cytoskeleton dynamics. In response to external cues, signals are transduced to elicit cytoskeletal responses. It has emerged that reactive oxygen species, including hydrogen peroxide, are important second messengers in pathways that influence the actin cytoskeleton, although the identities of key proteins regulated by hydrogen peroxide are largely unknown. We recently showed that oxidation of cofilin1 is elevated in migrating cells relative to stationary cells, and that the effect of this post-translational modification is to reduce cofilin1-actin binding and to inhibit filamentous-actin severing by cofilin1. These studies revealed that cofilin1 regulation by hydrogen peroxide contributes to directional cell migration, and established a template for discovering additional proteins that are regulated in an analogous manner.

Keywords: ROS; actin; chemotaxis; cofilin; cytoskeleton; hydrogen peroxide; motility.

Figure 1.

Model of cofilin oxidation in cell migration. Hydrogen peroxide (H₂O₂), acting directly as a chemoattractant or produced by activated NOX or MICAL enzymes, oxidizes cofilin1 at the leading edge of a cell. Consequently cofilin1 is prevented from binding to and severing or depolymerising filamentous actin, leading to net increases in actin polymerization. Meanwhile, cofilin1 further from the front of a protrusion remains active, supplying G-actin and polymerized actin barbed ends required to drive the continued growth of the protrusion. This localized control of cofilin1 activity facilitates cell migration by allowing protrusions to develop and extend.