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Originally published as MBC in Press, 10.1091/mbc.E09-02-0131 on April 8, 2009 Originally published as MBC in Press, 10.1091/mbc.E09-02-0131 on April 1, 2009

Vol. 20, Issue 11, 2650-2660, June 1, 2009

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Reactive Oxygen Species Regulate a Slingshot-Cofilin Activation Pathway

Jun-Sub Kim, Timothy Y. Huang, and Gary M. Bokoch

Department of Immunology and Microbial Science and Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037

Submitted February 13, 2009; Revised March 20, 2009; Accepted March 24, 2009
Monitoring Editor: Jonathan Chernoff

Cellular stimuli generate reactive oxygen species (ROS) via the local action of NADPH oxidases (Nox) to modulate cytoskeletal organization and cell migration through unknown mechanisms. Cofilin is a major regulator of cellular actin dynamics whose activity is controlled by phosphorylation/dephosphorylation at Ser3. Here we show that Slingshot-1L (SSH-1L), a selective cofilin regulatory phosphatase, is involved in H2O2-induced cofilin dephosphorylation and activation. SSH-1L is activated by its release from a regulatory complex with 14-3-3{zeta} protein through the redox-mediated oxidation of 14-3-3{zeta} by H2O2. The ROS-dependent activation of the SSH-1L-cofilin pathway stimulates the SSH-1L–dependent formation of cofilin-actin rods in cofilin-GFP–expressing HeLa cells. Similarly, the formation of endogenous ROS stimulated by angiotensin II (AngII) also activates the SSH-1L-cofilin pathway via oxidation of 14-3-3{zeta} to increase AngII-induced membrane ruffling and cell motility. These results suggest that the formation of ROS by NADPH oxidases engages a SSH-1L-cofilin pathway to regulate cytoskeletal organization and cell migration.


This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E09-02-0131) on April 1, 2009.

Address correspondence to: Gary M. Bokoch (bokoch{at}scripps.edu)




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