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Vol. 20, Issue 11, 2650-2660, June 1, 2009
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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
protein through the redox-mediated oxidation of 14-3-3
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
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.
Address correspondence to: Gary M. Bokoch (bokoch{at}scripps.edu)
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