title: Reactive oxygen species regulate a slingshot-cofilin activation pathway.
abstract: 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 H(2)O(2)-induced cofilin dephosphorylation and activation. SSH-1L is activated by its release from a regulatory complex with 14-3-3zeta protein through the redox-mediated oxidation of 14-3-3zeta by H(2)O(2). 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 14-3-3zeta 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.
authors.affiliation: Department of Immunology and Microbial Science and Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jun-Sub
authors.initials: JS
authors.lastname: Kim
authors.forename: Timothy Y
authors.initials: TY
authors.lastname: Huang
authors.forename: Gary M
authors.initials: GM
authors.lastname: Bokoch