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 14-3-3 protein through the redox-mediated oxidation of 14-3-3 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 14-3-3 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.

Current versus future reproduction and longevity: a re-evaluation of predictions and mechanisms

“…At least under relatively stable environmental and social conditions (Garratt et al, 2011), there is little reason to expect that ROS levels should increase, or that damage should accumulate, during reproduction. ROS can also induce a variety of intracellular signalling cascades that affect antioxidant capacity (D'Autreaux and Toledano, 2007), oxidative damage repair pathways (Morimoto and Santoro, 1998), cell proliferation (Le Belle et al, 2011), cell migration (Kim et al, 2009), mitochondrial biogenesis (Sano and Fukuda, 2008) and cellular apoptosis (Fleury et al, 2002). These responses to moderate ROS production have the potential to prevent or neutralize negative effects on bioenergetics and, in some cases, these responses may be responsible for positive effects (see below).…”

Targeting 14-3-3zeta in cancer therapy

“…The oxidation of 14-3-3zeta activates the SSH-1L-cofilin pathway to increase membrane ruffling and cell motility, and regulates cytoskeletal organization and cell migration. 55,56 The ADAM family contains disintegrin-like and metalloproteinase-like domains, which potentially have cell adhesion and protease activities. Exogenous 14-3-3zeta greatly enhanced the adhesion and spreading of cells overexpressing ADAM22.…”

Tumor metabolism, cancer cell transporters, and microenvironmental resistance

“…Furthermore, PPP maintains cellular redox status by providing a reduced form of glutathione which removes reactive oxygen species (ROS). Although the generation of ROS is an indication of cell death or induction of gene variation (mutation), ROS are also signaling molecules that are useful in the manipulation of cellular migration [3][4][5][6] . The generation of lactic acid is very helpful in allowing the progression of metastasis.…”