Reactive Oxygen Species Regulate a Slingshot-Cofilin Activation Pathway
Reactive Oxygen Species Regulate a Slingshot-Cofilin Activation Pathway
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DOI：
10.1091/mbc.e09-02-0131
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发表时间：
2009-06-01
影响因子：
3.3
通讯作者：
Bokoch, Gary M.
中科院分区：
文献类型：
--
作者：
Kim, Jun-Sub;Huang, Timothy Y.;Bokoch, Gary M.
细胞刺激通过 NADPH 氧化酶 (Nox) 的局部作用产生活性氧 (ROS)，通过未知机制调节细胞骨架组织和细胞迁移。 Cofilin 是细胞肌动蛋白动力学的主要调节因子，其活性由 Ser3 磷酸化/去磷酸化控制。在这里，我们证明 Slingshot-1L (SSH-1L) 是一种选择性肌动蛋白丝切蛋白调节磷酸酶，参与 H2O2 诱导的肌动蛋白丝切蛋白去磷酸化和激活。 SSH-1L 通过 H2O2 介导的氧化还原介导的 14-3-3 zeta 氧化从与 14-3-3 zeta 蛋白的调节复合物中释放而被激活。 SSH-1L-cofilin 通路的 ROS 依赖性激活刺激表达 cofilin-GFP 的 HeLa 细胞中 SSH-1L 依赖性 cofilin-肌动蛋白杆的形成。同样，血管紧张素 II (AngII) 刺激的内源性 ROS 的形成也会通过 14-3-3 zeta 的氧化激活 SSH-1L-cofilin 通路，从而增加 AngII 诱导的膜皱褶和细胞运动。这些结果表明，NADPH 氧化酶形成的 ROS 参与了 SSH-1L-cofilin 途径来调节细胞骨架组织和细胞迁移。
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.