A pathway of neuregulin-induced activation of cofilin-phosphatase Slingshot and cofilin in lamellipodia.
A pathway of neuregulin-induced activation of cofilin-phosphatase Slingshot and cofilin in lamellipodia.
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DOI：
10.1083/jcb.200401136
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发表时间：
2004-05-24
期刊：
影响因子：
--
通讯作者：
Mizuno K
中科院分区：
文献类型：
--
作者：
Nagata-Ohashi K;Ohta Y;Goto K;Chiba S;Mori R;Nishita M;Ohashi K;Kousaka K;Iwamatsu A;Niwa R;Uemura T;Mizuno K
Cofilin通过刺激迁移细胞前缘的肌动蛋白丝动态来介导板状伪足的延伸和极化细胞迁移。Cofilin通过Ser-3的磷酸化而失活，并通过Cofilin-phosphatase Slingshot-1 L（SSH 1 L）再活化。很少有人知道的cofilin激活的信号转导机制，以及这种激活是如何空间调节。在这里，我们发现，Cofilin磷酸酶活性增加10倍，与肌动蛋白丝，这表明肌动蛋白组装在前沿本身触发局部激活SSH 1 L，从而刺激Cofilin介导的肌动蛋白在板状伪足的营业额。我们还提供了证据表明，14-3-3蛋白抑制SSH 1 L活性，依赖于SSH 1 L的Ser-937和Ser-978的磷酸化。用神经调节蛋白-1 β刺激细胞诱导Ser-978去磷酸化，SSH 1 L易位到富含F-肌动蛋白的板状伪足上，以及cofilin去磷酸化。这些发现表明，SSH 1 L通过移位到板状伪足中的F-肌动蛋白并与之结合而局部激活，以响应神经调节蛋白-1 β，并且14-3-3蛋白通过将SSH 1 L隔离在细胞质中来负调节SSH 1 L活性。
Cofilin mediates lamellipodium extension and polarized cell migration by stimulating actin filament dynamics at the leading edge of migrating cells. Cofilin is inactivated by phosphorylation at Ser-3 and reactivated by cofilin-phosphatase Slingshot-1L (SSH1L). Little is known of signaling mechanisms of cofilin activation and how this activation is spatially regulated. Here, we show that cofilin-phosphatase activity of SSH1L increases ∼10-fold by association with actin filaments, which indicates that actin assembly at the leading edge per se triggers local activation of SSH1L and thereby stimulates cofilin-mediated actin turnover in lamellipodia. We also provide evidence that 14-3-3 proteins inhibit SSH1L activity, dependent on the phosphorylation of Ser-937 and Ser-978 of SSH1L. Stimulation of cells with neuregulin-1β induced Ser-978 dephosphorylation, translocation of SSH1L onto F-actin–rich lamellipodia, and cofilin dephosphorylation. These findings suggest that SSH1L is locally activated by translocation to and association with F-actin in lamellipodia in response to neuregulin-1β and 14-3-3 proteins negatively regulate SSH1L activity by sequestering it in the cytoplasm.
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影响因子：
3.3
作者：
MOON, A;DRUBIN, DG
通讯作者：
DRUBIN, DG
影响因子：
2.1
作者：
Ohta, Y;Kousaka, K;Mizuno, K
通讯作者：
Mizuno, K
影响因子：
9.2
作者：
Gohla, A;Bokoch, GM
通讯作者：
Bokoch, GM
影响因子：
4.8
作者：
Toshima, JY;Toshima, J;Mizuno, K
通讯作者：
Mizuno, K
影响因子：
9.2
作者：
Dawe, HR;Minamide, LS;Cramer, LP
通讯作者：
Cramer, LP