A pathway of neuregulin-induced activation of cofilin-phosphatase Slingshot and cofilin in lamellipodia.
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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
A pathway of neuregulin-induced activation of cofilin-phosphatase Slingshot and cofilin in lamellipodia.
J Cell Biol. 2004 May 24;165(4):465-71.
- PubMed ID
- 15159416 [ View in PubMed]
- Abstract
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 approximately 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-1beta 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-1beta and 14-3-3 proteins negatively regulate SSH1L activity by sequestering it in the cytoplasm.