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A pathway of neuregulin-induced activation of cofilin-phosphatase Slingshot and cofilin in lamellipodia

¹ Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan
² Department of Molecular Genetics, Institute for Virus Research, Kyoto University, and Core Research for Evolution Science and Technology (CREST), Japan Science and Technology Corporation (JST), Kyoto 606-8507, Japan
³ Protein Research Network, Inc., Fukuura, Yokohama 236-0004, Japan

Address correspondence to K. Mizuno, Dept. of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Aoba-ku, Sendai, Miyagi 980-8578, Japan. Tel.: 81-22-217-6676. Fax: 81-22-217-6678. email: kmizuno{at}biology.tohoku.ac.jp

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-1ß 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-1ß and 14-3-3 proteins negatively regulate SSH1L activity by sequestering it in the cytoplasm.

Key Words: LIM-kinase; cell polarity; 14-3-3; actin filaments; MCF-7

Abbreviations used in this paper: Lat-A, latrunculin-A; LIMK, LIM-kinase; NRG, neuregulin-1ß; P-cofilin, Ser-3–phosphorylated cofilin; pS, phospho-Ser; SSH1L, Slingshot-1L.

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