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

Kyoko Nagata-Ohashi, Yusaku Ohta, Kazumichi Goto, Shuhei Chiba, Reiko Mori, Michiru Nishita, Kazumasa Ohashi, Kazuyoshi Kousaka, Akihiro Iwamatsu, Ryusuke Niwa, Tadashi Uemura, Kensaku Mizuno

Research output: Contribution to journalArticlepeer-review

148 Citations (Scopus)

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 ∼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.

Original languageEnglish
Pages (from-to)465-471
Number of pages7
JournalJournal of Cell Biology
Volume165
Issue number4
DOIs
Publication statusPublished - 2004 May 24

Keywords

  • 14-3-3
  • Actin filaments
  • Cell polarity
  • LIM-kinase
  • MCF-7

ASJC Scopus subject areas

  • Cell Biology

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