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

J Cell Biol. 2004 May 24;165(4):465-71. doi: 10.1083/jcb.200401136.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins
  • Actin Cytoskeleton / metabolism
  • Actin Depolymerizing Factors
  • Animals
  • COS Cells
  • Cell Line, Tumor
  • Cell Movement / physiology*
  • Chlorocebus aethiops
  • Cytoplasm / metabolism
  • Humans
  • Microfilament Proteins / metabolism*
  • Neuregulin-1 / metabolism*
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation
  • Protein Transport / physiology
  • Pseudopodia / metabolism*
  • Pseudopodia / ultrastructure
  • Signal Transduction / physiology
  • Tyrosine 3-Monooxygenase / metabolism
  • Up-Regulation / physiology

Substances

  • 14-3-3 Proteins
  • Actin Depolymerizing Factors
  • Microfilament Proteins
  • Neuregulin-1
  • Tyrosine 3-Monooxygenase
  • Phosphoprotein Phosphatases
  • SSH1 protein, human