Activated by Actin

Science's STKE  01 Jun 2004:
Vol. 2004, Issue 235, pp. tw198-TW198
DOI: 10.1126/stke.2352004TW198

In order for cells to extend lamellipodia and migrate, there must be regulated assembly and disassembly of actin filaments. Cofilin promotes actin filament disassembly. Cofilin is regulated by phosphorylation, with the LIM-kinase phosphorylating and inactivating cofilin and the phosphatase Slingshot-1L (SSH1L) activating cofilin. Nagata-Ohashi et al. showed that exposure of MCF-7 breast cancer cells to neuregulin-1β stimulated the dephosphorylation of cofilin and formation of lamellipodia. This was accompanied by redistribution of SSH1L to actin-rich lamellipodia, which was blocked by disruption of the actin cytoskeleton with latrunculin A. Furthermore, latrunculin A prevented the dephosphorylation of cofilin in cells overexpressing SSH1L. In vitro, the activity of SSH1L was stimulated by filamentous actin (F-actin), but not by monomeric actin (G-actin). The authors searched for proteins that may serve to sequester SSH1L in unstimulated cells and identified members of the 14-3-3 family. In vitro, the presence of 14-3-3 proteins prevented the activation of SSH1L by F-actin. Cells overexpressing 14-3-3 proteins exhibited increased levels of phosphorylated cofilin, decreased lamellipodia formation, and blocked translocation of SSH1L to lamellipodia. Cell fractionation studies confirmed that neuregulin stimulated the insoluble (cytoskeleton-bound) pool of SSH1L, and this effect was blocked by overexpression of 14-3-3. Thus, the authors suggest that 14-3-3 may sequester SSH1L in the cytosol in unstimulated cells. Upon stimulation of cells by promigratory ligands, SSH1L may redistribute to the actin cytoskeleton, where it is activated and dephosphorylates cofilin, promoting actin filament turnover and allowing extension of lamellipodia and cell migration.

K. Nagata-Ohashi, Y. Ohta, K. Goto, S. Chiba, R. Mori, M. Nishita, K. Ohashi, K. Kousaka, A. Iwamatsu, R. Niwa, T. Uemura, K. Mizuno, A pathway of neuregulin-induced activation of cofilin-phosphatase Slingshot and cofilin in lamellipodia. J. Cell Biol. 165, 465-471 (2004). [Abstract] [Full Text]