Article

Arber, S. et al. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature 393, 805-809

Friedrich Miescher Institute, Basel, Switzerland.
Nature (Impact Factor: 42.35). 07/1998; 393(6687):805-9. DOI: 10.1038/31729
Source: PubMed

ABSTRACT Cell division, cell motility and the formation and maintenance of specialized structures in differentiated cells depend directly on the regulated dynamics of the actin cytoskeleton. To understand the mechanisms of these basic cellular processes, the signalling pathways that link external signals to the regulation of the actin cytoskeleton need to be characterized. Here we identify a pathway for the regulation of cofilin, a ubiquitous actin-binding protein that is essential for effective depolymerization of actin filaments. LIM-kinase 1, also known as KIZ, is a protein kinase with two amino-terminal LIM motifs that induces stabilization of F-actin structures in transfected cells. Dominant-negative LIM-kinasel inhibits the accumulation of the F-actin. Phosphorylation experiments in vivo and in vitro provide evidence that cofilin is a physiological substrate of LIM-kinase 1. Phosphorylation by LIM-kinase 1 inactivates cofilin, leading to accumulation of actin filaments. Constitutively active Rac augmented cofilin phosphorylation and LIM-kinase 1 autophosphorylation whereas phorbol ester inhibited these processes. Our results define a mechanism for the regulation of cofilin and hence of actin dynamics in vivo. By modulating the stability of actin cytoskeletal structures, this pathway should play a central role in regulating cell motility and morphogenesis.

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    • "Chai et al. (2009) have previously shown that Reelin phosphorylates the actindepolymerizing protein cofilin. Phosphorylation of cofilin renders it unable to depolymerize actin, thereby stabilizing the actin cytoskeleton (Arber et al. 1998; Yang et al. 1998). "
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    • "We have recently reported that the actin-severing activity of CFL-1 is crucial for its localization to the TGN as well as for the facilitation of secretory cargo sorting (von Blume et al., 2009, 2011). Phosphorylation of CFL-1 at Serine 3 (Ser3) by LIM kinase (LIMK) inactivates CFL-1, whereas dephosphorylation reactivates it (Arber et al., 1998). Furthermore, the phosphorylation of CFL-1 at this side impairs its ability to bind to F-actin (Agnew et al., 1995). "
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    • "An analysis of the levels of pY421-cortactin at various time points of the TTX treatment, revealed that there were reductions in the amount of pY421-cortactin at all time points analyzed (5, 10, 20 and 30 minutes, and 1, 2 and 24 hours of treatment) compared to the control conditions (data not shown). By contrast, blocking Na V 1.5 had no effect on the phosphorylation of cofilin on S3 (Fig. 4E), which has been shown to be critical for binding to actin (Arber et al., 1998). This suggests that Na V 1.5 might regulate Src kinase and not LIM kinase. "
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