Cell division, cell motility and the formation and maintenance of specialized structures in differentiated cells depend directly on the regulated dynamics of the actin cytoskeleton1,2. 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 characterized2,3. Here we identify a pathway for the regulation of cofilin, a ubiquitous actin-binding protein that is essential for effective depolymerization of actin filaments4,5,6,7,8. LIM-kinase 1, also known as KIZ, is a protein kinase with two amino-terminal LIM motifs9,10,11 that induces stabilization of F-actin structures in transfected cells. Dominant-negative LIM-kinase1 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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We thank J. Adams, T. Jessell, W. Krek, U. Müller and G. Thomas for comments on the manuscript. S.A. and H.H. were supported by grants from the Swiss Foundation for Research on Muscle Diseases. O.B. was supported by the Australian NH-MRC, and the Australian Cooperative Research Centre Scheme, and O.B. and C.A.S. were supported by the National Multiple Sclerosis Society of Australia.
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Arber, S., Barbayannis, F., Hanser, H. et al. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature 393, 805–809 (1998). https://doi.org/10.1038/31729
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