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: 41.46). 07/1998; 393(6687):805-9. DOI: 10.1038/31729
Source: PubMed


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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    • "Once activated, LIMKs phosphorylate members of the ADF/cofilin family (comprising ADF, cofilin 1 and 2) and inactivate them, preventing these actin depolymerization factors from severing filamentous actin and allowing accumulation of actin microfilaments [15]. ADF/cofilin are all mainly controlled by LIMKs and Slingshot phosphatases (SSH) through phosphorylation (inactivation) and dephosphorylation (activation) on their serine 3, respectively [16] [17]. SSH family includes three members: SSH1, SSH2 and SSH3 [18]. "
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    ABSTRACT: LIM kinase 1 (LIMK1) and LIM kinase 2 (LIMK2) regulate actin dynamics by phosphorylating cofilin. In this review, we outline studies that have shown an involvement of LIMKs in neuronal function and we detail some of the pathways and molecular mechanisms involving LIMKs in neurodevelop-ment and synaptic plasticity. We also review the involvement of LIMKs in neuronal diseases and emphasize the differences in the regulation of LIMKs expression and mode of action. We finally present the existence of a cofilin-independent pathway also involved in neuronal function. A better understanding of the differences between both LIMKs and of the precise molecular mechanisms involved in their mode of action and regulation is now required to improve our understanding of the physiopathology of the neuronal diseases associated with LIMKs.
    Full-text · Article · Nov 2015 · FEBS Letters
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    • "The ADF/cofilin family of proteins is essential for severing and depolymerizing actin filaments to increase the rate of actin filament turnover (Ono, 2007; Van Troys et al., 2008; Bernstein and Bamburg, 2010). ADF/cofilin is inactivated and reactivated via phosphorylation/ dephosphorylation by LIM-kinases (Limk) (Arber et al., 1998; Yang et al., 1998) and by Slingshot (SSH) (Niwa et al., 2002), respectively. The formation of WMS and the MTOC-TMA can be disrupted by injection of constitutively active Limk in Xenopus oocytes; this disruption by Limk can be suppressed when combined with a constitutively active form of Xenopus ADF/cofilin (XAC) (Abe et al., 1996; Takahashi et al., 2001). "
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    ABSTRACT: We have examined reorganization of actin filaments and microtubules during Xenopus oocyte maturation. Surrounding the germinal vesicle (GV) in immature oocytes, the cytoplasmic actin filaments reorganized to accumulate beneath the vegetal side of GV, where MTOC-TMA assembled, just before GV breakdown (GVBD). Immediately after GVBD, both Xenopus ADF/cofilin (XAC) and its phosphatase Slingshot (XSSH) accumulated into the nuclei and intranuclear actin filaments disassembled from the vegetal side with the shrinkage of GV. As the MTOC-TMA developed well, cytoplasmic actin filaments were retained at the MTOC-TMA base region. Suppression of XAC dephosphorylation by anti-XSSH antibody injection inhibited both the actin filament reorganization and the proper formation and localization of both the MTOC-TMA and meiotic spindles. Stabilization of actin filaments by phalloidin also inhibited the formation of the MTOC-TMA and the disassembly of intranuclear actin filaments without affecting the nuclear shrinkage. Nocodazole also caused the MTOC-TMA and the cytoplasmic actin filaments at its base region to disappear which further impeded disassembly of intranuclear actin filaments from the vegetal side. Taken together, XAC appears to reorganize cytoplasmic actin filaments required for precise assembly of the MTOC and, together with the MTOC-TMA, to regulate the intranuclear actin filament disassembly essential for meiotic spindle formation.
    Preview · Article · Sep 2015 · Molecular Biology of the Cell
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    • "In the last few decades, a large number of key molecules has been discovered and studied where they are understood to play an important role in the sensing of chemical stimuli as well as the subsequent polarization, regulation of the actin cytoskeleton and the generation of mechanical forces [46]. Among these molecules are small GTPases [45] [22], PI3K, PTEN, PIPs, [12] [5] [25], Arp2/3 [44] [47] and Cofilin [53] [2]. "
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    ABSTRACT: During cell migration, cells become polarized, change their shape, and move in response to various cues, both internal and external. Many existing mathematical models of cell polarization are formulated in one or two spatial dimensions and hence cannot accurately capture the effect of cell shape, as well as the response of the cell to signals from different directions in a three-dimensional environment. To study those effects, we introduce a three-dimensional reaction-diffusion model of a cell. As some key molecules in cell polarization, such as the small GTPases, can exist both membrane bound and soluble in the cytosol, we first look at the role of cell geometry on the membrane binding/unbinding dynamics of such molecules. We derive quite general conditions under which effective existing one or two-dimensional computational models are valid, and find novel renormalizations of parameters in the effective model. We then extend an established one-dimensional cell polarization pathway in our three-dimensional framework. Our simulations indicate that even in some quasi-one-dimensional scenarios, such as polarization of a cell along a linear growth factor gradient, the cell shape can influence the polarization behavior of the cell, with cells of some shape polarizing more efficiently than those of other shapes. We also investigate the role of the previously ignored membrane unbinding rate on polarization. Furthermore, we simulate the response of the cell when the external signal is changing directions, and we find that more symmetric cells can change their polarized state more effectively towards the new stimulus than cells which are elongated along the direction of the original stimulus.
    Full-text · Article · Aug 2015
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