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.
    FEBS Letters 11/2015; DOI:10.1016/j.febslet.2015.10.032 · 3.17 Impact Factor
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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.
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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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    ABSTRACT: Newborn neurons migrate along the processes of radial glial cells (RGCs) to reach their final positions in the cortex. Here, we visualized individual migrating neurons and RGCs using in utero electroporation. We show that branching of migrating neurons and RGCs is closely correlated spatiotemporally with the distribution of Reelin. Time-lapse imaging revealed that the leading processes of migrating neurons gave rise to increasingly more branches once their growth cones contacted the Reelin-containing marginal zone. This was accompanied by translocation of the nucleus and gradual shortening of the leading process. Absence of Reelin in reeler mice altered these processes resulting in misorientation, loss of bipolarity, and aberrant migration of cortical neurons. Moreover, in reeler, the branching of the basal processes of RGCs in the marginal zone was severely disrupted. Consistent with previous reports, we show that in dissociated reeler cortical cultures, exposure to recombinant Reelin enhanced dendritic complexity and glial branching. Our results suggest that Reelin induces branching of the leading processes of migrating neurons and that of basal processes of RGCs when they arrive at the Reelin-containing marginal zone. Branching of these processes may be crucial for the termination of nuclear translocation during the migratory process and for correct neuronal positioning.
    Cerebral Cortex 09/2014; DOI:10.1093/cercor/bhu216 · 8.67 Impact Factor
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