Phosphorylation of cofilin by LIM-kinase is necessary for semaphorin 3A-induced growth cone collapse

Abstract

Semaphorin 3A is a chemorepulsive axonal guidance molecule that depolymerizes the actin cytoskeleton and collapses growth cones of dorsal root ganglia neurons. Here we investigate the role of LIM-kinase 1, which phosphorylates an actin-depolymerizing protein, cofilin, in semaphorin 3A-induced growth cone collapse. Semaphorin 3A induced phosphorylation and dephosphorylation of cofilin at growth cones sequentially. A synthetic cell-permeable peptide containing a cofilin phosphorylation site inhibited LIM-kinase in vitro and in vivo, and essentially suppressed semaphorin 3A-induced growth cone collapse. A dominant-negative LIM kinase, which could not be activated by PAK or ROCK, suppressed the collapsing activity of semaphorin 3A. Phosphorylation of cofilin by LIM-kinase may be a critical signaling event in growth cone collapse by semaphorin 3A.

Phosphorylation of Actin-Depolymerizing Factor/Cofilin by LIM-Kinase Mediates Amyloid -Induced Degeneration: A Potential Mechanism of Neuronal Dystrophy in Alzheimer's Disease

“…4 A). This peptide has been successfully used to prevent LIMK1-mediated phosphorylation of ADF/cofilin after semaphorin 3A treatment (Aizawa et al, 2001). As expected, the addition of the S3 peptide to hippocampal cultures reduces the endogenous levels of P-cofilin in a time-and dose-dependent manner (Fig.…”

Signaling mechanisms that regulate actin‐based motility processes in the nervous system

“…Semaphorin 3A causes first phosphorylation, then dephosphorylation, of cofilin, suggesting that LIMK may be activated downstream of semaphorin 3A. A cell-permeable peptide fragment of cofilin that inhibits LIMK activity in vitro blocks semaphorin 3A-induced growth cone collapse, as does dominant-negative LIMK (Aizawa et al 2001). LIMK activity might be involved in synaptic maturation, as it becomes highly expressed in synaptic terminals during postnatal week 2, long after neurites have formed (Wang et al 2000).…”

Release of MICAL Autoinhibition by Semaphorin-Plexin Signaling Promotes Interaction with Collapsin Response Mediator Protein

“…After the binding of Sema3A to the coreceptor complex consisting of members of the Plexin-A (PlexA) and neuropilin-1 (NRP1) families of proteins (He and Tessier-Lavigne, 1997;Kolodkin et al, 1997;Takahashi et al, 1999;Tamagnone et al, 1999), neuronal growth cones collapse as a result of the dramatic rearrangement of the actin cytoskeleton and endocytosis of the plasma membrane (Luo et al, 1993;Fournier et al, 2000;Jurney et al, 2002;Castellani et al, 2004). A role for Rho-like GTPases (Jin and Strittmatter, 1997;Zanata et al, 2002;Turner et al, 2004;Toyofuku et al, 2005), protein phosphorylation (Aizawa et al, 2001;Eickholt et al, 2002;Mitsui et al, 2002;Sasaki et al, 2002), RanBPM (Togashi et al, 2006), and members of the collapsin response mediator protein (CRMP) family (Goshima et al, 1995;Deo et al, 2004) have all been shown to play a role in Sema3A signal transduction. In addition, the intracellular molecule interacting with CasL (MICAL) has been shown to bind to PlexA receptors in Drosophila and is required for proper guidance of motor axons (Terman et al, 2002).…”