Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization

Abstract

Rac is a small GTPase of the Rho family that mediates stimulus-induced actin cytoskeletal reorganization to generate lamellipodia. Little is known about the signalling pathways that link Rac activation to changes in actin filament dynamics. Cofilin is known to be a potent regulator of actin filament dynamics, and its ability to bind and depolymerize actin is abolished by phosphorylation of serine residue at 3; however, the kinases responsible for this phosphorylation have not been identified. Here we show that LIM-kinase 1 (LIMK-1), a serine/threonine kinase containing LIM and PDZ domains, phosphorylates cofilin at Ser 3, both in vitro and in vivo. When expressed in cultured cells, LIMK-1 induces actin reorganization and reverses cofilin-induced actin depolymerization. Expression of an inactive form of LIMK-1 suppresses lamellipodium formation induced by Rac or insulin. Furthermore, insulin and an active form of Rac increase the activity of LIMK-1. Taken together, our results indicate that LIMK-1 participates in Rac-mediated actin cytoskeletal reorganization, probably by phosphorylating cofilin.

Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: A perspective

“…While Rac entrains PAK for this function [66,67], Cdc42 signals through MRCK [36,65]. Finally, the recently discovered TESKs can directly phosphorylate cofilin [68], perhaps in response to Rac signaling [69] (Fig.…”

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

“…LIMK is the regulatory link between rho GTPase signaling and cofilin activity. Inactive LIMK blocks rac-and insulin-induced lamellipodium formation (Yang et al 1998), as well as rho-induced stress fibers and cdc42-induced filopodia (Sumi et al 1999). Rac and cdc42 signal to LIMK via PAK, which phosphorylates and activates LIMK on threonine 508 (Edwards et al 1999).…”

Cofilin-1 is involved in regulation of actin reorganization during influenza A virus assembly and budding

“…The major actin-depolymerizing factor (ADF)/cofilin isoform, Cofilin-1 is primarily responsible for dynamic actin cytoskeletal reorganization [15], and functions depending on its local concentration of active form relative to actin: relative low concentrations of active cofilin to actin favor severing, whereas high concentrations of cofilin favor nucleating actin assembly [34]. Cofilin-1 is deactivated by phosphorylation on Ser-3 by LIM-kinase1 (LIMK1), and results in an increase in F-actin [35,36]. Disruption of the LIMK1-cofilin pathway affected viral releases of Mason-Pfizer monkey virus (M-PMV) and HIV-1 [21], as well as the entry and replication of HSV-1 [22,23,24].…”