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First published online December 22, 2004
doi: 10.1242/10.1242/jcs.01631

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Cofilin takes the lead

Department of Anatomy and Structural Biology, Albert Einstein College of Medicine Bronx, 1300 Morris Park Avenue, Bronx, NY 10461, USA

View larger version (32K): [in a new window]   Fig. 1. The steady-state and stimulated protrusion models. (A) In the steady-state model [based on Pollard et al. (Pollard et al., 2000)], cofilin functions only as a G-actin-recycling factor, depolymerizing filaments to G-actin at the base of the lamellipodium to sustain steady-state actin polymerization at the leading edge when G-actin is limiting (e.g. in continuously moving cells such as keratocytes). Dendritic nucleation at the leading edge occurs from the Arp2/3 complex at the interface with the cell membrane. (B) The stimulated protrusion model applies to situations when motility is not continuous and G-actin is not limiting. In this case, initiation of movement involves the localized activation of cofilin at the leading edge. Severing of actin filaments in the quiescent cortical cytoskeleton by cofilin creates free barbed ends that define the site of activation of the Arp2/3 complex. Polymerization of actin occurs from a pool of pre-existing G-actin and is not tightly coupled to depolymerization.

View larger version (23K): [in a new window]   Fig. 2. A hypothetical model for the activity cycle of cofilin in crawling tissue cells. Some motile cells, such as neutrophils, regulate cofilin by dephosphoylation of an inactive phosphorylated pool upon chemotactic stimulation (not shown). By contrast, others, such as carcinoma cells, might maintain the majority of cofilin prior to stimulation in a dephosphorylated yet inactive state (cfi) generated through interaction of cofilin with PtdIns(4,5)P2 and/or formation of cofilin–G-actin heterodimers. Following EGF stimulation, a PLC-dependent step releases activated cofilin (cfa), which then associates with F-actin to promote F-actin severing. This leads both to polymerization and depolymerization, the balance being determined by the relative availability of G-actin. Cofilin is rescued from the cofilin–G-actin heterodimer by two mechanisms. (1) Phosphorylation by LIM kinase (LIMK) or TES kinase (TESK) turns off the actin-binding activity of cf, releasing G-actin and phospho-cofilin. Cofilin phosphatases such as PP1, PP2A or SSH (slingshot) can then replenish the pool of dephosphorylated cofilin. (2) CAP can bind to the cofilin–G-actin heterodimer and release free cofilin and G-actin. The freed cofilin can bind to PtdIns(4,5)P2 to form an inhibitory complex that is released locally by EGF-stimulated receptors to begin the activity cycle again. Cofilin may bind directly to PtdIns(4,5)P2 or through another protein (X). CAP is a candidate for X since it regulates cofilin location in vivo. Localized activation of cofilin by PtdIns(4,5)P2 hydrolysis causes local actin polymerization and protrusion, and sets the direction of movement.

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