The cofilin activity cycle in lamellipodia and invadopodia

Abstract

The actin severing protein cofilin is essential for directed cell migration and chemotaxis, in many cell types and is also important for tumor cell invasion during metastasis. Through its severing activity, cofilin increases the number of free barbed ends to initiate actin polymerization for actin-based protrusion in two distinct subcellular compartments in invasive tumor cells: lamellipodia and invadopodia. Cofilin severing activity is tightly regulated and multiple mechanisms are utilized to regulate cofilin activity. In this prospect, we have grouped the primary on/off regulation into two broad categories, both of which are important for inhibiting cofilin from binding to F-actin or G-actin: (1) Blocking cofilin activity by the binding of cofilin to either PI(4,5)P2 at lamellipodia, or cortactin at invadopodia. (2) Blocking cofilin's ability to bind to actin via serine phosphorylation. Although the literature suggests that these cofilin regulatory mechanisms may be cell-type dependent, we propose the existence of a common cofilin activity cycle in which both operate. In this common cycle, the mechanism used to initiate cofilin activity is determined by the starting point in the cycle in a given subcellular compartment.

βArrestin1 Regulates the Guanine Nucleotide Exchange Factor RasGRF2 Expression and the Small GTPase Rac-mediated Formation of Membrane Protrusion and Cell Motility

“…Phosphorylation of serine 3 by LIM kinase inhibits cofilin binding to actin, and dephosphorylation of cofilin by slingshot or chronophin activates it (38). Our results show that depletion of ␤Arr1 results in cofilin dephosphorylation, which is a direct effect of up-regulated expression of RasGRF2 and consequent activation of Rac.…”

“…Rac is known to promote actin polymerization at cell protrusions through the activation of, among others, the actin-severing protein cofilin (37) whose activity is tightly controlled by phosphorylation (38). Phosphorylation of serine 3 by LIM kinase inhibits cofilin binding to actin, and dephosphorylation of cofilin by slingshot or chronophin activates it (38).…”

Focus on ADF/Cofilin: Beyond Actin Cytoskeletal Regulation

“…ADF/cofilin not only severs or depolymerizes actin filaments but also cooperates with other actin-binding proteins to assemble stress fiber and lamellipodia formed by filamentous actin [21,22]. Formation of stress fibers and lamellipodia is regulated by Rho signaling pathway, which mediates various downstream kinase activity to phosphorylate ADF/cofilin, tropomyosin, and light chain of myosin II (MLC) [23].…”

Globular adiponectin induces LKB1/AMPK-dependent glucose uptake via actin cytoskeleton remodeling

“…Thus, adiponectin induces specific remodeling of actin cytoskeleton in different cell types with diverse functional outcomes. Cofilin is an actin-severing protein known to regulate actin dynamics by depolymerizing F-actin, resulting in free actin monomers and creating barbed ends along F-actin structures, both of these functioning to maintain a steady state of actin polymerization (Oser & Condeelis 2009). In its unphosphorylated state, cofilin is active and dephosphorylates filamentous actin, resulting in free globular actin units (Ridley 2006, Oser & Condeelis 2009.…”

“…Cofilin is an actin-severing protein known to regulate actin dynamics by depolymerizing F-actin, resulting in free actin monomers and creating barbed ends along F-actin structures, both of these functioning to maintain a steady state of actin polymerization (Oser & Condeelis 2009). In its unphosphorylated state, cofilin is active and dephosphorylates filamentous actin, resulting in free globular actin units (Ridley 2006, Oser & Condeelis 2009. When phosphorylated at serine-3 by LIMK1, cofilin is inactive and filamentous actin remains intact, thus allowing for the extension of the F-actin network (Bernard 2007, Oser & Condeelis 2009).…”