The common cofilin activity cycle in invasive tumor cells and inflammatory cells. Cofilin molecules cycle through three compartments in the cell: the cytosol, F-actin and the PM compartments. Cofilin is inactivated at the PM by binding to PtdIns(4,5)P₂, and in the cytosol by either low pH levels or phosphorylation. Upon activation, cofilin translocates from the PM and cytosolic compartments to the F-actin compartment. The translocation of cofilin from the PM to the F-actin compartment is induced by a PLCγ-mediated decrease in PtdIns(4,5)P₂ levels, which is amplified by an increase in pH (mediated by the Na⁺-H⁺ exchanger NHE1), which reduces the affinity of cofilin for PtdIns(4,5)P₂, whereas the translocation from the cytosol to the PM compartment is induced by dephosphorylation of cofilin. At the F-actin compartment, cofilin binds to and severs actin filaments, which results in filaments with free barbed ends and the formation of cofilin–G-actin complexes. These complexes cannot bind to actin or the PM, and therefore diffuse to the cytosol compartment, where cofilin is phosphorylated and released from the cofilin–G-actin complex by LIMK. A new cycle is started when cofilin is dephosphorylated (by SSH, for example), which results in the re-entry of cofilin to the PM or F-actin compartment. The generation of actin free barbed ends by cofilin initiates the polymerization of new actin filaments to which the ARP2/3 complex prefers to bind, which amplifies cofilin-induced actin polymerization and results in the formation of cellular protrusions. `+' indicates pH increase.

The actin-severing and -depolymerization activity of cofilin is regulated by several mechanisms. (A) The barbed ends of filamentous actin (F-actin) can be capped by capping proteins, preventing further polymerization. Cofilin binds to and severs F-actin, creating both barbed and pointed ends. From the pointed ends, the filaments depolymerize and thereby increase the concentration of monomeric globular actin (G-actin). The new `free' barbed ends can be extended by incorporation of G-actin. Therefore, cofilin can induce both the polymerization and depolymerization of F-actin. (B) The binding of cofilin to actin is inhibited by the phosphorylation of cofilin at Ser3, and by the binding of PtdIns(4,5)P₂ to cofilin. Upon dephosphorylation of cofilin, or release of cofilin from PtdIns(4,5)P₂ by PLCγ-dependent hydrolysis, cofilin becomes active.