Figure 2. Recently discovered roles for cofilin in lipid metabolism and signaling and in pH-regulated actin remodeling.

(a) Phospho-cofilin is an activator of phospholipase D1 (PLD1) and thus a regulator of phosphatidic acid (PtdOH) production. PtdOH plays multiple roles in the activation of Rac1, a Rho family GTPase, as well as directly activating PAK1, a kinase that is also downstream of active Rac1. PAK1 is an activator of the cofilin kinase LIMK1. Thus a phospho-cofilin/PtdOH positive feedback cycle exists. (b) Many receptors along with intracellular acidity activate the Na⁺/H⁺ exchanger (NHE1), linked via molecules in the ezrin/moesin/radixin family (shown in pink) to the actin cytoskeleton. The influx of Na⁺ and efflux of H⁺ locally elevates pH that enhances the release of cofilin from its inhibitory membrane binding to PtdIns(3,4)P₂. Released cofilin may then contribute to actin remodeling that can decrease the flux of the NHE1 and lower pH. Thus cofilin is a likely regulator of pH homeostasis.