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Figure 2.
Possible roles of cofilin and phospho-cofilin in the establishment of the leading edge
In response to signaling through a receptor tyrosine kinase (RTK), phospholipase C gamma (PLCĪ³) is activated and hydrolyzes phosphatidylinositol-4,5-bisphosphate (PtdIns4,5P2), releasing active cofilin from its inhibitory binding, allowing severing of capped quiescent filaments, and generating free barbed ends for driving assembly. Actin-related protein 2 and 3 (Arp2/3) complex is also activated via Wiskott-Aldrich syndrome protein (WASP) to set up the branched filament network driving forward protrusion of the membrane. The RTK also recruits phosphatidylinositol 3-kinase (PIK), generating PtdIns3,4,5P3, which serves as a docking site for the binding of dedicator of cytokinesis 2 (DOCK2). The Rac1 guanine nucleotide exchange activity of DOCK2 is exposed only upon binding of the tail of DOCK2 to phosphatidic acid (PA). PA is generated from the hydrolysis of other phospholipids, such as phosphatidylcholine (PC), by the enzyme phospholipase D1 (PLD1), which is activated by P-cofilin. Active Rac1 activates the p21-activated kinase (PAK1), which activates the cofilin phosphorylation through LIM kinase (LIMK). This feed-forward cycle maintains active Rac1 at the leading edge but becomes self-limiting when cofilin phosphatases also are recruited or become active through downstream signals from these (e.g., inositol triphosphate [IP3] → calcium → calmodulin → calcineurin → slingshot phosphatase) and/or other pathways. DAG, diacylglycerol; GEF, guanine nucleotide exchange factor; NCK, adaptor molecule with src homology domains 2 and 3; PIP2, phosphatidyinositol diphosphate; PIP3, phosphatidyinositol triphosphate. |
