Studies on molecular mechanisms that regulate Filamin A subcellular localization and resultant changes in cell morphology.

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Directed cell movement is accompanied with lamellipodium formation at the front side. Phosphatidylinositol 3,4,5-triphosphates (PtdIns(3,4,5)P_3) is accumulated at the leading edge of directed migrating cell and works, at least in a part, as a compass to indicate directionality. We here demonstrate that a novel mechanism of cytoskeletal regulation of lamellipodium formation at the site of PtdIns(3,4,5)P_3 accumulation in COS-7 cells. An actin binding protein Filamin A, which is capable of crosslinking F-actin, helps a cell to form dynamic lamellipodia, together with its binding partner LL5β. LL5β, whose subcellular localization is directed by membrane PtdIns(3,4,5)P_3, recruits Filamin A near the plasma membrane where PtdIns(3,4,5)P_3 is accumulated. Since F-actin is newly polymerized near the plasma membrane, it is likely that Filamin A efficiently crosslinks newly polymerized F-actin together with LL5βv, leading to the enhanced lamellipodium formation. Therefore, it is likely that LL5β promotes efficient migration during directed movement through Filamin A, in a manner dependent on membrane phosphoinositides, including PtdIns(3,4,5)P_3.