| Flightless I belongs to the gelsolin family of actin-remodeling proteins distinguished by its N-terminal leucine-rich repeat (LRR) protein-protein interaction domain and C-terminal gelsolin-like actin-binding domain lacking severing activity. The LRR domain facilitates binding to partners like LRRFIP1/2, nuclear receptors, and signaling effectors, while the gelsolin domain caps actin filament barbed ends to inhibit polymerization and modulates cofilin-mediated depolymerization. FLII sequesters nuclear β-catenin to suppress Wnt/TCF transcription, competes with Dishevelled to disrupt Wnt signaling, and interacts with MyD88 to attenuate TLR4/NLRP3 inflammasome activation via LRRFIP1/2 recruitment, dampening NF-κB and IL-1β release. In TGF-β pathways, FLII associates with c-fos/c-jun (AP-1) and nuclear Akt to fine-tune Smad signaling, while actin interactions via G-actin binding regulate Hippo-YAP/TAZ nuclear localization for proliferation/apoptosis control. Nuclear translocation enables co-activator/co-repressor roles with glucocorticoid receptors and PPARγ for gene regulation. Physiologically, FLII governs cellular motility, adhesion, proliferation, differentiation, and survival critical for embryonic development, wound re-epithelialization, and tissue homeostasis. Overexpression impairs keratinocyte migration and healing by reducing Rac1/PAK signaling, whereas knockdown accelerates closure via enhanced lamellipodia. FLII promotes EMT, invasion, and metastasis through invadopodia formation and radiation resistance in colorectal tumors; in muscular dystrophy, it destabilizes dystrophin-actin links leading to fragility. |
