{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nFlotillin proteins serve as essential scaffolds that organize cholesterol‐enriched membrane microdomains, thereby regulating diverse membrane trafficking and signaling events. For example, flotillins associate with the cholesterol importer NPC1L1 to form microdomains that drive efficient dietary cholesterol uptake, while their dynamic coupling to cortical F‑actin modulates their lateral mobility and clustering. Moreover, copper levels influence flotillin‐2 localization within lipid rafts to affect amyloid precursor protein (APP) endocytosis and subsequent amyloidogenic processing. Flotillins also play roles in receptor tyrosine kinase signaling; their proper expression is required to fine‐tune downstream cascades, and their perturbation can lead to altered EGFR internalization and downstream MAPK/ERK signaling, impacting tumor-related gene regulation and metastasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to their roles in lipid raft organization, flotillins are crucial for cytoskeletal remodeling and the targeted delivery of membrane cargo. They are essential for neutrophil migration by localizing to the uropod and interacting with myosin IIa and spectrins, a process required for effective chemotaxis. In the nervous system, upregulation of flotillin (also known as reggie) expression promotes axon regeneration and overcomes inhibitory signals through activation of Src, PI3K, and Rac1 pathways, thereby enhancing neurite outgrowth. Flotillin-mediated, Rab11a-dependent recycling ensures proper trafficking of synaptic proteins such as PSD-95, N-cadherin, and glutamate receptors, which is important for spine synapse formation and long-term potentiation. Flotillin functions also extend to other specialized settings, including neural differentiation via Fyn-mediated phosphorylation and organization of cardiac intercalated discs that are vital for proper heart remodeling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFlotillins also modulate immune and reproductive functions. In immune cells, lipid raft modulation by flotillin-2 is involved in beta-glycosphingolipid–mediated regulation of STAT signaling in natural killer T cells via a CD1d-dependent mechanism. Furthermore, deficiency of flotillin in B cells leads to increased expression of pro-inflammatory cytokines and exacerbates sepsis, highlighting their role in controlling inflammation. In the reproductive system, post-transcriptional regulation by miR-124 reduces flotillin-2 levels, which in turn perturbs caveolin-independent vesicle trafficking during sperm acrosome biogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Matthias F Langhorst, Gonzalo P Solis, Sylvia Hannbeck, et al. 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