Affinage

FLOT1

Flotillin-1 · UniProt O75955

Length
427 aa
Mass
47.4 kDa
Annotated
2026-06-09
21 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FLOT1 is a membrane-associated scaffold protein that organizes clathrin-independent endocytic and macropinocytic membrane trafficking and couples these events to growth, survival, and inflammatory signaling (PMID:29162604, PMID:41500583). Through its N-terminal hydrophobic domain it binds the transmembrane/cytoplasmic region of syndecan-1 to drive syndecan-1-dependent endocytosis and lysosomal disposal of remnant lipoproteins, a function whose loss raises plasma triglycerides and is rescued by wild-type but not N-terminal-deletion FLOT1 in vivo (PMID:29162604). FLOT1 is required for circular dorsal ruffle-derived macropinosome formation and for growth-factor-stimulated mTORC1 activation, linking membrane uptake to nutrient sensing (PMID:41500583), and it participates in an SDC1-TGM2-FLOT1-BHMT assembly that delivers TGM2 to lysosomes to coordinate autophagosome-lysosome fusion and sustain autophagic flux (PMID:37441590). In cancer cells FLOT1 acts as an upstream driver of Akt/ERK signaling, promoting proliferation, cell-cycle progression, and epithelial-mesenchymal transition: it suppresses FOXO3a-dependent induction of p21 and p27 while sustaining cyclin D1 (PMID:21447726, PMID:30838797), interacts with BCAR1 to regulate its phosphorylation and ERK-dependent migration and invasion (PMID:37928269), operates downstream of EIF4A3 in a PI3K-AKT-ERK-P70S6K cascade (PMID:37011005), and controls apoptosis and pyroptosis sensitivity (PMID:36697954). FLOT1 expression is induced transcriptionally by SMARCC1, downstream of which it promotes M2 macrophage polarization and ferroptosis resistance (PMID:40108025), and in microglia FLOT1 complexes with the transcription factor FOSL2 to upregulate EphA2 and activate p38/MAPK-driven pro-inflammatory polarization in Alzheimer's disease models (PMID:41548752).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2011 Medium

    Established that FLOT1 is not merely a structural raft marker but actively promotes proliferation, by defining the Akt-FOXO3a-cell cycle axis it controls.

    Evidence siRNA knockdown with Western blot, luciferase reporter, and in vivo tumorigenicity in breast cancer cells

    PMID:21447726

    Open questions at the time
    • Does not show how FLOT1 mechanistically engages Akt
    • No direct binding partner linking FLOT1 to Akt identified
  2. 2017 High

    Defined a specific molecular mechanism for FLOT1 in endocytosis by mapping its N-terminal hydrophobic domain to the syndecan-1 cytoplasmic region and demonstrating physiological rescue of lipoprotein clearance in vivo.

    Evidence Reciprocal Co-IP, domain-deletion mutagenesis, knockdown in liver cells, and adenoviral rescue with triglyceride assays in T2DM mice

    PMID:29162604

    Open questions at the time
    • Does not resolve whether caveolin-independent uptake is general or syndecan-1-specific
    • Structural basis of the hydrophobic-domain interaction not determined
  3. 2019 Medium

    Generalized FLOT1's role as an upstream activator of Erk/Akt beyond breast cancer, linking it to EMT and cell-cycle progression in lung adenocarcinoma.

    Evidence Lentiviral knockdown and overexpression with Western blotting of EMT/cell-cycle and pathway markers

    PMID:30838797

    Open questions at the time
    • Mechanism connecting FLOT1 to Erk/Akt activation not defined
    • No direct molecular intermediary identified
  4. 2023 Medium

    Identified direct protein partners and upstream regulators that channel FLOT1 into ERK/PI3K signaling, moving from correlation to molecular epistasis.

    Evidence Co-IP and mass-spectrometry interaction (BCAR1; EIF4A3), site-directed mutagenesis (BCAR1 Y410F), and knockdown rescue with pathway inhibitors in gastric and lung cancer cells

    PMID:37011005 PMID:37928269

    Open questions at the time
    • Whether BCAR1 and EIF4A3 act in the same or parallel pathways is unresolved
    • No reciprocal validation across independent labs
  5. 2023 Medium

    Extended FLOT1's trafficking function to autophagy, placing it in a defined SDC1-TGM2-FLOT1-BHMT complex that couples lysosomal cargo delivery to autophagosome fusion and radioresistance.

    Evidence Co-IP, immunofluorescence, mRFP-GFP-LC3 flux assay, and TEM in glioblastoma cells

    PMID:37441590

    Open questions at the time
    • Direct binding interfaces within the four-member complex not mapped
    • Stoichiometry and assembly order beyond Co-IP unestablished
  6. 2023 Medium

    Showed FLOT1 controls cell-death decisions, regulating both apoptosis and pyroptosis in addition to proliferation.

    Evidence Knockdown/overexpression with flow cytometry and xenograft engraftment in AML cells

    PMID:36697954

    Open questions at the time
    • Molecular link between FLOT1 and pyroptotic machinery not identified
    • Whether death regulation is downstream of its known signaling roles is unclear
  7. 2025 Medium

    Identified upstream transcriptional control of FLOT1 (SMARCC1) and post-transcriptional control (m6A), and linked FLOT1 to immune polarization and ferroptosis resistance.

    Evidence ChIP, knockdown/overexpression rescue, GSH:GSSG and lipid peroxidation assays (SMARCC1); m6A analysis with methylation inhibitor and xenografts (ovarian)

    PMID:40066501 PMID:40108025

    Open questions at the time
    • Specific m6A writer/eraser for FLOT1 mRNA not identified
    • Mechanism by which FLOT1 suppresses ferroptosis not defined
  8. 2026 Medium

    Defined non-cancer functions: FLOT1 drives macropinocytosis-coupled mTORC1 activation in podocytes and complexes with FOSL2 to drive neuroinflammatory microglial polarization in Alzheimer's models.

    Evidence Flot1 knockout cells with macropinosome and mTORC1 assays (podocytes); Co-IP, ChIP, luciferase, and APP/PS1 mouse behavior (microglia)

    PMID:41500583 PMID:41548752

    Open questions at the time
    • How macropinosome-localized FLOT1 transmits the signal to mTORC1 is not resolved
    • Whether the FOSL2 interaction is direct or scaffolded is not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether FLOT1's diverse signaling roles (Akt/ERK, mTORC1, autophagy, inflammation) all derive from a single core function in raft-based membrane trafficking, or represent independent scaffold activities, remains unresolved.
  • No structural model of FLOT1 in any of its complexes
  • No unifying biochemical mechanism connecting its endocytic and transcription-associated roles

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0008289 lipid binding 1
Localization
GO:0005764 lysosome 2 GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9612973 Autophagy 1
Partners
BCAR1EIF4A3FOSL2SDC1TGM2
Complex memberships
FLOT1-FOSL2 complexSDC1-TGM2-FLOT1-BHMT complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 Knockdown of FLOT1 in breast cancer cells suppressed Akt activity, enhanced transcriptional activity of FOXO3a, upregulated CDK inhibitors p21(Cip1) and p27(Kip1), and downregulated cyclin D1, establishing FLOT1 as a promoter of proliferation via the Akt-FOXO3a-cell cycle axis. siRNA knockdown, Western blotting, luciferase reporter assay, in vitro and in vivo proliferation/tumorigenicity assays Clinical Cancer Research Medium 21447726
2017 FLOT1 co-immunoprecipitates with syndecan-1 (but not caveolin-1) in liver cells; C-TRL binding to syndecan-1 enhances this association; the two molecules traffic together into lysosomes. The interaction requires the transmembrane/cytoplasmic region of syndecan-1 and the N-terminal hydrophobic domain of FLOT1. FLOT1 knockdown substantially inhibited syndecan-1 endocytosis. Adenoviral re-expression of wild-type FLOT1 (but not a mutant lacking the N-terminal hydrophobic domain) normalized plasma triglycerides in T2DM mice, demonstrating that FLOT1 mediates syndecan-1-dependent disposal of remnant lipoproteins. Co-immunoprecipitation, domain-deletion mutagenesis, siRNA knockdown in cultured liver cells, adenoviral overexpression in T2DM mice, plasma triglyceride/retinyl ester assays Arteriosclerosis, Thrombosis, and Vascular Biology High 29162604
2019 FLOT1 overexpression or knockdown in lung adenocarcinoma cells respectively activates or suppresses the Erk/Akt signaling pathway, promoting epithelial-mesenchymal transition and cell cycle progression, establishing FLOT1 as an upstream regulator of Erk/Akt in LUAD. Lentiviral knockdown and overexpression, Western blotting for EMT and cell cycle markers, Erk/Akt pathway analysis Thoracic Cancer Medium 30838797
2023 FLOT1 interacts with BCAR1 (breast cancer anti-estrogen resistance 1), regulates BCAR1 phosphorylation and translocation, and promotes gastric cancer cell proliferation, migration, and invasion via ERK signaling. Re-expression of wild-type but not Y410F-mutant BCAR1 partially restored migration/invasion after FLOT1 knockdown, and an ERK inhibitor blocked this rescue. Co-immunoprecipitation, BCAR1 knockdown epistasis, site-directed mutagenesis (Y410F), ERK inhibitor treatment, cell migration/invasion assays International Journal of Biological Sciences Medium 37928269
2023 After irradiation, SDC1 carries TGM2 from the cell membrane into the cytoplasm and transports it to lysosomes by binding to FLOT1; TGM2 then recognizes BHMT on autophagosomes to coordinate autophagosome-lysosome fusion. This SDC1-TGM2-FLOT1-BHMT complex maintains autophagic flux and enhances radioresistance of glioblastoma. Co-immunoprecipitation, immunofluorescence, mRFP-GFP-LC3 autophagy flux assay, transmission electron microscopy, colony formation, flow cytometry Theranostics Medium 37441590
2023 EIF4A3 physically interacts with FLOT1 in lung adenocarcinoma cells (identified by mass spectrometry), positively regulates FLOT1 protein expression, and FLOT1 knockdown reverses EIF4A3-overexpression-induced activation of the PI3K-AKT-ERK1/2-P70S6K pathway and autophagy, placing FLOT1 downstream of EIF4A3 in this signaling cascade. Mass spectrometry co-immunoprecipitation, siRNA knockdown epistasis, Western blotting for pathway components, transcriptome sequencing Molecular Cancer Research Medium 37011005
2023 FLOT1 knockdown in AML cells triggers both apoptosis and pyroptosis, while FLOT1 overexpression promotes cell growth and apoptosis resistance, establishing FLOT1 as a regulator of cell death pathways in AML. siRNA knockdown, overexpression, flow cytometry for apoptosis/pyroptosis, in vivo xenograft engraftment assay Annals of Hematology Medium 36697954
2025 SMARCC1 activates FLOT1 transcription by binding to the FLOT1 promoter (identified by ChIP), and FLOT1 downstream promotes M2 macrophage polarization and reduces ferroptosis (maintaining GSH:GSSG ratio, reducing lipid peroxidation) in lung cancer; FLOT1 overexpression rescues the inhibitory effects of SMARCC1 knockdown on macrophage polarization and ferroptosis resistance. Chromatin immunoprecipitation (ChIP), siRNA knockdown, overexpression rescue, GSH:GSSG ratio measurement, lipid peroxidation assay, transmission electron microscopy, xenograft models, co-culture assays Journal of Molecular Medicine Medium 40108025
2025 m6A modification of FLOT1 mRNA is significantly elevated in ovarian cancer cells compared to normal ovarian epithelial cells, leading to increased FLOT1 mRNA expression; treatment with the methylation inhibitor 3-deazaadenosine decreases FLOT1 mRNA expression and suppresses tumor formation in xenograft mice. m6A modification analysis, qRT-PCR, methylation inhibitor treatment, xenograft tumor model Cell Biology International Low 40066501
2026 FLOT1 interacts with the transcription factor FOSL2 (confirmed by Co-IP), and this complex upregulates EphA2 transcription (confirmed by ChIP and dual-luciferase assay), activating the p38/MAPK signaling pathway to drive pro-inflammatory microglial polarization in Alzheimer's disease models; FLOT1 silencing in APP/PS1 mice reduced neuroinflammatory markers and improved spatial memory. Co-immunoprecipitation, chromatin immunoprecipitation, dual-luciferase reporter assay, siRNA knockdown, APP/PS1 mouse model, Morris water maze Neuropharmacology Medium 41548752
2026 FLOT1 localizes to circular dorsal ruffles (CDRs) in podocytes and is required for CDR-derived macropinosome formation; depletion of FLOT1 impairs growth-factor-stimulated mTORC1 activation, demonstrating that FLOT1 links macropinocytosis to nutrient sensing and mTORC1 activity in podocytes. Imaging/immunostaining for CDR localization, Flot1 knockout cells, macropinosome formation assay, biochemical mTORC1 activation assay, cell growth measurement Cell Structure and Function Medium 41500583

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Knockdown of FLOT1 impairs cell proliferation and tumorigenicity in breast cancer through upregulation of FOXO3a. Clinical cancer research : an official journal of the American Association for Cancer Research 106 21447726
2015 miRNA-target network reveals miR-124as a key miRNA contributing to clear cell renal cell carcinoma aggressive behaviour by targeting CAV1 and FLOT1. Oncotarget 72 26002553
2015 MiR-506 is down-regulated in clear cell renal cell carcinoma and inhibits cell growth and metastasis via targeting FLOT1. PloS one 57 25793370
2019 Integration of GWAS and brain eQTL identifies FLOT1 as a risk gene for major depressive disorder. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 34 30771789
2023 SDC1-TGM2-FLOT1-BHMT complex determines radiosensitivity of glioblastoma by influencing the fusion of autophagosomes with lysosomes. Theranostics 32 37441590
2019 HOTAIR/miR-214-3p/FLOT1 axis plays an essential role in the proliferation, migration, and invasion of hepatocellular carcinoma. International journal of clinical and experimental pathology 30 31933720
2020 Long Non-Coding RNA TUG1 Promotes Cell Proliferation and Inhibits Cell Apoptosis, Autophagy in Clear Cell Renal Cell Carcinoma via MiR-31-5p/FLOT1 Axis. OncoTargets and therapy 24 32606796
2023 The roles of FLOT1 in human diseases (Review). Molecular medicine reports 23 37772385
2017 Suppression of Hepatic FLOT1 (Flotillin-1) by Type 2 Diabetes Mellitus Impairs the Disposal of Remnant Lipoproteins via Syndecan-1. Arteriosclerosis, thrombosis, and vascular biology 23 29162604
2019 FLOT1 promotes tumor development, induces epithelial-mesenchymal transition, and modulates the cell cycle by regulating the Erk/Akt signaling pathway in lung adenocarcinoma. Thoracic cancer 22 30838797
2023 FLOT1 promotes gastric cancer progression and metastasis through BCAR1/ERK signaling. International journal of biological sciences 15 37928269
2020 MiR-1294 acts as a tumor inhibitor in cervical cancer by regulating FLOT1 expression. Journal of biological regulators and homeostatic agents 14 32329296
2023 EIF4A3 Acts on the PI3K-AKT-ERK1/2-P70S6K Pathway through FLOT1 to Influence the Development of Lung Adenocarcinoma. Molecular cancer research : MCR 12 37011005
2021 Long non-coding RNA A1BG-AS1 promotes tumorigenesis in breast cancer by sponging microRNA-485-5p and consequently increasing expression of FLOT1 expression. Human cell 12 34115333
2023 FLOT1 knockdown inhibits growth of AML cells through triggering apoptosis and pyroptosis. Annals of hematology 8 36697954
2025 SMARCC1 promotes M2 macrophage polarization and reduces ferroptosis in lung cancer by activating FLOT1 transcription. Journal of molecular medicine (Berlin, Germany) 5 40108025
2025 FLOT1 Is a Novel Serum Biomarker of Ovarian Cancer Targeted by N6-methyladenosine Modification Inhibition. Cell biology international 4 40066501
2024 Circ_0003855 involvement of esophageal cancer progression through miR-622/FLOT1. Oncology research 2 38686057
2026 Depletion of Flot1 attenuates macropinosome-dependent mTORC1 activation in podocytes. Cell structure and function 0 41500583
2026 The interaction between FLOT1 and FOSL2 promotes EphA2 transcription, regulating microglial polarization and affecting neuroinflammation in Alzheimer's disease. Neuropharmacology 0 41548752
2025 Luteolin suppresses cell migration and invasion via targeting miR-6809-5p/FLOT1/FAK and eliciting EMT in hepatocellular carcinoma. Translational oncology 0 40857906

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