Affinage

FLCN

Folliculin · UniProt Q8NFG4

Length
579 aa
Mass
64.5 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FLCN (folliculin) is a tumor suppressor that functions at the intersection of amino acid sensing, growth factor signaling, lysosomal homeostasis, and mitochondrial metabolism. FLCN heterodimerizes with FNIP1 or FNIP2 through their Longin domains to form a GTPase-activating protein (GAP) for RagC/D GTPases, using an arginine finger (Arg164) to catalyze GTP hydrolysis on RagC/D; this activity is required for mTORC1-dependent cytoplasmic retention of transcription factors TFEB and TFE3, while leaving canonical mTORC1 substrates (S6K, 4E-BP1) largely unaffected (PMID:31704029, PMID:36103527, PMID:27913603). Loss of FLCN causes constitutive nuclear TFE3/TFEB accumulation, driving PGC-1α/β-dependent mitochondrial biogenesis, AMPK hyperactivation, glycogenesis, and pro-inflammatory cytokine expression across multiple tissues (PMID:21209915, PMID:23150719, PMID:27151976, PMID:30917316, PMID:32049013). FLCN is recruited to lysosomes in a GATOR1-dependent manner by sensing RagA/B-GDP, is phosphorylated by mTOR, AKT1 (at Ser62), and ULK1, and is sequestered away from its Rag substrates by GABARAP during autophagy, providing multiple layers of regulation that integrate nutrient availability, insulin signaling, and autophagic flux (PMID:29848618, PMID:37083230, PMID:25126726, PMID:34597140).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2006 High

    Identification of FNIP1 as a direct FLCN-binding partner that bridges FLCN to AMPK, and demonstration that FLCN phosphorylation is regulated by both mTOR and AMPK, placed FLCN within the nutrient-sensing signaling network for the first time.

    Evidence Co-immunoprecipitation, mass spectrometry identification of FNIP1, phosphorylation assays with rapamycin/AMPK inhibitors in mammalian cells

    PMID:17028174

    Open questions at the time
    • Kinase directly phosphorylating FLCN not yet identified
    • Functional consequence of FLCN phosphorylation unknown
    • Whether FLCN-FNIP complex has enzymatic activity unresolved
  2. 2008 High

    Kidney-specific Flcn knockout demonstrated that FLCN is a bona fide upstream negative regulator of mTOR in vivo, with rapamycin rescuing the cystic phenotype, establishing the first causal tissue-level pathway link.

    Evidence Conditional kidney-specific KO mice (Ksp-Cre) with rapamycin rescue

    PMID:18974783

    Open questions at the time
    • Mechanism of mTOR activation upon FLCN loss unknown
    • Whether FLCN acts directly on mTOR or through intermediaries unresolved
  3. 2009 High

    Homozygous FLCN loss causes embryonic lethality, and heterozygous tumors show dual mTORC1/mTORC2 activation with elevated AKT protein, revealing that FLCN loss deregulates both mTOR complexes and may stabilize AKT post-translationally.

    Evidence BHD knockout mice (homozygous and heterozygous), immunoblotting for mTORC1/mTORC2 substrates, qRT-PCR

    PMID:19850877

    Open questions at the time
    • Mechanism of AKT protein stabilization unknown
    • Whether mTORC2 activation is a direct or indirect consequence of FLCN loss not determined
  4. 2010 High

    Discovery that FLCN loss causes nuclear TFE3 accumulation and transcriptional activation identified the first specific transcription factor target downstream of FLCN, shifting the field beyond generic mTOR activation toward a substrate-selective model.

    Evidence FLCN knockdown/reconstitution in renal cancer cells, TFE3 localization in cells/mouse kidneys/human tumors

    PMID:21209915

    Open questions at the time
    • Mechanism linking FLCN to TFE3 phosphorylation not known
    • Whether TFEB is similarly regulated not tested
    • RagC/D involvement not yet suspected
  5. 2012 High

    Tissue-specific knockouts established FLCN as a negative regulator of PGC-1α-driven mitochondrial biogenesis, linking FLCN tumor suppression to metabolic reprogramming.

    Evidence Muscle-specific Flcn KO with PGC-1α double-KO rescue, oxygen consumption measurements, FLCN reconstitution in kidney cancer cells

    PMID:23150719

    Open questions at the time
    • Whether PGC-1α induction is a direct transcriptional effect of TFE3 or an indirect consequence not resolved
    • Relative contribution of AMPK vs. TFE3 to PGC-1α induction unclear
  6. 2014 High

    Identification of FLCN-GABARAP interaction and ULK1-mediated phosphorylation of FLCN at Ser406/Ser537/Ser542 linked FLCN directly to the autophagy machinery, and loss of FLCN was shown to impair basal autophagic flux.

    Evidence Co-IP of FLCN-GABARAP, in vitro ULK1 kinase assay with mass spectrometry site mapping, autophagic flux assays

    PMID:25126726

    Open questions at the time
    • Functional consequence of individual ULK1 phosphorylation sites not determined
    • How FLCN promotes autophagic flux mechanistically undefined
  7. 2016 High

    Two complementary adipose-specific knockout studies resolved parallel downstream pathways: one showing FLCN restrains TFE3-PGC-1β-driven browning via RagC/D (separable from TSC-S6K signaling), the other showing FLCN restrains AMPK-PGC-1α/ERRα-driven mitochondrial biogenesis, together establishing FLCN as a dual-axis metabolic gatekeeper.

    Evidence Adipose-specific Flcn KO with TFE3/PGC-1β double-KO rescue, and separate adipose Flcn KO with AMPK activity assays and metabolic phenotyping

    PMID:27151976 PMID:27913603

    Open questions at the time
    • Whether the TFE3/RagC and AMPK axes are independent or converge at a single node is unresolved
    • Relative in vivo contribution of each axis in kidney tumorigenesis unknown
  8. 2018 High

    The discovery that FLCN-FNIP is recruited to lysosomes in a GATOR1-dependent manner by sensing RagA/B-GDP established the molecular logic of how amino acid status is read by FLCN to coordinate Rag heterodimer nucleotide states.

    Evidence Lysosomal fractionation, RagA/B nucleotide-loading mutants, GATOR1 knockdown, co-immunoprecipitation

    PMID:29848618

    Open questions at the time
    • Structural basis of FLCN recognition of RagA-GDP not yet determined
    • Whether other signals besides GATOR1 regulate FLCN lysosomal recruitment unknown
  9. 2019 High

    Cryo-EM structure of the inactive FLCN-FNIP2-Rag-Ragulator complex revealed the catalytic arginine finger mechanism of FLCN GAP activity toward RagC/D, providing the first atomic-level understanding of FLCN's enzymatic function.

    Evidence Cryo-EM at near-atomic resolution, mutagenesis of catalytic arginine, in vitro GAP assays

    PMID:31704029

    Open questions at the time
    • Complex captured in inactive conformation; the active GAP transition state not yet visualized
    • Whether FNIP1 and FNIP2 confer different catalytic properties unresolved
  10. 2019 High

    FLCN-AMPK-TFE3 axis was shown to operate in innate immunity independently of mTORC1, with FLCN loss or AMPK activation inducing TFEB/TFE3-dependent pro-inflammatory cytokine expression in macrophages, broadening FLCN's role beyond metabolic sensing to immune regulation.

    Evidence C. elegans FLCN ortholog mutants, mammalian FLCN KO macrophages, pharmacological AMPK activation, TFEB/TFE3 knockdown, cytokine assays

    PMID:30917316

    Open questions at the time
    • Whether FLCN-dependent immune phenotypes contribute to BHD disease manifestations unknown
    • Mechanism by which AMPK activates TFEB/TFE3 independently of mTORC1 not defined
  11. 2021 High

    GABARAP was found to sequester FLCN-FNIP via a LIR motif during autophagy (CASM, mitophagy, xenophagy), explaining how autophagic flux activates TFEB by physically displacing FLCN from its Rag substrates — a key mechanistic link between autophagy and lysosomal biogenesis.

    Evidence GABARAP-FLCN co-IP, LIR motif mutagenesis, GABARAP-specific vs. LC3-specific depletion, TFEB phosphorylation assays

    PMID:34597140

    Open questions at the time
    • Whether GABARAP-FLCN sequestration occurs on specific membrane compartments in vivo not fully mapped
    • Quantitative contribution relative to other TFEB activation mechanisms unclear
  12. 2022 High

    Cryo-EM of the active FLCN complex revealed a ~90° reorientation of FLCN that breaks RagA contact and positions Arg164 for RagC catalysis; disruption of active-complex interfaces eliminated GAP activity and caused nuclear TFE3 retention without affecting S6K/4E-BP1, providing the structural basis for substrate-selective mTORC1 regulation.

    Evidence Cryo-EM of FLCN-FNIP2-SLC38A9-Rag-Ragulator active complex, interface mutagenesis, TFE3 localization and mTORC1 substrate phosphorylation assays

    PMID:36103527

    Open questions at the time
    • How SLC38A9 triggers the conformational switch in FLCN mechanistically unclear
    • Whether additional regulators facilitate the inactive-to-active transition in vivo unknown
  13. 2023 Medium

    AKT1 was identified as the kinase phosphorylating FLCN at Ser62 downstream of insulin/mTORC2, and this phosphorylation inhibits RagC GAP activity, establishing FLCN as a convergence point for growth factor and amino acid signaling toward mTORC1.

    Evidence AKT1 kinase assay, Ser62 mutants, lysosomal fractionation with RagD mutants, mTORC1 activity and tumor growth assays

    PMID:37083230

    Open questions at the time
    • Whether Ser62 phosphorylation affects FLCN conformation or Rag binding directly not structurally resolved
    • In vivo physiological significance beyond tumor xenografts not tested
    • Single lab finding awaiting independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FLCN's multiple regulatory inputs (ULK1 phosphorylation, AKT1 phosphorylation, GABARAP sequestration, FNIP2 degradation) are integrated in real time to calibrate RagC/D activity in different physiological contexts remains unresolved, as does the relative contribution of FLCN's Rab11A-dependent vesicular trafficking function versus its lysosomal GAP activity to tumor suppression.
  • No unified quantitative model integrating all FLCN regulatory inputs
  • Structural basis of FLCN-Rab11A interaction and its relationship to GAP function unresolved
  • Whether FLCN has additional enzymatic activities beyond RagC/D GAP unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005764 lysosome 3 GO:0005829 cytosol 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1430728 Metabolism 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 2
Partners
FNIP1FNIP2GABARAPPRKAA1RAB11ARRAGARRAGCTARDBP
Complex memberships
FLCN-FNIP1 complexFLCN-FNIP2 complexFLCN-FNIP2-Rag-Ragulator complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 FLCN (folliculin) interacts directly with FNIP1 (folliculin-interacting protein 1), which in turn interacts with AMPK. FNIP1 is phosphorylated by AMPK, and FLCN phosphorylation is regulated by both mTOR (reduced by rapamycin and amino acid starvation) and AMPK signaling, placing FLCN in the AMPK-mTOR nutrient-sensing pathway. Co-immunoprecipitation, mass spectrometry identification of FNIP1, in vitro phosphorylation assays, AMPK inhibitor/rapamycin treatment Proceedings of the National Academy of Sciences of the United States of America High 17028174
2009 Homozygous loss of BHD/FLCN causes embryonic lethality at E5.5-E6.5 in mice. Kidney tumors from BHD heterozygous knockout mice and human BHD patients show activation of both mTORC1 and mTORC2, and elevated total AKT protein (without increased mRNA), suggesting FLCN regulates AKT post-translationally or post-transcriptionally. Mouse knockout model (homozygous and heterozygous), immunoblotting for mTORC1/mTORC2 substrates, qRT-PCR, LOH analysis Proceedings of the National Academy of Sciences of the United States of America High 19850877
2008 Kidney-specific deletion of BHD/FLCN in mice activates the mTOR pathway, and rapamycin treatment suppresses cystogenesis and extends survival, establishing FLCN as a functional upstream negative regulator of mTOR in renal cells. Conditional kidney-specific knockout (Ksp-Cre), rapamycin treatment rescue experiment, histological and biochemical analysis PloS one High 18974783
2010 FLCN inactivation causes increased nuclear localization of TFE3 (accompanied by decreased TFE3 phosphorylation), leading to elevated TFE3 transcriptional activity and upregulation of GPNMB expression. This establishes TFE3 nuclear translocation as a downstream consequence of FLCN loss. FLCN knockdown/restoration in renal cancer cells, TFE3 knockdown, immunostaining of TFE3 in cells/mouse kidneys/human tumors, mRNA/protein expression analysis PloS one High 21209915
2019 FLCN-FNIP2 functions as a GTPase-activating protein (GAP) for RagC/D GTPases. Cryo-EM structure of the FLCN-FNIP2-Rag-Ragulator complex reveals that FLCN and FNIP2 adopt an extended conformation with Longin domains heterodimerizing and contacting Rag nucleotide-binding domains, while DENN domains interact distally. A conserved arginine on FLCN acts as the catalytic arginine finger for RagC/D GAP activity. Cryo-EM structure determination, biochemical GAP activity assays, mutagenesis of catalytic arginine Cell High 31704029
2022 Cryo-EM structure of the active FLCN complex (AFC) containing FLCN, FNIP2, SLC38A9 N-terminal tail, RagA(GDP):RagC(GDP·BeFx), and Ragulator reveals that during GAP activation FLCN reorients ~90° relative to the inactive lysosomal complex, breaks contact with RagA, and makes new contacts with RagC that position Arg164 for catalysis. Disruption of AFC-specific FLCN-RagC interfaces eliminates GAP activity and causes nuclear retention of TFE3 without affecting S6K or 4E-BP1 phosphorylation, demonstrating substrate-selective mTORC1 regulation. Cryo-EM structure determination, mutagenesis of interface residues, GAP activity assays, TFE3 localization assays Science advances High 36103527
2018 FLCN-FNIP complex is recruited to lysosomes during amino acid starvation in a manner dependent on GATOR1 GAP activity toward RagA/B (which converts RagA/B to GDP-bound state). By binding RagA/B(GDP) and acting as a GAP on RagC/D, the FLCN-FNIP complex coordinates nucleotide status between Rag heterodimer subunits in response to amino acid availability. Lysosomal fractionation, RagA/B nucleotide-loading mutants, GATOR1 knockdown, co-immunoprecipitation The Journal of cell biology High 29848618
2016 Adipose-specific deletion of FLCN relieves mTOR-dependent cytoplasmic retention of TFE3, leading to nuclear TFE3 and direct induction of PGC-1α/PGC-1β, driving mitochondrial biogenesis and adipose browning. This FLCN-mTOR-TFE3-PGC-1β pathway is separable from canonical TSC-mTOR-S6K signaling and is driven by RagC/D. Adipose-specific conditional KO, TFE3 and PGC-1β co-deletion rescue, inducible PGC-1β expression, amino acid sensitivity assays Genes & development High 27913603
2016 Adipose-specific loss of FLCN causes chronic hyperactivation of AMPK, which in turn induces and activates PGC-1α and ERRα, driving mitochondrial biogenesis and browning of white adipose tissue through the AMPK/PGC-1α/ERRα axis. Adipose-specific FLCN knockout mouse, AMPK activity assays, gene expression analysis, metabolic phenotyping Genes & development High 27151976
2012 Muscle-targeted FLCN knockout leads to increased mitochondrial biogenesis and oxidative phosphorylation in a PGC-1α (PPARGC1A)-dependent manner. Reconstitution of FLCN-null kidney cancer cells with wild-type FLCN suppresses mitochondrial metabolism and PGC-1α expression, establishing FLCN as a negative regulator of PGC-1α-driven mitochondrial oxidative metabolism. Conditional muscle/kidney KO mice, PPARGC1A double KO rescue, electron microscopy, oxygen consumption measurement, FLCN reconstitution in null cells Journal of the National Cancer Institute High 23150719
2021 GABARAP (but not LC3) directly binds to a previously unidentified LIR motif in the FLCN/FNIP complex, sequestering it to GABARAP-conjugated membrane compartments during autophagy (CASM, mitophagy, xenophagy). This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired mTOR-dependent phosphorylation of TFEB, thereby activating TFEB/TFE3 to control lysosomal capacity. Co-IP identifying GABARAP-FLCN interaction, LIR motif identification/mutagenesis, GABARAP-specific vs. LC3-specific depletion, TFEB phosphorylation assays Science advances High 34597140
2014 FLCN interacts with GABARAP (autophagy protein), and this interaction is modulated by FNIP1 or FNIP2. ULK1 phosphorylates FLCN at Ser406, Ser537, and Ser542. Loss of FLCN impairs basal autophagic flux; re-expression of FLCN rescues autophagy. Co-IP (FLCN-GABARAP), in vitro ULK1 phosphorylation assay with site identification by mass spectrometry, autophagic flux assays with LC3/SQSTM1 Autophagy High 25126726
2009 FLCN phosphorylation is regulated downstream of the TSC2-mTORC1 axis: downregulation of tuberin or Rheb expression induces multiple FLCN phosphorylation events. Phosphorylation at Ser62 and Ser302 are differentially regulated by mTORC1-dependent pathways, and FLCN phosphorylation state modulates its complex formation with AMPK. Tuberin/Rheb overexpression/knockdown with immunoblotting for FLCN phospho-sites, co-immunoprecipitation of FLCN-AMPK complex Biochemical and biophysical research communications Medium 19695222
2019 FLCN and AMPK act upstream of TFEB/TFE3 in the innate immune response independently of mTORC1. Loss of FLCN or pharmacological AMPK activation induces TFEB/TFE3-dependent pro-inflammatory cytokine expression in mammalian macrophages; LPS treatment causes acute AMPK activation accompanied by TFEB nuclear localization. C. elegans FLCN ortholog loss-of-function, mammalian FLCN KO cells, AMPK pharmacological activation, TFEB/TFE3 knockdown, cytokine/reporter assays Cell reports High 30917316
2015 In C. elegans, loss of FLCN-1 (FLCN ortholog) increases resistance to hyperosmotic stress via constitutive AMPK-dependent accumulation of glycogen; upon stress, glycogen is degraded to glycerol. This pathway requires glycogen synthase, glycogen phosphorylase, and GPDH enzymes. Glycogen accumulates in kidneys from FLCN-knockout mice and BHD patient renal tumors. C. elegans FLCN-1 loss-of-function, double mutants with AMPK/glycogen metabolism genes (epistasis), mouse kidney fractionation, BHD patient tumor analysis PLoS genetics High 26439621
2006 The Drosophila BHD homolog (DBHD) is required for male germline stem cell (GSC) maintenance. RNAi-mediated reduction of DBHD suppresses GSC overproliferation caused by overexpression of JAK-STAT ligand (upd) or BMP ligand (dpp), placing DBHD downstream or in parallel of JAK/STAT and Dpp signaling pathways. RNAi knockdown in Drosophila testis, genetic interaction assays with upd/dpp overexpression (epistasis), GSC counting Oncogene Medium 16636660
2014 Cardiac-specific loss of FLCN causes severe cardiac hypertrophy with mTORC1 upregulation; rapamycin treatment reduces heart mass. FLCN deficiency reduces phospho-AMPK (T172) and elevates PGC-1α (PPARGC1A), increasing mitochondrial metabolism. Inactivation of PPARGC1A in FLCN-deficient hearts restores phospho-AMPK levels and suppresses mTORC1, establishing a FLCN-PPARGC1A-AMPK-mTORC1 axis in cardiac hypertrophy. Cardiac-specific conditional KO, PPARGC1A double KO rescue, rapamycin treatment, AMPK activity assays, ATP level measurement Human molecular genetics High 24908670
2010 FLCN reconstitution in FLCN-null renal cells suppresses tumor formation in nude mice and upregulates TGF-β signaling components (TGFB2, INHBA/activin A, THBS1, SMAD3). Activin A (INHBA homodimer) completely suppresses anchorage-independent growth of FLCN-null cells, identifying TGF-β/activin signaling as a downstream effector of FLCN tumor suppression. Stable FLCN re-expression in null cell line, nude mouse xenograft, gene expression profiling, anchorage-independent growth assay Molecular cancer Medium 20573232
2011 FLCN directly interacts with TDP-43 via FLCN amino acids 202-299 binding to the RRM domains of TDP-43. Both exogenous and endogenous FLCN promote TDP-43 cytoplasmic translocation, protein aggregation, and stress granule formation. Co-immunoprecipitation, domain mapping by deletion constructs, FLCN knockdown and overexpression with TDP-43 localization assays, stress granule imaging Human molecular genetics Medium 26516189
2011 FLCN, MAPO1 (FNIP2), and AMPK form a complex required for apoptosis induced by O6-methylguanine alkylation. After MNU treatment, AMPKα phosphorylation occurs in an MLH1-dependent manner and requires both MAPO1 and FLCN expression; AICAR-induced AMPK activation is also MAPO1- and FLCN-dependent. siRNA knockdown of FLCN/MAPO1/AMPK, sub-G1 DNA content assay, AICAR/MNU treatment, mitochondrial membrane potential assay DNA repair Medium 22209521
2017 FNIP2 protein is degraded via β-TRCP/CK1-directed ubiquitination in a nutrition-dependent manner. FNIP2 degradation leads to lysosomal dissociation of FLCN and subsequent lysosomal association of mTOR, promoting renal cancer cell proliferation. Ubiquitination assays, β-TRCP co-IP, lysosomal fractionation, CK1 inhibition Oncotarget Medium 28039480
2018 FLCN binds to Rab11A through its C-terminal DENN-like domain and promotes loading of the amino acid transporter PAT1 onto Rab11A-positive recycling vesicles, maintaining PAT1 on the plasma membrane rather than at lysosomes, thereby sustaining lysosomal amino acid signaling and mTORC1 activity. Co-IP of FLCN-Rab11A, domain mapping, in vitro GEF assay (negative result), PAT1 localization by imaging, mTORC1 activity assays Journal of cell science Medium 30446510
2021 FLCN promotes Rab11A binding to transferrin receptor 1 (TfR1) to facilitate TfR1 recycling transport. Loss of FLCN attenuates Rab11A-TfR1 interaction, delays TfR1 recycling, causes iron deficiency, and induces HIF activity. Iron supplementation reverses HIF activation in FLCN-deficient cells; dietary iron rescues BHD phenotype in Drosophila. Co-IP (FLCN-Rab11A-TfR1), FLCN KO cells, TfR1 recycling assay, HIF reporter, Drosophila dietary rescue The Journal of biological chemistry Medium 33609526
2016 FLCN maintains the leucine level within lysosomes by inhibiting accumulation of the amino acid transporter PAT1 on the lysosome surface, thereby sustaining lysosomal leucine as a signal to activate mTORC1. Supplementation with high leucine (but not other amino acids) rescues mTORC1 activity lost upon FLCN suppression. FLCN knockdown/overexpression in HEK293, lysosomal leucine measurement, PAT1 localization assays, amino acid rescue experiments PloS one Medium 27280402
2019 AMPK promotes expression of FLCN through activation of TFEB (independently of mTOR), identifying a novel AMPK-TFEB-FLCN axis. AMPK-induced FLCN expression is abolished in MEFs lacking TFEB/TFE3, and mutation of the putative TFEB-binding site in the FLCN promoter reduces promoter activity. This axis is conserved in zebrafish. Whole-genome transcriptome profiling, TFEB/TFE3 double KO MEFs, promoter-luciferase reporter assay with TFEB site mutation, zebrafish AMPK KO model FASEB journal Medium 31404503
2020 FLCN loss in hematopoietic cells activates TFE3, which stimulates glycogenesis by transcriptionally upregulating glycogenesis genes (Gys1, Gyg). TFE3 also transcriptionally activates FLCN expression (feedback loop). Tfe3 deletion in FLCN-KO mice reduces phagocyte expansion and LSD-like phenotypes, establishing a FLCN-TFE3 rheostat controlling lysosome activity and glycogenesis. Hematopoietic-lineage conditional Flcn KO, Tfe3/Flcn double KO rescue, ChIP/transcriptional target analysis, metabolite analysis Cell reports High 32049013
2020 Genetic deficiency of FLCN in mice leads to nuclear translocation of TFE3 in venous endothelial cells, which drives ectopic expression of Prox1 (master transcription factor for lymphatic specification) by binding a regulatory element in the Prox1 gene, causing misconnection of blood and lymphatic vessels. Endothelial-specific Flcn KO mouse, TFE3 ChIP on Prox1 regulatory element, Prox1 expression analysis, vascular phenotype characterization Nature communications High 33298956
2019 Loss of FLCN in human renal tubular epithelial cells activates TFE3 (upregulating RRAGD and GPNMB) without modifying bulk mTORC1 activity, and independently induces STAT1/STAT2-dependent interferon response genes via increased STAT2 chromatin recruitment, slowing cellular proliferation. CRISPR KO of FLCN/FNIP1/FNIP2 in RPTEC/TERT1 cells, RNA-seq, ChIP-seq (STAT2), TFE3 nuclear localization, proliferation assays eLife High 33459596
2019 Loss of FLCN in mouse embryonic fibroblasts and lung fibroblasts inhibits canonical WNT signaling via TFE3: FLCN deficiency decreases Wnt2/Wnt7b expression and TCF/LEF activity; silencing TFE3 completely reverses this phenotype whereas constitutively active β-catenin only partially rescues it. Flcn KO in MEFs and MRC-5 cells, RNA-seq, TCF/LEF reporter assay, TFE3 siRNA rescue, active β-catenin rescue Human molecular genetics Medium 31272105
2017 FLCN H255Y missense mutation fails to rescue multi-cystic kidney phenotype in Flcn-KO mice, demonstrating loss of tumor suppressor function. The FLCN K508R missense mutation partially rescues but can also cause cystic kidneys and cardiac hypertrophy in heterozygous KO mice, suggesting a dominant negative effect on wild-type FLCN function. BAC recombineering transgenic rescue in kidney-specific Flcn KO mice, histological phenotype analysis Human molecular genetics Medium 28007907
2011 Pathogenic FLCN missense and in-frame deletion mutations significantly disrupt the stability of the FLCN protein product, while missense variants that do not impair protein stability also do not impair tumor suppressor activity or intracellular localization, indicating that protein stability is a key determinant of folliculin tumor suppressor function. In vitro protein stability assays, growth suppression assay, intracellular localization by fluorescence microscopy, evolutionary conservation analysis Human mutation Medium 21538689
2017 A splice-site mutation (c.1177-5_-3delCTC) causes exon 11 skipping in FLCN, producing a truncated protein that is strongly destabilized (reversible by proteasomal and lysosomal degradation inhibitors) and has altered subcellular localization compared to wild-type FLCN. Minigene splicing assay, TALEN-mediated transgenesis in cultured cells, protein stability assays with inhibitors, subcellular localization by immunofluorescence BMC medical genetics Medium 28499369
2023 FLCN is phosphorylated at Ser62 by AKT1 (downstream of insulin/mTORC2). RagD-specific recruitment of mTORC2-AKT1 to lysosomes is required for insulin-stimulated FLCN phosphorylation. FLCN Ser62 phosphorylation inhibits RagC GTPase activity and is essential for insulin-induced mTORC1 activation, identifying FLCN as a cross-talk node between amino acid and growth factor (insulin) mTORC1 activation pathways. Phosphorylation site identification, AKT1 kinase assays, lysosomal fractionation, RagD mutants, mTORC1 activity assays, in vivo tumor growth assays Advanced science Medium 37083230
2023 PRDM10 directly binds a regulatory motif in the FLCN promoter to control FLCN mRNA and protein expression. The pathogenic PRDM10 Cys677Tyr variant loses affinity for this FLCN promoter binding motif, abolishing cellular FLCN expression. Promoter binding assay, PRDM10 variant functional analysis, FLCN mRNA/protein quantification in cells overexpressing wild-type vs. mutant PRDM10 Human molecular genetics Medium 36440963

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proceedings of the National Academy of Sciences of the United States of America 395 17028174
2008 BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. Journal of medical genetics 358 18234728
2005 Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. American journal of human genetics 304 15852235
2009 Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2. Proceedings of the National Academy of Sciences of the United States of America 191 19850877
2005 High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors. Journal of the National Cancer Institute 182 15956655
2010 Inactivation of the FLCN tumor suppressor gene induces TFE3 transcriptional activity by increasing its nuclear localization. PloS one 142 21209915
2017 FLCN: The causative gene for Birt-Hogg-Dubé syndrome. Gene 133 28970150
2011 Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families. British journal of cancer 126 22146830
2003 A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog. Human molecular genetics 120 14532326
2008 Deficiency of FLCN in mouse kidney led to development of polycystic kidneys and renal neoplasia. PloS one 113 18974783
2016 The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue. Genes & development 110 27913603
2021 GABARAP sequesters the FLCN-FNIP tumor suppressor complex to couple autophagy with lysosomal biogenesis. Science advances 105 34597140
2019 Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex. Cell 105 31704029
2005 A 4-bp deletion in the Birt-Hogg-Dubé gene (FLCN) causes dominantly inherited spontaneous pneumothorax. American journal of human genetics 97 15657874
2019 The Transcription Factors TFEB and TFE3 Link the FLCN-AMPK Signaling Axis to Innate Immune Response and Pathogen Resistance. Cell reports 94 30917316
2003 Inactivation of BHD in sporadic renal tumors. Cancer research 92 12907635
2016 Chronic AMPK activation via loss of FLCN induces functional beige adipose tissue through PGC-1α/ERRα. Genes & development 90 27151976
2010 A new locus-specific database (LSDB) for mutations in the folliculin (FLCN) gene. Human mutation 88 19802896
2012 Regulation of mitochondrial oxidative metabolism by tumor suppressor FLCN. Journal of the National Cancer Institute 77 23150719
2010 Investigation of the Birt-Hogg-Dube tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer. Journal of medical genetics 73 20522427
2010 Tumor suppressor FLCN inhibits tumorigenesis of a FLCN-null renal cancer cell line and regulates expression of key molecules in TGF-beta signaling. Molecular cancer 73 20573232
2004 A germ-line insertion in the Birt-Hogg-Dubé (BHD) gene gives rise to the Nihon rat model of inherited renal cancer. Proceedings of the National Academy of Sciences of the United States of America 69 14769940
2008 Mutation analysis of the FLCN gene in Chinese patients with sporadic and familial isolated primary spontaneous pneumothorax. Clinical genetics 65 18505456
2006 Novel mutations in the BHD gene and absence of loss of heterozygosity in fibrofolliculomas of Birt-Hogg-Dubé patients. The Journal of investigative dermatology 64 17124507
2014 FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation. Autophagy 62 25126726
2003 Analysis of the Birt-Hogg-Dubé (BHD) tumour suppressor gene in sporadic renal cell carcinoma and colorectal cancer. Journal of medical genetics 58 14627671
2018 GATOR1-dependent recruitment of FLCN-FNIP to lysosomes coordinates Rag GTPase heterodimer nucleotide status in response to amino acids. The Journal of cell biology 57 29848618
2006 Mutations in BHD and TP53 genes, but not in HNF1beta gene, in a large series of sporadic chromophobe renal cell carcinoma. British journal of cancer 57 17133269
2019 AMPK promotes induction of the tumor suppressor FLCN through activation of TFEB independently of mTOR. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 56 31404503
2008 Familial non-VHL clear cell (conventional) renal cell carcinoma: clinical features, segregation analysis, and mutation analysis of FLCN. Clinical cancer research : an official journal of the American Association for Cancer Research 51 18794106
2014 Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation. Human molecular genetics 50 24908670
2011 Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dubé syndrome. Genes, chromosomes & cancer 47 21412933
2015 FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores. PLoS genetics 46 26439621
2006 The Drosophila homolog of the human tumor suppressor gene BHD interacts with the JAK-STAT and Dpp signaling pathways in regulating male germline stem cell maintenance. Oncogene 43 16636660
2017 Dihydromyricetin prevents obesity-induced slow-twitch-fiber reduction partially via FLCN/FNIP1/AMPK pathway. Biochimica et biophysica acta. Molecular basis of disease 36 28363698
2011 Constitutional FLCN mutations in patients with suspected Birt-Hogg-Dubé syndrome ascertained for non-cutaneous manifestations. Clinical genetics 34 20618353
2011 Birt Hogg-Dubé syndrome-associated FLCN mutations disrupt protein stability. Human mutation 33 21538689
2017 The ABCs of BHD: An In-Depth Review of Birt-Hogg-Dubé Syndrome. AJR. American journal of roentgenology 31 28981362
2022 Structural basis for FLCN RagC GAP activation in MiT-TFE substrate-selective mTORC1 regulation. Science advances 29 36103527
2006 Natural history of the Nihon (Bhd gene mutant) rat, a novel model for human Birt-Hogg-Dubé syndrome. Virchows Archiv : an international journal of pathology 25 16447066
2015 Disruption of tubular Flcn expression as a mouse model for renal tumor induction. Kidney international 22 26083655
2011 Familial multiple discoid fibromas: a look-alike of Birt-Hogg-Dubé syndrome not linked to the FLCN locus. Journal of the American Academy of Dermatology 22 21794948
2009 Regulation of folliculin (the BHD gene product) phosphorylation by Tsc2-mTOR pathway. Biochemical and biophysical research communications 22 19695222
2020 Blood and lymphatic systems are segregated by the FLCN tumor suppressor. Nature communications 21 33298956
2008 Birt-Hogg-Dubé (BHD) syndrome: report of two novel germline mutations in the folliculin (FLCN) gene. European journal of dermatology : EJD 21 18573707
2016 FLCN Maintains the Leucine Level in Lysosome to Stimulate mTORC1. PloS one 20 27280402
2021 Loss of FLCN-FNIP1/2 induces a non-canonical interferon response in human renal tubular epithelial cells. eLife 18 33459596
2020 A FLCN-TFE3 Feedback Loop Prevents Excessive Glycogenesis and Phagocyte Activation by Regulating Lysosome Activity. Cell reports 18 32049013
2019 Loss of FLCN inhibits canonical WNT signaling via TFE3. Human molecular genetics 18 31272105
2017 H255Y and K508R missense mutations in tumour suppressor folliculin (FLCN) promote kidney cell proliferation. Human molecular genetics 18 28007907
2013 A de novo FLCN mutation in a patient with spontaneous pneumothorax and renal cancer; a clinical and molecular evaluation. Familial cancer 18 23264078
2011 Activation of AMP-activated protein kinase by MAPO1 and FLCN induces apoptosis triggered by alkylated base mismatch in DNA. DNA repair 18 22209521
2023 PRDM10 directs FLCN expression in a novel disorder overlapping with Birt-Hogg-Dubé syndrome and familial lipomatosis. Human molecular genetics 17 36440963
2021 A systematic review assessing the existence of pneumothorax-only variants of FLCN. Implications for lifelong surveillance of renal tumours. European journal of human genetics : EJHG 17 34267338
2015 FLCN intragenic deletions in Chinese familial primary spontaneous pneumothorax. American journal of medical genetics. Part A 17 25807935
2018 BHD-associated kidney cancer exhibits unique molecular characteristics and a wide variety of variants in chromatin remodeling genes. Human molecular genetics 16 29767721
2016 Case Report of Birt-Hogg-Dubé Syndrome: Germline Mutations of FLCN Detected in Patients With Renal Cancer and Thyroid Cancer. Medicine 16 27258496
2015 Folliculin, a tumor suppressor associated with Birt-Hogg-Dubé (BHD) syndrome, is a novel modifier of TDP-43 cytoplasmic translocation and aggregation. Human molecular genetics 16 26516189
2012 Novel in-frame deletion mutation in FLCN gene in a Korean family with recurrent primary spontaneous pneumothorax. Gene 16 22446046
2004 Natural history of the Nihon rat model of BHD. Current molecular medicine 16 15579036
2023 Comparative analyses define differences between BHD-associated renal tumour and sporadic chromophobe renal cell carcinoma. EBioMedicine 15 37182269
2019 Genotypic characteristics of Chinese patients with BHD syndrome and functional analysis of FLCN variants. Orphanet journal of rare diseases 15 31615547
2016 Genetic screening of the FLCN gene identify six novel variants and a Danish founder mutation. Journal of human genetics 15 27734835
2018 Early onset renal cell carcinoma in an adolescent girl with germline FLCN exon 5 deletion. Familial cancer 14 28623476
2017 Nutrient-induced FNIP degradation by SCFβ-TRCP regulates FLCN complex localization and promotes renal cancer progression. Oncotarget 14 28039480
2016 Bilateral renal tumors in an adult man with Smith-Magenis syndrome: The role of the FLCN gene. European journal of medical genetics 14 27633572
2015 Flcn-deficient renal cells are tumorigenic and sensitive to mTOR suppression. Oncotarget 13 26418749
2011 The impact of germline BHD mutation on histological concordance and clinical treatment of patients with bilateral renal masses and known unilateral oncocytoma. The Journal of urology 13 21496834
2018 Birt-Hogg-Dubé syndrome in two Chinese families with mutations in the FLCN gene. BMC medical genetics 12 29357828
2023 Germline- and Somatic-Inactivating FLCN Variants in Parathyroid Cancer and Atypical Parathyroid Tumors. The Journal of clinical endocrinology and metabolism 11 36935552
2018 Splice-site mutation causing partial retention of intron in the FLCN gene in Birt-Hogg-Dubé syndrome: a case report. BMC medical genomics 11 29720200
2017 Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer. BMC medical genetics 11 28499369
2018 FLCN is a novel Rab11A-interacting protein that is involved in the Rab11A-mediated recycling transport. Journal of cell science 10 30446510
2011 FLCN gene-mutated renal cell neoplasms: mother and daughter cases with a novel germline mutation. International journal of urology : official journal of the Japanese Urological Association 10 22211584
2006 Transgenic rescue from embryonic lethality and renal carcinogenesis in the Nihon rat model by introduction of a wild-type Bhd gene. Oncogene 10 16369488
2021 Loss of hepatic Flcn protects against fibrosis and inflammation by activating autophagy pathways. Scientific reports 9 34711912
2009 Loss of heterozygosity at the FLCN locus in early renal cystic lesions in dogs with renal cystadenocarcinoma and nodular dermatofibrosis. Mammalian genome : official journal of the International Mammalian Genome Society 9 19387735
2009 Novel intronic germline FLCN gene mutation in a patient with multiple ipsilateral renal neoplasms. Human pathology 9 19733897
2008 Second hits in the FLCN gene in a hereditary renal cancer syndrome in dogs. Mammalian genome : official journal of the International Mammalian Genome Society 9 18219524
2023 Role of FLCN Phosphorylation in Insulin-Mediated mTORC1 Activation and Tumorigenesis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 8 37083230
2023 Exons 1-3 deletion in FLCN is associated with increased risk of pneumothorax in Chinese patients with Birt-Hogg-Dubé syndrome. Orphanet journal of rare diseases 8 37170274
2020 FLCN-regulated miRNAs suppressed reparative response in cells and pulmonary lesions of Birt-Hogg-Dubé syndrome. Thorax 8 32184379
2020 Quantitative genetic screening reveals a Ragulator-FLCN feedback loop that regulates the mTORC1 pathway. Science signaling 8 32934076
2017 Birt-Hogg-Dubé syndrome: a literature review and case study of a Chinese woman presenting a novel FLCN mutation. BMC pulmonary medicine 8 28222720
2022 A retrospective two centre study of Birt-Hogg-Dubé syndrome reveals a pathogenic founder mutation in FLCN in the Swedish population. PloS one 7 35176117
2013 Knockdown of Slingshot 2 (SSH2) serine phosphatase induces Caspase3 activation in human carcinoma cell lines with the loss of the Birt-Hogg-Dubé tumour suppressor gene (FLCN). Oncogene 7 23416984
2007 Postoperative fibromatosis-type fibromas in the Bhd gene mutant (Nihon) rat. Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie 7 18036795
2024 The Prevalence and Radiologic Features of Renal Cancers Associated with FLCN, BAP1, SDH, and MET Germline Mutations. Radiology. Imaging cancer 6 38456787
2024 Integrated systems pharmacology, molecular docking, and MD simulations investigation elucidating the therapeutic mechanisms of BHD in Alzheimer's disease treatment. Metabolic brain disease 6 39556154
2023 FLCN-Driven Functional Adrenal Cortical Carcinoma with High Mitotic Tumor Grade: Extending the Endocrine Manifestations of Birt-Hogg-Dubé Syndrome. Endocrine pathology 6 36701047
2022 Minigene Assay as an Effective Molecular Diagnostic Strategy in Determining the Pathogenicity of Noncanonical Splice-Site Variants in FLCN. The Journal of molecular diagnostics : JMD 6 36410626
2021 FLCN regulates transferrin receptor 1 transport and iron homeostasis. The Journal of biological chemistry 6 33609526
2021 A Novel FLCN Intragenic Deletion Identified by NGS in a BHDS Family and Literature Review. Frontiers in genetics 6 33927747
2019 Unilateral renal cystadenocarcinoma and nodular dermatofibrosis in a mixed-breed dog carrying a FLCN gene mutation. Veterinary dermatology 6 30672048
2019 FLCN alteration drives metabolic reprogramming towards nucleotide synthesis and cyst formation in salivary gland. Biochemical and biophysical research communications 6 31806376
2017 Birt-Hogg-Dube Syndrome with a Novel Mutation in the FLCN Gene. Genetic testing and molecular biomarkers 6 28805452
2016 Birt-Hogg-Dubé syndrome: novel FLCN frameshift deletion in daughter and father with renal cell carcinomas. Familial cancer 6 26342594
2017 Novel germline mutations in FLCN gene identified in two Chinese patients with Birt-Hogg-Dubé syndrome. Chinese journal of cancer 5 28069055
2016 Are lung cysts in renal cell cancer (RCC) patients an indication for FLCN mutation analysis? Familial cancer 5 26603437
2016 Novel folliculin (FLCN) mutation and familial spontaneous pneumothorax. QJM : monthly journal of the Association of Physicians 5 27486260