id: Q8NFG4 gene_symbol: FLCN product_type: PROTEIN status: DRAFT taxon: id: NCBITaxon:9606 label: Homo sapiens description: 'Folliculin (FLCN) is a tumor-suppressor protein with Longin and DENN domains. In complexes with FNIP1 or FNIP2, it stimulates GTP hydrolysis by RagC and RagD, enabling Rag-dependent mTORC1 phosphorylation and cytoplasmic retention of TFEB and TFE3. Its cytosolic and lysosomal-membrane pools respond to nutrient availability: starvation promotes an inhibited lysosomal complex, while refeeding permits catalytic activation. Effects on other mTORC1 substrates vary with cellular conditions. GABARAP-dependent sequestration and AMPK phosphorylation of FNIP1 regulate this pathway. FLCN also directly binds and inhibits LDHA in biochemical and cellular experiments, restraining glycolysis. It participates in nutrient-dependent lysosome positioning through RILP/Rab34 and has additional context-dependent roles in ciliary signaling, epithelial junctions, metabolism and differentiation. Germline loss-of-function variants cause Birt-Hogg-Dube syndrome, characterized by fibrofolliculomas, pulmonary cysts and pneumothorax, and renal tumors.' alternative_products: - name: '1' id: Q8NFG4-1 - name: '2' id: Q8NFG4-2 sequence_note: VSP_017314, VSP_017315 - name: '3' id: Q8NFG4-3 sequence_note: VSP_017312, VSP_017313 existing_annotations: - term: id: GO:0000122 label: negative regulation of transcription by RNA polymerase II evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - MGI:MGI:2442184 - PANTHER:PTN001265854 - UniProtKB:Q8NFG4 review: summary: FLCN-dependent repression of TFE3 target transcription is supported by human loss/restoration experiments (PMID:21209915). action: KEEP_AS_NON_CORE reason: FLCN-dependent repression of TFE3 target transcription is supported by human loss/restoration experiments (PMID:21209915). FLCN regulates the transcription factor rather than binding DNA itself, so this downstream process is non-core. The exact positive IBD at PTN001265854, placed at Metazoa-Choanoflagellida in the actual PANTHER release-19 API tree (the original IBD GAF taxon is blank), is on the human target path; human experimental evidence among its seeds is legitimate, not circular. supported_by: - reference_id: PMID:21209915 supporting_text: Conversely, wildtype FLCN suppressed GPNMB expression in FLCN-null cells. - reference_id: PMID:21209915 supporting_text: FLCN inactivation was correlated with increased TFE3 transcriptional activity accompanied by its nuclear localization - reference_id: PMID:24081491 supporting_text: In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:21209915 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0000122 label: negative regulation of transcription by RNA polymerase II evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in supporting_entities: - ARBA:ARBA00029133 - UniProtKB:Q8QZS3 - ensembl:ENSMUSP00000099758 review: summary: The combined electronic mouse/rule transfer agrees with FLCN-dependent repression of TFE3 target transcription in human cells (PMID:21209915). action: KEEP_AS_NON_CORE reason: The combined electronic mouse/rule transfer agrees with FLCN-dependent repression of TFE3 target transcription in human cells (PMID:21209915). Retain this downstream process as non-core; neither DNA binding by FLCN nor a separate PAINT experiment is implied by this electronic context. supported_by: - reference_id: PMID:21209915 supporting_text: Conversely, wildtype FLCN suppressed GPNMB expression in FLCN-null cells. - reference_id: PMID:21209915 supporting_text: FLCN inactivation was correlated with increased TFE3 transcriptional activity accompanied by its nuclear localization - reference_id: PMID:24081491 supporting_text: In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:21209915 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0000122 label: negative regulation of transcription by RNA polymerase II evidence_type: IMP original_reference_id: PMID:21209915 qualifier: involved_in review: summary: Human FLCN restoration and knockdown experiments support repression of TFE3-dependent transcription (PMID:21209915). action: KEEP_AS_NON_CORE reason: Human FLCN restoration and knockdown experiments support repression of TFE3-dependent transcription (PMID:21209915). This cellular regulatory effect is retained as non-core, without assigning DNA-binding activity to FLCN. Later Rag/TORC1 studies explain a regulatory route but were not experiments performed in this early paper. supported_by: - reference_id: PMID:21209915 supporting_text: Conversely, wildtype FLCN suppressed GPNMB expression in FLCN-null cells. - reference_id: PMID:21209915 supporting_text: FLCN inactivation was correlated with increased TFE3 transcriptional activity accompanied by its nuclear localization - reference_id: PMID:24081491 supporting_text: In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0001701 label: in utero embryonic development evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 review: summary: Mouse developmental and differentiation phenotypes support a non-core ortholog association. action: KEEP_AS_NON_CORE reason: The current mouse donor PMID:21258407 reports early embryo abnormalities and lethality together with yolk-sac and embryoid-body differentiation defects in Bhd-null ES cells. These developmental endpoints provide positive support for retaining the curated ortholog association as non-core, beyond a generic viability phenotype. E6.5 abnormal embryos were not individually genotyped, and the contributions of lineage-autonomous differentiation, survival and extraembryonic tissues remain unresolved. PMID:19850877 supplies corroborating developmental evidence from a separate null allele. No human embryo experiment or established TFE3 mechanism of lethality is inferred. additional_reference_ids: - PMID:19850877 - PMID:21258407 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:19850877 - reference_id: PMID:21258407 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0004857 label: enzyme inhibitor activity evidence_type: IDA original_reference_id: PMID:34381247 qualifier: enables review: summary: Purified human FLCN directly inhibits human LDHA, including kinetic and inhibitory-loop experiments in PMID:34381247. action: MODIFY reason: Purified human FLCN directly inhibits human LDHA, including kinetic and inhibitory-loop experiments in PMID:34381247. Replace the broad enzyme-inhibitor term with GO:0160193 L-lactate dehydrogenase inhibitor activity, consistent with a distinct measured molecular function. The synthetic 219–228 peptide is not a natural FLCN product; independent physiological replication and the behavior of the truncated natural products remain open. proposed_replacement_terms: - id: GO:0160193 label: L-lactate dehydrogenase inhibitor activity supported_by: - reference_id: PMID:34381247 supporting_text: Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005096 label: GTPase activator activity evidence_type: IDA original_reference_id: PMID:24095279 qualifier: enables review: summary: PMID:24095279 directly measures partner-dependent FLCN-FNIP2 GAP activity with RagC/D specificity; isolated subunits were inactive under the tested conditions. action: ACCEPT reason: PMID:24095279 directly measures partner-dependent FLCN-FNIP2 GAP activity with RagC/D specificity; isolated subunits were inactive under the tested conditions. This is a core catalytic function. No GEF or GDI activity was detected in those assays; later catalytic-residue and structural studies corroborate the GAP mechanism. supported_by: - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:31672913 supporting_text: First, we identified Arg164 of FLCN as a catalytically required arginine residue for GAP activity. - reference_id: PMID:31704029 supporting_text: Furthermore, we identified the catalytic residue necessary for the GAP activity, which leads us to interpret our structure as an on-pathway intermediate. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005096 label: GTPase activator activity evidence_type: IDA original_reference_id: PMID:31672913 qualifier: enables review: summary: PMID:31672913 uses biochemical assays and Arg164 mutagenesis to establish FLCN catalytic contribution to RagC/D GAP activity. action: ACCEPT reason: PMID:31672913 uses biochemical assays and Arg164 mutagenesis to establish FLCN catalytic contribution to RagC/D GAP activity. The captured lysosomal folliculin complex is inhibited and places the arginine away from the nucleotide; that structure alone is not an active catalytic state. The independently measured activity is core. supported_by: - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:31672913 supporting_text: First, we identified Arg164 of FLCN as a catalytically required arginine residue for GAP activity. - reference_id: PMID:31704029 supporting_text: Furthermore, we identified the catalytic residue necessary for the GAP activity, which leads us to interpret our structure as an on-pathway intermediate. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005096 label: GTPase activator activity evidence_type: IDA original_reference_id: PMID:31704029 qualifier: enables review: summary: PMID:31704029 directly measures RagC hydrolysis with purified human FLCN-FNIP2 and strong loss of activity with R164A. action: ACCEPT reason: PMID:31704029 directly measures RagC hydrolysis with purified human FLCN-FNIP2 and strong loss of activity with R164A. The captured nine-subunit complex is a structural intermediate, not a transition-state view of arginine insertion. These biochemical data support the core GAP activity. supported_by: - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:31672913 supporting_text: First, we identified Arg164 of FLCN as a catalytically required arginine residue for GAP activity. - reference_id: PMID:31704029 supporting_text: Furthermore, we identified the catalytic residue necessary for the GAP activity, which leads us to interpret our structure as an on-pathway intermediate. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005096 label: GTPase activator activity evidence_type: IDA original_reference_id: PMID:32612235 qualifier: enables review: summary: FLCN RagC/D GAP activity is independently established by purified assays (PMID:24095279, PMID:31704029). action: ACCEPT reason: FLCN RagC/D GAP activity is independently established by purified assays (PMID:24095279, PMID:31704029). The original PMID:32612235 context measures human FLCN-loss and Rag-mutant bypass effects on TFEB phosphorylation; it is retained without misdescribing that study as a new isolated FLCN turnover experiment. supported_by: - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:31672913 supporting_text: First, we identified Arg164 of FLCN as a catalytically required arginine residue for GAP activity. - reference_id: PMID:31704029 supporting_text: Furthermore, we identified the catalytic residue necessary for the GAP activity, which leads us to interpret our structure as an on-pathway intermediate. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:24095279 - PMID:31704029 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005096 label: GTPase activator activity evidence_type: IDA original_reference_id: PMID:36103527 qualifier: enables review: summary: PMID:36103527 resolves an active FLCN-FNIP2/Rag catalytic complex and tests catalytic contributions. action: ACCEPT reason: PMID:36103527 resolves an active FLCN-FNIP2/Rag catalytic complex and tests catalytic contributions. The F118D, SLC38A9-FNIP2 fusion and nucleotide-state constructs are experimental tools, not natural FLCN isoforms. Together with independent turnover assays, these experiments support the core GAP function. supported_by: - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:31672913 supporting_text: First, we identified Arg164 of FLCN as a catalytically required arginine residue for GAP activity. - reference_id: PMID:31704029 supporting_text: Furthermore, we identified the catalytic residue necessary for the GAP activity, which leads us to interpret our structure as an on-pathway intermediate. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005096 label: GTPase activator activity evidence_type: IDA original_reference_id: PMID:37079666 qualifier: enables review: summary: PMID:37079666 demonstrates AMPK/FNIP1 control of the FLCN-dependent TFEB pathway. action: ACCEPT reason: PMID:37079666 demonstrates AMPK/FNIP1 control of the FLCN-dependent TFEB pathway. AMPK phosphorylates FNIP1; this is not kinase activity of FLCN or a new purified FLCN turnover assay. The original experimental context is retained with independently demonstrated FLCN GAP activity (PMID:24095279, PMID:31704029). supported_by: - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:31672913 supporting_text: First, we identified Arg164 of FLCN as a catalytically required arginine residue for GAP activity. - reference_id: PMID:31704029 supporting_text: Furthermore, we identified the catalytic residue necessary for the GAP activity, which leads us to interpret our structure as an on-pathway intermediate. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:24095279 - PMID:31704029 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005096 label: GTPase activator activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables supporting_entities: - InterPro:IPR037520 review: summary: The InterPro electronic assignment agrees with direct target-specific RagC/D GAP assays (PMID:24095279, PMID:31704029). action: ACCEPT reason: The InterPro electronic assignment agrees with direct target-specific RagC/D GAP assays (PMID:24095279, PMID:31704029). Family/domain membership is corroboration rather than a substitute for these biochemical experiments; the assigned activity is core. supported_by: - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:31672913 supporting_text: First, we identified Arg164 of FLCN as a catalytically required arginine residue for GAP activity. - reference_id: PMID:31704029 supporting_text: Furthermore, we identified the catalytic residue necessary for the GAP activity, which leads us to interpret our structure as an on-pathway intermediate. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:24095279 - PMID:31704029 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17028174 qualifier: enables supporting_entities: - UniProtKB:Q8TF40 review: summary: PMID:17028174 establishes FLCN-FNIP1 association by interaction and coimmunoprecipitation experiments. action: KEEP_AS_NON_CORE reason: PMID:17028174 establishes FLCN-FNIP1 association by interaction and coimmunoprecipitation experiments. The AMPK-binding clause in the inherited excerpt concerns FNIP1, not independently demonstrated binary FLCN-AMPK binding. Retain the supported FLCN partner association as non-core under the campaign generic-binding policy; do not infer an adapter or kinase-binding subtype. supported_by: - reference_id: PMID:17028174 supporting_text: Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5' AMP-activated protein kinase (AMPK) - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18403135 qualifier: enables supporting_entities: - UniProtKB:Q8TF40 review: summary: PMID:18403135 supports FLCN association with FNIP1 alongside the characterization of FNIP2. action: KEEP_AS_NON_CORE reason: PMID:18403135 supports FLCN association with FNIP1 alongside the characterization of FNIP2. Retain the FNIP1 source context as non-core generic binding; this interaction alone does not establish a new molecular-function subtype or the later GAP assay. supported_by: - reference_id: PMID:17028174 supporting_text: Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5' AMP-activated protein kinase (AMPK) - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18403135 qualifier: enables supporting_entities: - UniProtKB:Q9P278 review: summary: PMID:18403135 directly characterizes FNIP2 and its association with FLCN. action: KEEP_AS_NON_CORE reason: PMID:18403135 directly characterizes FNIP2 and its association with FLCN. Retain this supported partner interaction as non-core generic binding. Tested deletion or disease constructs do not show that all natural FLCN products bind equivalently. supported_by: - reference_id: PMID:18403135 supporting_text: C-terminally-deleted FLCN mutants, similar to those produced by naturally-occurring germline mutations in BHD patients, were unable to bind FNIP2. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18663353 qualifier: enables supporting_entities: - UniProtKB:Q9P278 review: summary: The accessible PMID:18663353 abstract reports FLCN-FnipL/FNIP2 interaction, while its full body remains inaccessible. action: KEEP_AS_NON_CORE reason: The accessible PMID:18663353 abstract reports FLCN-FnipL/FNIP2 interaction, while its full body remains inaccessible. Independent primary PMID:18403135 establishes the same FLCN-FNIP2 association. Retain the clearly supported association as non-core without claiming the exact original assay or inventing a more specific binding activity. supported_by: - reference_id: PMID:18403135 supporting_text: C-terminally-deleted FLCN mutants, similar to those produced by naturally-occurring germline mutations in BHD patients, were unable to bind FNIP2. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:18403135 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22965878 qualifier: enables supporting_entities: - UniProtKB:Q99569 review: summary: PMID:22965878 supports FLCN-p0071/PKP4 association by yeast two-hybrid and coimmunoprecipitation experiments. action: KEEP_AS_NON_CORE reason: PMID:22965878 supports FLCN-p0071/PKP4 association by yeast two-hybrid and coimmunoprecipitation experiments. Junction/midbody colocalization is separate evidence and is not itself a binary binding assay. Retain the partner association as non-core without assigning a structural junction or adapter molecular function. supported_by: - reference_id: PMID:22965878 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25126726 qualifier: enables supporting_entities: - UniProtKB:O75385 review: summary: PMID:25126726 reports coimmunoprecipitation of FLCN with ULK1, stronger for kinase-inactive K46I than wild type. action: KEEP_AS_NON_CORE reason: PMID:25126726 reports coimmunoprecipitation of FLCN with ULK1, stronger for kinase-inactive K46I than wild type. FLCN is a substrate in assays using immunoprecipitated ULK1; the Ser406/407 assignment remains ambiguous and the triple-site mutant does not fully explain complex dissociation. Retain non-core association without turning phosphorylation into evidence for FLCN kinase activity or a specific kinase-binding function. supported_by: - reference_id: PMID:25126726 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25126726 qualifier: enables supporting_entities: - UniProtKB:O95166 review: summary: PMID:25126726 supports FLCN-GABARAP association with cell-lysate GST pull-down and coimmunoprecipitation assays. action: KEEP_AS_NON_CORE reason: PMID:25126726 supports FLCN-GABARAP association with cell-lysate GST pull-down and coimmunoprecipitation assays. These do not establish purified binary binding. Retain non-core association; later GABARAP-complex structural work places the direct interface on FNIP1/2 (PMID:34597140), which is compatible with a co-complex interaction. supported_by: - reference_id: PMID:25126726 supporting_text: our findings demonstrate that FLCN interacts with a second integral component of the autophagy machinery, GABA(A) receptor-associated protein (GABARAP). - reference_id: PMID:34597140 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:34597140 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25126726 qualifier: enables supporting_entities: - UniProtKB:O95166 - UniProtKB:Q8TF40 review: summary: PMID:25126726 supports a GABARAP-associated FLCN complex in the FNIP1 context recorded in this row. action: KEEP_AS_NON_CORE reason: PMID:25126726 supports a GABARAP-associated FLCN complex in the FNIP1 context recorded in this row. Cell-lysate pull-down/coimmunoprecipitation is not proof of purified binary FLCN-GABARAP binding. Retain the association as non-core and preserve both source partners; later direct GABARAP recognition by FNIP1/2 is a separate mechanistic result (PMID:34597140). supported_by: - reference_id: PMID:25126726 supporting_text: our findings demonstrate that FLCN interacts with a second integral component of the autophagy machinery, GABA(A) receptor-associated protein (GABARAP). - reference_id: PMID:34597140 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:34597140 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25126726 qualifier: enables supporting_entities: - UniProtKB:O95166 - UniProtKB:Q9P278 review: summary: PMID:25126726 supports a GABARAP-associated FLCN complex in the FNIP2 context recorded in this row. action: KEEP_AS_NON_CORE reason: PMID:25126726 supports a GABARAP-associated FLCN complex in the FNIP2 context recorded in this row. Retain this distinct co-complex association as non-core; the lysate assays do not establish an autonomous FLCN cargo-adapter function or purified binary GABARAP binding. Later FNIP-mediated recognition is consistent with this limit (PMID:34597140). supported_by: - reference_id: PMID:25126726 supporting_text: our findings demonstrate that FLCN interacts with a second integral component of the autophagy machinery, GABA(A) receptor-associated protein (GABARAP). - reference_id: PMID:34597140 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:34597140 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27113757 qualifier: enables supporting_entities: - UniProtKB:Q96NA2 review: summary: PMID:27113757 supports FLCN-RILP association and FLCN-DENN-dependent loading of active Rab34 onto RILP. action: KEEP_AS_NON_CORE reason: PMID:27113757 supports FLCN-RILP association and FLCN-DENN-dependent loading of active Rab34 onto RILP. The loading experiment is not itself a binary binding assay, and Rab34 nucleotide exchange was not detected under the tested conditions. Retain non-core association without inferring GEF, GDI or a stable ternary-adapter mechanism. supported_by: - reference_id: PMID:27113757 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27353360 qualifier: enables supporting_entities: - UniProtKB:O95433 review: summary: PMID:27353360 supports FLCN association with AHSA1 in the interaction/proteomic chaperone-complex experiments. action: KEEP_AS_NON_CORE reason: PMID:27353360 supports FLCN association with AHSA1 in the interaction/proteomic chaperone-complex experiments. Retain this specific partner context as non-core generic binding; association need not be purified binary contact. FLCN is an Hsp90 client, whereas FNIP1/2 are the cochaperones. Purified FLCN did not bind Hsp90 alpha without FNIP1 in the tested reconstitution; no cochaperone activity is assigned to FLCN. supported_by: - reference_id: PMID:27353360 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27353360 qualifier: enables supporting_entities: - UniProtKB:P07900 review: summary: PMID:27353360 supports FLCN association with HSP90AA1/Hsp90 alpha in the interaction/proteomic chaperone-complex experiments. action: KEEP_AS_NON_CORE reason: PMID:27353360 supports FLCN association with HSP90AA1/Hsp90 alpha in the interaction/proteomic chaperone-complex experiments. Retain this specific partner context as non-core generic binding; association need not be purified binary contact. FLCN is an Hsp90 client, whereas FNIP1/2 are the cochaperones. Purified FLCN did not bind Hsp90 alpha without FNIP1 in the tested reconstitution; no cochaperone activity is assigned to FLCN. supported_by: - reference_id: PMID:27353360 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27353360 qualifier: enables supporting_entities: - UniProtKB:P31948 review: summary: PMID:27353360 supports FLCN association with STIP1 in the interaction/proteomic chaperone-complex experiments. action: KEEP_AS_NON_CORE reason: PMID:27353360 supports FLCN association with STIP1 in the interaction/proteomic chaperone-complex experiments. Retain this specific partner context as non-core generic binding; association need not be purified binary contact. FLCN is an Hsp90 client, whereas FNIP1/2 are the cochaperones. Purified FLCN did not bind Hsp90 alpha without FNIP1 in the tested reconstitution; no cochaperone activity is assigned to FLCN. supported_by: - reference_id: PMID:27353360 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27353360 qualifier: enables supporting_entities: - UniProtKB:P53041 review: summary: PMID:27353360 supports FLCN association with PPP5C in the interaction/proteomic chaperone-complex experiments. action: KEEP_AS_NON_CORE reason: PMID:27353360 supports FLCN association with PPP5C in the interaction/proteomic chaperone-complex experiments. Retain this specific partner context as non-core generic binding; association need not be purified binary contact. FLCN is an Hsp90 client, whereas FNIP1/2 are the cochaperones. Purified FLCN did not bind Hsp90 alpha without FNIP1 in the tested reconstitution; no cochaperone activity is assigned to FLCN. supported_by: - reference_id: PMID:27353360 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27353360 qualifier: enables supporting_entities: - UniProtKB:P78371 review: summary: PMID:27353360 supports FLCN association with CCT2 in the interaction/proteomic chaperone-complex experiments. action: KEEP_AS_NON_CORE reason: PMID:27353360 supports FLCN association with CCT2 in the interaction/proteomic chaperone-complex experiments. Retain this specific partner context as non-core generic binding; association need not be purified binary contact. FLCN is an Hsp90 client, whereas FNIP1/2 are the cochaperones. Purified FLCN did not bind Hsp90 alpha without FNIP1 in the tested reconstitution; no cochaperone activity is assigned to FLCN. supported_by: - reference_id: PMID:27353360 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27353360 qualifier: enables supporting_entities: - UniProtKB:Q15185 review: summary: PMID:27353360 supports FLCN association with PTGES3 in the interaction/proteomic chaperone-complex experiments. action: KEEP_AS_NON_CORE reason: PMID:27353360 supports FLCN association with PTGES3 in the interaction/proteomic chaperone-complex experiments. Retain this specific partner context as non-core generic binding; association need not be purified binary contact. FLCN is an Hsp90 client, whereas FNIP1/2 are the cochaperones. Purified FLCN did not bind Hsp90 alpha without FNIP1 in the tested reconstitution; no cochaperone activity is assigned to FLCN. supported_by: - reference_id: PMID:27353360 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27353360 qualifier: enables supporting_entities: - UniProtKB:Q16543 review: summary: PMID:27353360 supports FLCN association with CDC37 in the interaction/proteomic chaperone-complex experiments. action: KEEP_AS_NON_CORE reason: PMID:27353360 supports FLCN association with CDC37 in the interaction/proteomic chaperone-complex experiments. Retain this specific partner context as non-core generic binding; association need not be purified binary contact. FLCN is an Hsp90 client, whereas FNIP1/2 are the cochaperones. Purified FLCN did not bind Hsp90 alpha without FNIP1 in the tested reconstitution; no cochaperone activity is assigned to FLCN. supported_by: - reference_id: PMID:27353360 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27353360 qualifier: enables supporting_entities: - UniProtKB:Q8TF40 review: summary: PMID:27353360 supports FLCN association with FNIP1 in the interaction/proteomic chaperone-complex experiments. action: KEEP_AS_NON_CORE reason: PMID:27353360 supports FLCN association with FNIP1 in the interaction/proteomic chaperone-complex experiments. Retain this specific partner context as non-core generic binding; association need not be purified binary contact. FLCN is an Hsp90 client, whereas FNIP1/2 are the cochaperones. Purified FLCN did not bind Hsp90 alpha without FNIP1 in the tested reconstitution; no cochaperone activity is assigned to FLCN. supported_by: - reference_id: PMID:27353360 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27353360 qualifier: enables supporting_entities: - UniProtKB:Q9P278 review: summary: PMID:27353360 supports FLCN association with FNIP2 in the interaction/proteomic chaperone-complex experiments. action: KEEP_AS_NON_CORE reason: PMID:27353360 supports FLCN association with FNIP2 in the interaction/proteomic chaperone-complex experiments. Retain this specific partner context as non-core generic binding; association need not be purified binary contact. FLCN is an Hsp90 client, whereas FNIP1/2 are the cochaperones. Purified FLCN did not bind Hsp90 alpha without FNIP1 in the tested reconstitution; no cochaperone activity is assigned to FLCN. supported_by: - reference_id: PMID:27353360 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27353360 qualifier: enables supporting_entities: - UniProtKB:Q9UNE7 review: summary: PMID:27353360 supports FLCN association with STUB1 in the interaction/proteomic chaperone-complex experiments. action: KEEP_AS_NON_CORE reason: PMID:27353360 supports FLCN association with STUB1 in the interaction/proteomic chaperone-complex experiments. Retain this specific partner context as non-core generic binding; association need not be purified binary contact. FLCN is an Hsp90 client, whereas FNIP1/2 are the cochaperones. Purified FLCN did not bind Hsp90 alpha without FNIP1 in the tested reconstitution; no cochaperone activity is assigned to FLCN. supported_by: - reference_id: PMID:27353360 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005634 label: nucleus evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - FB:FBgn0261111 - PANTHER:PTN002833743 - UniProtKB:Q8NFG4 review: summary: Nuclear localization is a peripheral, context-dependent pool. action: KEEP_AS_NON_CORE reason: Nuclear localization is a peripheral, context-dependent pool. Tagged FLCN localization in PMID:17028174 and the accessible PMID:18663353 abstract support it. Knockout controls in PMID:29848618 identify nonspecific nuclear staining for that study's antibody, but its authors do not exclude a small nuclear pool; this does not refute every independent nuclear observation. The positive IBD at PTN002833743 lies on the human target path and includes both fly and human experimental grounding. supported_by: - reference_id: PMID:17028174 supporting_text: FLCN also localized in the nucleus. - reference_id: PMID:18663353 supporting_text: FnipL/Fnip2 and Flcn were located together in the cytoplasm in a reticular pattern, although solely expressed Flcn was found mainly in the nucleus. - reference_id: PMID:29848618 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:17028174 - PMID:18663353 - PMID:29848618 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:17028174 qualifier: located_in review: summary: Nuclear localization is a peripheral, context-dependent pool. action: KEEP_AS_NON_CORE reason: Nuclear localization is a peripheral, context-dependent pool. Tagged FLCN localization in PMID:17028174 and the accessible PMID:18663353 abstract support it. Knockout controls in PMID:29848618 identify nonspecific nuclear staining for that study's antibody, but its authors do not exclude a small nuclear pool; this does not refute every independent nuclear observation. Retain the original tagged-protein experimental context without generalizing to all products or endogenous conditions. supported_by: - reference_id: PMID:17028174 supporting_text: FLCN also localized in the nucleus. - reference_id: PMID:18663353 supporting_text: FnipL/Fnip2 and Flcn were located together in the cytoplasm in a reticular pattern, although solely expressed Flcn was found mainly in the nucleus. - reference_id: PMID:29848618 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:18663353 - PMID:29848618 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:18663353 qualifier: located_in review: summary: Nuclear localization is a peripheral, context-dependent pool. action: KEEP_AS_NON_CORE reason: Nuclear localization is a peripheral, context-dependent pool. Tagged FLCN localization in PMID:17028174 and the accessible PMID:18663353 abstract support it. Knockout controls in PMID:29848618 identify nonspecific nuclear staining for that study's antibody, but its authors do not exclude a small nuclear pool; this does not refute every independent nuclear observation. The original source remains abstract-only for this audit; independent target evidence supports retention without claiming access to its full assay details. supported_by: - reference_id: PMID:17028174 supporting_text: FLCN also localized in the nucleus. - reference_id: PMID:18663353 supporting_text: FnipL/Fnip2 and Flcn were located together in the cytoplasm in a reticular pattern, although solely expressed Flcn was found mainly in the nucleus. - reference_id: PMID:29848618 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:17028174 - PMID:29848618 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0191 review: summary: Nuclear localization is a peripheral, context-dependent pool. action: KEEP_AS_NON_CORE reason: Nuclear localization is a peripheral, context-dependent pool. Tagged FLCN localization in PMID:17028174 and the accessible PMID:18663353 abstract support it. Knockout controls in PMID:29848618 identify nonspecific nuclear staining for that study's antibody, but its authors do not exclude a small nuclear pool; this does not refute every independent nuclear observation. The UniProt location mapping is corroborating electronic evidence, not an additional localization experiment. supported_by: - reference_id: PMID:17028174 supporting_text: FLCN also localized in the nucleus. - reference_id: PMID:18663353 supporting_text: FnipL/Fnip2 and Flcn were located together in the cytoplasm in a reticular pattern, although solely expressed Flcn was found mainly in the nucleus. - reference_id: PMID:29848618 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:17028174 - PMID:18663353 - PMID:29848618 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:17028174 qualifier: located_in review: summary: The broad cytoplasmic localization in PMID:17028174 is valid. action: MODIFY reason: The broad cytoplasmic localization in PMID:17028174 is valid. Refine it to the independently resolved cytosol and lysosomal membrane (PMID:24081491, PMID:29848618). The original early localization/association experiments do not by themselves resolve both subcompartments; the replacement uses the combined target evidence and retains the original source context. proposed_replacement_terms: - id: GO:0005829 label: cytosol - id: GO:0005765 label: lysosomal membrane supported_by: - reference_id: PMID:17028174 supporting_text: HA-FNIP1 and FLAG-FLCN, transiently cotransfected into HeLa cells, colocalized in the cytoplasm with a reticular pattern - reference_id: PMID:24095279 supporting_text: Thus, FLCN localizes to the lysosomal surface during amino acid starvation, but leaves this site upon amino acid stimulation in an mTORC1 activity-independent manner. - reference_id: PMID:24081491 - reference_id: PMID:29848618 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:24081491 - PMID:29848618 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:18663353 qualifier: located_in review: summary: The broad cytoplasmic localization in PMID:18663353 is valid. action: MODIFY reason: The broad cytoplasmic localization in PMID:18663353 is valid. Refine it to the independently resolved cytosol and lysosomal membrane (PMID:24081491, PMID:29848618). The original early localization/association experiments do not by themselves resolve both subcompartments; the replacement uses the combined target evidence and retains the original source context. proposed_replacement_terms: - id: GO:0005829 label: cytosol - id: GO:0005765 label: lysosomal membrane supported_by: - reference_id: PMID:17028174 supporting_text: HA-FNIP1 and FLAG-FLCN, transiently cotransfected into HeLa cells, colocalized in the cytoplasm with a reticular pattern - reference_id: PMID:24095279 supporting_text: Thus, FLCN localizes to the lysosomal surface during amino acid starvation, but leaves this site upon amino acid stimulation in an mTORC1 activity-independent manner. - reference_id: PMID:24081491 - reference_id: PMID:29848618 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:24081491 - PMID:29848618 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:22965878 qualifier: located_in review: summary: The broad cytoplasmic localization in PMID:22965878 is valid. action: MODIFY reason: The broad cytoplasmic localization in PMID:22965878 is valid. Refine it to the independently resolved cytosol and lysosomal membrane (PMID:24081491, PMID:29848618). The original early localization/association experiments do not by themselves resolve both subcompartments; the replacement uses the combined target evidence and retains the original source context. proposed_replacement_terms: - id: GO:0005829 label: cytosol - id: GO:0005765 label: lysosomal membrane supported_by: - reference_id: PMID:17028174 supporting_text: HA-FNIP1 and FLAG-FLCN, transiently cotransfected into HeLa cells, colocalized in the cytoplasm with a reticular pattern - reference_id: PMID:24095279 supporting_text: Thus, FLCN localizes to the lysosomal surface during amino acid starvation, but leaves this site upon amino acid stimulation in an mTORC1 activity-independent manner. - reference_id: PMID:24081491 - reference_id: PMID:29848618 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:24081491 - PMID:29848618 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005764 label: lysosome evidence_type: TAS original_reference_id: PMID:25126726 qualifier: located_in review: summary: Lysosome is an informative core organelle location, retained under the repository root-organelle exception even though lysosomal membrane is also annotated. action: ACCEPT reason: Lysosome is an informative core organelle location, retained under the repository root-organelle exception even though lysosomal membrane is also annotated. The original TAS is supported by independent localization in PMID:24081491 and PMID:29848618. FLCN associates with the cytosolic membrane face; neither luminal residence nor integral membrane insertion is asserted. supported_by: - reference_id: PMID:24081491 supporting_text: We further demonstrated that FLCN itself was selectively recruited to the surface of lysosomes after amino acid depletion and directly bound to RagA via its GTPase domain. - reference_id: PMID:29848618 supporting_text: FLCN is recruited to lysosomes during amino acid starvation, where it interacts with RagA/B as a heterodimeric complex with FLCN-interacting proteins (FNIPs). - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:24081491 - PMID:29848618 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005765 label: lysosomal membrane evidence_type: IDA original_reference_id: PMID:24081491 qualifier: located_in review: summary: PMID:24081491 distinguishes overexpressed mouse FLCN/FNIP1 from independently CRISPR-tagged endogenous human FLCN. action: ACCEPT reason: PMID:24081491 distinguishes overexpressed mouse FLCN/FNIP1 from independently CRISPR-tagged endogenous human FLCN. The human tagged-locus experiments show starvation recruitment and refeeding dispersal; vacuolin-assisted imaging distinguishes limiting membrane from lumen. This is a core location for regulated FLCN complexes. supported_by: - reference_id: PMID:24081491 supporting_text: We further demonstrated that FLCN itself was selectively recruited to the surface of lysosomes after amino acid depletion and directly bound to RagA via its GTPase domain. - reference_id: PMID:31672913 supporting_text: FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding - reference_id: PMID:29848618 supporting_text: FLCN is recruited to lysosomes during amino acid starvation, where it interacts with RagA/B as a heterodimeric complex with FLCN-interacting proteins (FNIPs). - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005765 label: lysosomal membrane evidence_type: IDA original_reference_id: PMID:24095279 qualifier: located_in review: summary: PMID:24095279 demonstrates dynamic lysosomal association of the FLCN-FNIP complex alongside partner-dependent RagC/D GAP activity. action: ACCEPT reason: PMID:24095279 demonstrates dynamic lysosomal association of the FLCN-FNIP complex alongside partner-dependent RagC/D GAP activity. This membrane-associated pool is central to amino-acid-responsive Rag regulation, without implying that every recruited complex is actively hydrolyzing GTP. supported_by: - reference_id: PMID:24081491 supporting_text: We further demonstrated that FLCN itself was selectively recruited to the surface of lysosomes after amino acid depletion and directly bound to RagA via its GTPase domain. - reference_id: PMID:31672913 supporting_text: FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding - reference_id: PMID:29848618 supporting_text: FLCN is recruited to lysosomes during amino acid starvation, where it interacts with RagA/B as a heterodimeric complex with FLCN-interacting proteins (FNIPs). - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005765 label: lysosomal membrane evidence_type: IDA original_reference_id: PMID:27113757 qualifier: located_in review: summary: PMID:27113757 supports FLCN association with the lysosomal membrane in its RILP/Rab34 trafficking experiments. action: ACCEPT reason: PMID:27113757 supports FLCN association with the lysosomal membrane in its RILP/Rab34 trafficking experiments. This agrees with the core lysosomal pool. Artificial mitochondrial recruitment is an experimental relocation and does not establish native mitochondrial FLCN localization. supported_by: - reference_id: PMID:24081491 supporting_text: We further demonstrated that FLCN itself was selectively recruited to the surface of lysosomes after amino acid depletion and directly bound to RagA via its GTPase domain. - reference_id: PMID:31672913 supporting_text: FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding - reference_id: PMID:29848618 supporting_text: FLCN is recruited to lysosomes during amino acid starvation, where it interacts with RagA/B as a heterodimeric complex with FLCN-interacting proteins (FNIPs). - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005765 label: lysosomal membrane evidence_type: IDA original_reference_id: PMID:29848618 qualifier: located_in review: summary: The actual primary Results of PMID:29848618 show knockout-validated endogenous human cytoplasmic/lysosomal FLCN signal, RagA/B knockout/restoration and GATOR1/RagA nucleotide-state dependence. action: ACCEPT reason: The actual primary Results of PMID:29848618 show knockout-validated endogenous human cytoplasmic/lysosomal FLCN signal, RagA/B knockout/restoration and GATOR1/RagA nucleotide-state dependence. These support core lysosomal recruitment. The nonspecific nuclear component of the tested antibody is a separate observation. supported_by: - reference_id: PMID:24081491 supporting_text: We further demonstrated that FLCN itself was selectively recruited to the surface of lysosomes after amino acid depletion and directly bound to RagA via its GTPase domain. - reference_id: PMID:31672913 supporting_text: FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding - reference_id: PMID:29848618 supporting_text: FLCN is recruited to lysosomes during amino acid starvation, where it interacts with RagA/B as a heterodimeric complex with FLCN-interacting proteins (FNIPs). - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005765 label: lysosomal membrane evidence_type: IDA original_reference_id: PMID:31672913 qualifier: located_in review: summary: PMID:31672913 supports starvation-dependent assembly and recruitment of the lysosomal folliculin complex. action: ACCEPT reason: PMID:31672913 supports starvation-dependent assembly and recruitment of the lysosomal folliculin complex. This is a core membrane-associated location, although the captured complex inhibits the GAP configuration rather than showing constitutive active turnover. supported_by: - reference_id: PMID:24081491 supporting_text: We further demonstrated that FLCN itself was selectively recruited to the surface of lysosomes after amino acid depletion and directly bound to RagA via its GTPase domain. - reference_id: PMID:31672913 supporting_text: FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding - reference_id: PMID:29848618 supporting_text: FLCN is recruited to lysosomes during amino acid starvation, where it interacts with RagA/B as a heterodimeric complex with FLCN-interacting proteins (FNIPs). - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005765 label: lysosomal membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0157 review: summary: The UniProt subcellular-location mapping is corroborated by direct human lysosomal recruitment experiments (PMID:24081491, PMID:29848618). action: ACCEPT reason: The UniProt subcellular-location mapping is corroborated by direct human lysosomal recruitment experiments (PMID:24081491, PMID:29848618). Retain this core membrane-associated location without treating the electronic source as another experiment. supported_by: - reference_id: PMID:24081491 supporting_text: We further demonstrated that FLCN itself was selectively recruited to the surface of lysosomes after amino acid depletion and directly bound to RagA via its GTPase domain. - reference_id: PMID:31672913 supporting_text: FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding - reference_id: PMID:29848618 supporting_text: FLCN is recruited to lysosomes during amino acid starvation, where it interacts with RagA/B as a heterodimeric complex with FLCN-interacting proteins (FNIPs). - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:24081491 - PMID:29848618 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005813 label: centrosome evidence_type: IDA original_reference_id: PMID:23784378 qualifier: located_in review: summary: Actual Methods and Results in PMID:23784378 identify human EGFP-FLCN at centrosomes in MDCK host cells, with separate endogenous mouse IMCD3 observations. action: KEEP_AS_NON_CORE reason: Actual Methods and Results in PMID:23784378 identify human EGFP-FLCN at centrosomes in MDCK host cells, with separate endogenous mouse IMCD3 observations. Retain this peripheral localization as non-core without assigning a centrosome-specific molecular function. Construct species and host species are distinct; figure pixels and supplements were not independently inspected. supported_by: - reference_id: PMID:23784378 supporting_text: Our data indicate that FLCN localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005813 label: centrosome evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0048 review: summary: Actual Methods and Results in PMID:23784378 identify human EGFP-FLCN at centrosomes in MDCK host cells, with separate endogenous mouse IMCD3 observations. action: KEEP_AS_NON_CORE reason: Actual Methods and Results in PMID:23784378 identify human EGFP-FLCN at centrosomes in MDCK host cells, with separate endogenous mouse IMCD3 observations. Retain this peripheral localization as non-core without assigning a centrosome-specific molecular function. Construct species and host species are distinct; figure pixels and supplements were not independently inspected. supported_by: - reference_id: PMID:23784378 supporting_text: Our data indicate that FLCN localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:23784378 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005819 label: spindle evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0251 review: summary: The observed specific compartment is the mitotic spindle in human HK2 cells expressing EGFP-FLCN (PMID:23784378). action: MODIFY reason: The observed specific compartment is the mitotic spindle in human HK2 cells expressing EGFP-FLCN (PMID:23784378). Replace broad spindle with GO:0072686 mitotic spindle, a verified ontology refinement. Localization does not establish a spindle-assembly molecular activity. proposed_replacement_terms: - id: GO:0072686 label: mitotic spindle supported_by: - reference_id: PMID:23784378 supporting_text: Our data indicate that FLCN localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:23784378 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005829 label: cytosol evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - PANTHER:PTN002833743 - UniProtKB:Q8NFG4 review: summary: The positive cytosol IBD at PTN002833743 lies on the exact human target path, with legitimate human experimental grounding. action: ACCEPT reason: The positive cytosol IBD at PTN002833743 lies on the exact human target path, with legitimate human experimental grounding. Human localization experiments independently support the cytosolic pool (PMID:24081491, PMID:29848618). A single experimental seed is not weak or circular phylogenetic support. supported_by: - reference_id: PMID:24095279 supporting_text: Thus, FLCN localizes to the lysosomal surface during amino acid starvation, but leaves this site upon amino acid stimulation in an mTORC1 activity-independent manner. - reference_id: PMID:31672913 supporting_text: FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding - reference_id: PMID:24081491 - reference_id: PMID:29848618 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:24081491 - PMID:29848618 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Retain the original Human Protein Atlas IDA context for a well-supported core cytosolic pool. action: ACCEPT reason: Retain the original Human Protein Atlas IDA context for a well-supported core cytosolic pool. No independent inspection of the specific Atlas image is claimed; target experiments in PMID:24081491 and PMID:29848618 independently establish cytoplasmic/cytosolic localization. supported_by: - reference_id: PMID:24095279 supporting_text: Thus, FLCN localizes to the lysosomal surface during amino acid starvation, but leaves this site upon amino acid stimulation in an mTORC1 activity-independent manner. - reference_id: PMID:31672913 supporting_text: FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding - reference_id: PMID:24081491 - reference_id: PMID:29848618 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:24081491 - PMID:29848618 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: PMID:24081491 qualifier: located_in review: summary: PMID:24081491 shows diffuse basal signal from endogenous-locus tagged human FLCN and starvation/refeeding-dependent redistribution. action: ACCEPT reason: PMID:24081491 shows diffuse basal signal from endogenous-locus tagged human FLCN and starvation/refeeding-dependent redistribution. This supports core cytosolic localization. The separate mouse overexpression constructs are not mislabeled as human protein solely because of their host cell. supported_by: - reference_id: PMID:24095279 supporting_text: Thus, FLCN localizes to the lysosomal surface during amino acid starvation, but leaves this site upon amino acid stimulation in an mTORC1 activity-independent manner. - reference_id: PMID:31672913 supporting_text: FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: PMID:24095279 qualifier: located_in review: summary: PMID:24095279 supports a dynamic cytosolic FLCN-FNIP pool that redistributes with amino-acid availability. action: ACCEPT reason: PMID:24095279 supports a dynamic cytosolic FLCN-FNIP pool that redistributes with amino-acid availability. Cytosol is a core location; the experiments do not assign identical localization to each truncated natural product. supported_by: - reference_id: PMID:24095279 supporting_text: Thus, FLCN localizes to the lysosomal surface during amino acid starvation, but leaves this site upon amino acid stimulation in an mTORC1 activity-independent manner. - reference_id: PMID:31672913 supporting_text: FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: PMID:29848618 qualifier: located_in review: summary: Knockout controls in the actual primary PMID:29848618 validate endogenous human cytoplasmic FLCN staining and its regulated recruitment. action: ACCEPT reason: Knockout controls in the actual primary PMID:29848618 validate endogenous human cytoplasmic FLCN staining and its regulated recruitment. Retain core cytosolic localization while separating the nonspecific nuclear antibody signal. supported_by: - reference_id: PMID:24095279 supporting_text: Thus, FLCN localizes to the lysosomal surface during amino acid starvation, but leaves this site upon amino acid stimulation in an mTORC1 activity-independent manner. - reference_id: PMID:31672913 supporting_text: FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: PMID:31672913 qualifier: located_in review: summary: PMID:31672913 supports cytosolic FLCN and regulated movement into the lysosomal complex. action: ACCEPT reason: PMID:31672913 supports cytosolic FLCN and regulated movement into the lysosomal complex. The location is core, but recruitment and nucleotide state govern the activity; this does not imply constant autonomous cytosolic catalysis. supported_by: - reference_id: PMID:24095279 supporting_text: Thus, FLCN localizes to the lysosomal surface during amino acid starvation, but leaves this site upon amino acid stimulation in an mTORC1 activity-independent manner. - reference_id: PMID:31672913 supporting_text: FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005829 label: cytosol evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0091 review: summary: The electronic cytosol assignment agrees with direct endogenous human localization and dynamic recruitment (PMID:24081491, PMID:29848618). action: ACCEPT reason: The electronic cytosol assignment agrees with direct endogenous human localization and dynamic recruitment (PMID:24081491, PMID:29848618). Retain the core location without making a product-universal localization claim. supported_by: - reference_id: PMID:24095279 supporting_text: Thus, FLCN localizes to the lysosomal surface during amino acid starvation, but leaves this site upon amino acid stimulation in an mTORC1 activity-independent manner. - reference_id: PMID:31672913 supporting_text: FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding - reference_id: PMID:24081491 - reference_id: PMID:29848618 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:24081491 - PMID:29848618 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005929 label: cilium evidence_type: IDA original_reference_id: PMID:23784378 qualifier: located_in review: summary: PMID:23784378 supports ciliary localization in human HK2 and nasal epithelial experiments, with separate tagged and other-species assays. action: KEEP_AS_NON_CORE reason: PMID:23784378 supports ciliary localization in human HK2 and nasal epithelial experiments, with separate tagged and other-species assays. Actual PMID:27072130 studies flow-dependent ciliary LKB1/AMPK regulation. Retain the peripheral ciliary pool as non-core. The latter paper's proposed FLCN-LKB1 transport model is distinct from a localization measurement; no direct transporter or kinase function is inferred. additional_reference_ids: - PMID:27072130 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:23784378 supporting_text: Our data indicate that FLCN localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. - reference_id: PMID:27072130 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005929 label: cilium evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0066 review: summary: PMID:23784378 supports ciliary localization in human HK2 and nasal epithelial experiments, with separate tagged and other-species assays. action: KEEP_AS_NON_CORE reason: PMID:23784378 supports ciliary localization in human HK2 and nasal epithelial experiments, with separate tagged and other-species assays. Actual PMID:27072130 studies flow-dependent ciliary LKB1/AMPK regulation. Retain the peripheral ciliary pool as non-core. The latter paper's proposed FLCN-LKB1 transport model is distinct from a localization measurement; no direct transporter or kinase function is inferred. additional_reference_ids: - PMID:23784378 - PMID:27072130 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:23784378 supporting_text: Our data indicate that FLCN localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. - reference_id: PMID:27072130 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0005929 label: cilium evidence_type: TAS original_reference_id: PMID:25126726 qualifier: located_in review: summary: PMID:23784378 supports ciliary localization in human HK2 and nasal epithelial experiments, with separate tagged and other-species assays. action: KEEP_AS_NON_CORE reason: PMID:23784378 supports ciliary localization in human HK2 and nasal epithelial experiments, with separate tagged and other-species assays. Actual PMID:27072130 studies flow-dependent ciliary LKB1/AMPK regulation. Retain the peripheral ciliary pool as non-core. The latter paper's proposed FLCN-LKB1 transport model is distinct from a localization measurement; no direct transporter or kinase function is inferred. additional_reference_ids: - PMID:23784378 - PMID:27072130 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:23784378 supporting_text: Our data indicate that FLCN localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. - reference_id: PMID:27072130 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0007043 label: cell-cell junction assembly evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 - ensembl:ENSMUSP00000099758 review: summary: Junction organization and barrier assays support contextual junction-assembly involvement. action: KEEP_AS_NON_CORE reason: PMID:22965878 combines human junctional FLCN-p0071 association with reduced transepithelial resistance, disrupted claudin-1/E-cadherin organization and abnormal 3D colonies after Flcn knockdown in mouse IMCD3 cells. The junction-specific organization and barrier endpoints support regulatory participation in junction assembly, so retain this context as non-core. FLCN need not be a permanent structural junction component for this process association to hold. Day-8 resistance is an endpoint, no junction-specific rescue was recovered, and the assembly mechanism remains unresolved. additional_reference_ids: - PMID:22965878 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:22965878 supporting_text: Deficiency of folliculin and of p0071 resulted in tight junction defects and mislocalization of E-cadherin in mouse inner medullary collecting duct-3 renal tubular cells. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0007043 label: cell-cell junction assembly evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 review: summary: Junction organization and barrier assays support contextual junction-assembly involvement. action: KEEP_AS_NON_CORE reason: PMID:22965878 combines human junctional FLCN-p0071 association with reduced transepithelial resistance, disrupted claudin-1/E-cadherin organization and abnormal 3D colonies after Flcn knockdown in mouse IMCD3 cells. The junction-specific organization and barrier endpoints support regulatory participation in junction assembly, so retain this context as non-core. FLCN need not be a permanent structural junction component for this process association to hold. Day-8 resistance is an endpoint, no junction-specific rescue was recovered, and the assembly mechanism remains unresolved. additional_reference_ids: - PMID:22965878 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:22965878 supporting_text: Deficiency of folliculin and of p0071 resulted in tight junction defects and mislocalization of E-cadherin in mouse inner medullary collecting duct-3 renal tubular cells. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0009267 label: cellular response to starvation evidence_type: IDA original_reference_id: PMID:24095279 qualifier: involved_in review: summary: The perturbation in PMID:24095279 is amino-acid starvation, with regulated FLCN-FNIP localization and Rag association. action: MODIFY reason: The perturbation in PMID:24095279 is amino-acid starvation, with regulated FLCN-FNIP localization and Rag association. Refine broad starvation response to GO:0034198 cellular response to amino acid starvation. This does not establish direct amino-acid binding or sensing by FLCN. proposed_replacement_terms: - id: GO:0034198 label: cellular response to amino acid starvation supported_by: - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:31672913 supporting_text: FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0009267 label: cellular response to starvation evidence_type: IDA original_reference_id: PMID:31672913 qualifier: involved_in review: summary: PMID:31672913 examines amino-acid-starvation-dependent lysosomal complex assembly and its catalytic checkpoint. action: MODIFY reason: PMID:31672913 examines amino-acid-starvation-dependent lysosomal complex assembly and its catalytic checkpoint. Refine the broad starvation response to GO:0034198 cellular response to amino acid starvation, without treating the inhibited structural state as active hydrolysis or direct nutrient binding. proposed_replacement_terms: - id: GO:0034198 label: cellular response to amino acid starvation supported_by: - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:31672913 supporting_text: FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0010508 label: positive regulation of autophagy evidence_type: IDA original_reference_id: PMID:25126726 qualifier: involved_in review: summary: Actual PMID:25126726 reports a moderate basal autophagic-flux effect in human HK2 depletion experiments, including LC3/chloroquine measurements and SQSTM1 reduction after FLCN re-expression. action: KEEP_AS_NON_CORE reason: Actual PMID:25126726 reports a moderate basal autophagic-flux effect in human HK2 depletion experiments, including LC3/chloroquine measurements and SQSTM1 reduction after FLCN re-expression. Retain contextual positive regulation as non-core. ULK1 phosphorylation makes FLCN a substrate, not a kinase or demonstrated cargo adapter; later GABARAP-dependent sequestration is a distinct regulatory context, not a refutation of this assay. supported_by: - reference_id: PMID:25126726 supporting_text: Here, we identify that loss of FLCN moderately impairs basal autophagic flux, while re-expression of FLCN rescues autophagy. - reference_id: PMID:25126726 supporting_text: our findings demonstrate that FLCN interacts with a second integral component of the autophagy machinery, GABA(A) receptor-associated protein (GABARAP). - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0010508 label: positive regulation of autophagy evidence_type: IMP original_reference_id: PMID:25126726 qualifier: involved_in review: summary: Actual PMID:25126726 reports a moderate basal autophagic-flux effect in human HK2 depletion experiments, including LC3/chloroquine measurements and SQSTM1 reduction after FLCN re-expression. action: KEEP_AS_NON_CORE reason: Actual PMID:25126726 reports a moderate basal autophagic-flux effect in human HK2 depletion experiments, including LC3/chloroquine measurements and SQSTM1 reduction after FLCN re-expression. Retain contextual positive regulation as non-core. ULK1 phosphorylation makes FLCN a substrate, not a kinase or demonstrated cargo adapter; later GABARAP-dependent sequestration is a distinct regulatory context, not a refutation of this assay. supported_by: - reference_id: PMID:25126726 supporting_text: Here, we identify that loss of FLCN moderately impairs basal autophagic flux, while re-expression of FLCN rescues autophagy. - reference_id: PMID:25126726 supporting_text: our findings demonstrate that FLCN interacts with a second integral component of the autophagy machinery, GABA(A) receptor-associated protein (GABARAP). - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0019899 label: enzyme binding evidence_type: IPI original_reference_id: PMID:34381247 qualifier: enables supporting_entities: - UniProtKB:P00338 review: summary: PMID:34381247 goes beyond FLCN-LDHA association to direct inhibition of purified human LDHA. action: MODIFY reason: PMID:34381247 goes beyond FLCN-LDHA association to direct inhibition of purified human LDHA. Replace generic enzyme binding with GO:0160193 L-lactate dehydrogenase inhibitor activity. The measured molecular capacity is distinct from untested physiological universality and from synthetic inhibitory peptide or truncated-natural-product equivalence. proposed_replacement_terms: - id: GO:0160193 label: L-lactate dehydrogenase inhibitor activity supported_by: - reference_id: PMID:34381247 supporting_text: Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0030097 label: hemopoiesis evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 review: summary: Mouse embryoid-body hematopoietic endpoints support a non-core differentiation association. action: KEEP_AS_NON_CORE reason: The current mouse IMP donor PMID:21258407 measures failure of hemoglobinized colonies and strongly reduced Gata1/CD34 in Bhd-null embryoid bodies under hematopoietic differentiation conditions. These lineage-related functional endpoints support retaining the existing hematopoietic differentiation association as non-core. CD34 is not HSC-specific, and hematopoietic lineage autonomy versus associated yolk-sac/endoderm effects remains unresolved. PMID:22709692 supplies separate Flcn B-cell evidence, not the current donor for this broad term. additional_reference_ids: - PMID:21258407 - PMID:22709692 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:22709692 - reference_id: PMID:21258407 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0030496 label: midbody evidence_type: IDA original_reference_id: PMID:22965878 qualifier: colocalizes_with review: summary: PMID:22965878 includes endogenous HaCat midbody staining, restored FTC133 cells and HeLa bimolecular fluorescence complementation. action: KEEP_AS_NON_CORE reason: PMID:22965878 includes endogenous HaCat midbody staining, restored FTC133 cells and HeLa bimolecular fluorescence complementation. Retain non-core midbody association without reducing all observations to a single overexpression image or assigning FLCN a structural cytokinesis function. supported_by: - reference_id: PMID:22965878 supporting_text: Folliculin and p0071 partially co-localized at cell junctions and in mitotic cells, at the midbody during cytokinesis. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0030511 label: positive regulation of transforming growth factor beta receptor signaling pathway evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - MGI:MGI:2442184 - PANTHER:PTN001265856 review: summary: 'PMID:21258407 supports contextual TGF-beta regulation in mouse ES cells: phosphorylated Smad nuclear accumulation persists, while target-promoter acetylation/transcription and Bim induction are defective; HDAC inhibition restores measured responses.' action: KEEP_AS_NON_CORE reason: 'PMID:21258407 supports contextual TGF-beta regulation in mouse ES cells: phosphorylated Smad nuclear accumulation persists, while target-promoter acetylation/transcription and Bim induction are defective; HDAC inhibition restores measured responses. Retain this downstream process as non-core. These experiments do not establish the previously proposed TFE3 mediation or direct chromatin-modifying activity of FLCN. The positive IBD is on the target path at Deuterostomia node PTN001265856, not a vertebrate-specific node.' additional_reference_ids: - PMID:21258407 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:21258407 supporting_text: In aggregate, this work identifies a specific tumor suppressive mechanism for BHD in regulating TGFβ-dependent transcription and apoptosis - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0030511 label: positive regulation of transforming growth factor beta receptor signaling pathway evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 review: summary: 'PMID:21258407 supports contextual TGF-beta regulation in mouse ES cells: phosphorylated Smad nuclear accumulation persists, while target-promoter acetylation/transcription and Bim induction are defective; HDAC inhibition restores measured responses.' action: KEEP_AS_NON_CORE reason: 'PMID:21258407 supports contextual TGF-beta regulation in mouse ES cells: phosphorylated Smad nuclear accumulation persists, while target-promoter acetylation/transcription and Bim induction are defective; HDAC inhibition restores measured responses. Retain this downstream process as non-core. These experiments do not establish the previously proposed TFE3 mediation or direct chromatin-modifying activity of FLCN. This is the distinct mouse ortholog-transfer context, not another IBA experiment.' additional_reference_ids: - PMID:21258407 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:21258407 supporting_text: In aggregate, this work identifies a specific tumor suppressive mechanism for BHD in regulating TGFβ-dependent transcription and apoptosis - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0032006 label: regulation of TOR signaling evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 review: summary: Specific positive and negative TOR processes both entail broad TOR regulation. action: TOO_GENERAL reason: 'Broad TOR regulation is supported but less informative than the retained positive TORC1 and contextual negative TOR annotations, both with verified ontology paths to this term. Mark TOO_GENERAL rather than retaining only the positive branch: human flow/ciliary experiments (PMID:27072130) and renal loss models support context-specific suppression, alongside the predominant Rag/TFEB activation mechanism. TOO_GENERAL records this correct ancestor as redundant with retained descendants; it does not assert that TOR regulation is absent or has one universal direction.' supported_by: - reference_id: PMID:32612235 supporting_text: Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation - reference_id: PMID:37079666 supporting_text: The FLCN-FNIP1 complex functions as a GAP for RagC and RagD, promoting the GDP-bound state of RagC and RagD, which is required for mTOR recruitment to the lysosome - reference_id: PMID:27072130 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:27072130 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0032007 label: negative regulation of TOR signaling evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 review: summary: FLCN supports context-specific suppression of TOR signaling in flow and renal models. action: KEEP_AS_NON_CORE reason: Human flow/ciliary experiments in PMID:27072130 support FLCN-dependent LKB1/AMPK/TSC2 suppression of mTORC1, while renal models provide context-specific loss phenotypes. PMID:32612235 identifies TFEB-dependent feedback in mouse kidney hyperactivation. Retain negative TOR regulation as non-core; this is not direct inhibition of mTOR by FLCN and does not contradict its positive Rag/TFEB role. The original mouse transfer is retained with its tissue/model scope (PMID:18182616, PMID:18974783). The inherited TFEB-feedback excerpts are retained under the PMID:32612235 reference finding, where their renal context is explicit; the human flow mechanism is supported by the separately cited primary Results, without a new quotation. additional_reference_ids: - PMID:18182616 - PMID:18974783 - PMID:27072130 - PMID:32612235 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:18182616 - reference_id: PMID:18974783 - reference_id: PMID:27072130 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0032007 label: negative regulation of TOR signaling evidence_type: NAS original_reference_id: PMID:17028174 qualifier: involved_in review: summary: FLCN supports context-specific suppression of TOR signaling in flow and renal models. action: KEEP_AS_NON_CORE reason: Human flow/ciliary experiments in PMID:27072130 support FLCN-dependent LKB1/AMPK/TSC2 suppression of mTORC1, while renal models provide context-specific loss phenotypes. PMID:32612235 identifies TFEB-dependent feedback in mouse kidney hyperactivation. Retain negative TOR regulation as non-core; this is not direct inhibition of mTOR by FLCN and does not contradict its positive Rag/TFEB role. PMID:17028174 provides early FLCN/FNIP/AMPK interaction context and a regulatory hypothesis, not the later flow mechanism; the NAS source remains intact. The inherited TFEB-feedback excerpts are retained under the PMID:32612235 reference finding, where their renal context is explicit; the human flow mechanism is supported by the separately cited primary Results, without a new quotation. additional_reference_ids: - PMID:27072130 - PMID:32612235 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:27072130 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0032007 label: negative regulation of TOR signaling evidence_type: NAS original_reference_id: PMID:31672913 qualifier: involved_in review: summary: FLCN supports context-specific suppression of TOR signaling in flow and renal models. action: KEEP_AS_NON_CORE reason: Human flow/ciliary experiments in PMID:27072130 support FLCN-dependent LKB1/AMPK/TSC2 suppression of mTORC1, while renal models provide context-specific loss phenotypes. PMID:32612235 identifies TFEB-dependent feedback in mouse kidney hyperactivation. Retain negative TOR regulation as non-core; this is not direct inhibition of mTOR by FLCN and does not contradict its positive Rag/TFEB role. PMID:31672913 resolves the inhibited lysosomal complex and separately tests catalytic requirements; its NAS is not presented as a direct mTOR inhibition assay. The inherited TFEB-feedback excerpts are retained under the PMID:32612235 reference finding, where their renal context is explicit; the human flow mechanism is supported by the separately cited primary Results, without a new quotation. additional_reference_ids: - PMID:27072130 - PMID:32612235 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:27072130 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0032008 label: positive regulation of TOR signaling evidence_type: IDA original_reference_id: PMID:24081491 qualifier: involved_in review: summary: Refine positive TOR regulation to GO:1904263 positive regulation of TORC1 signaling, the supported RagC/D-dependent branch. action: MODIFY reason: Refine positive TOR regulation to GO:1904263 positive regulation of TORC1 signaling, the supported RagC/D-dependent branch. PMID:24081491 combines human depletion/localization with separately identified mouse recombinant FLCN binding experiments. Independent TFEB-pathway assays (PMID:32612235) establish downstream function without implying uniform effects on every mTORC1 substrate. proposed_replacement_terms: - id: GO:1904263 label: positive regulation of TORC1 signaling supported_by: - reference_id: PMID:24081491 supporting_text: In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:32612235 supporting_text: Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:32612235 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0032008 label: positive regulation of TOR signaling evidence_type: IDA original_reference_id: PMID:24095279 qualifier: involved_in review: summary: Refine positive TOR regulation to GO:1904263 positive regulation of TORC1 signaling, the supported RagC/D-dependent branch. action: MODIFY reason: Refine positive TOR regulation to GO:1904263 positive regulation of TORC1 signaling, the supported RagC/D-dependent branch. PMID:24095279 directly establishes partner-dependent RagC/D GAP activity. Independent TFEB-pathway assays (PMID:32612235) establish downstream function without implying uniform effects on every mTORC1 substrate. proposed_replacement_terms: - id: GO:1904263 label: positive regulation of TORC1 signaling supported_by: - reference_id: PMID:24081491 supporting_text: In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:32612235 supporting_text: Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:32612235 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0032008 label: positive regulation of TOR signaling evidence_type: IDA original_reference_id: PMID:31672913 qualifier: involved_in review: summary: Refine positive TOR regulation to GO:1904263 positive regulation of TORC1 signaling, the supported RagC/D-dependent branch. action: MODIFY reason: Refine positive TOR regulation to GO:1904263 positive regulation of TORC1 signaling, the supported RagC/D-dependent branch. PMID:31672913 resolves an inhibited complex and separately tests catalytic-residue requirements. Independent TFEB-pathway assays (PMID:32612235) establish downstream function without implying uniform effects on every mTORC1 substrate. proposed_replacement_terms: - id: GO:1904263 label: positive regulation of TORC1 signaling supported_by: - reference_id: PMID:24081491 supporting_text: In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:32612235 supporting_text: Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:32612235 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0032008 label: positive regulation of TOR signaling evidence_type: IDA original_reference_id: PMID:31704029 qualifier: involved_in review: summary: Refine positive TOR regulation to GO:1904263 positive regulation of TORC1 signaling, the supported RagC/D-dependent branch. action: MODIFY reason: Refine positive TOR regulation to GO:1904263 positive regulation of TORC1 signaling, the supported RagC/D-dependent branch. PMID:31704029 directly measures human RagC hydrolysis with FLCN-FNIP2 and R164A controls. Independent TFEB-pathway assays (PMID:32612235) establish downstream function without implying uniform effects on every mTORC1 substrate. proposed_replacement_terms: - id: GO:1904263 label: positive regulation of TORC1 signaling supported_by: - reference_id: PMID:24081491 supporting_text: In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:32612235 supporting_text: Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:32612235 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0032008 label: positive regulation of TOR signaling evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in supporting_entities: - ARBA:ARBA00092062 review: summary: Refine positive TOR regulation to GO:1904263 positive regulation of TORC1 signaling, the supported RagC/D-dependent branch. action: MODIFY reason: Refine positive TOR regulation to GO:1904263 positive regulation of TORC1 signaling, the supported RagC/D-dependent branch. The ARBA assignment is electronic corroboration, not a new target experiment. Independent TFEB-pathway assays (PMID:32612235) establish downstream function without implying uniform effects on every mTORC1 substrate. proposed_replacement_terms: - id: GO:1904263 label: positive regulation of TORC1 signaling supported_by: - reference_id: PMID:24081491 supporting_text: In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:32612235 supporting_text: Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:32612235 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0032008 label: positive regulation of TOR signaling evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 review: summary: Refine positive TOR regulation to GO:1904263 positive regulation of TORC1 signaling, the supported RagC/D-dependent branch. action: MODIFY reason: Refine positive TOR regulation to GO:1904263 positive regulation of TORC1 signaling, the supported RagC/D-dependent branch. The mouse ortholog transfer agrees with independently demonstrated target GAP and TFEB-pathway activity. Independent TFEB-pathway assays (PMID:32612235) establish downstream function without implying uniform effects on every mTORC1 substrate. proposed_replacement_terms: - id: GO:1904263 label: positive regulation of TORC1 signaling supported_by: - reference_id: PMID:24081491 supporting_text: In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:32612235 supporting_text: Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:32612235 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0032418 label: lysosome localization evidence_type: IDA original_reference_id: PMID:27113757 qualifier: involved_in review: summary: PMID:27113757 supports starvation-dependent lysosome positioning through FLCN-RILP association and active Rab34 loading. action: KEEP_AS_NON_CORE reason: PMID:27113757 supports starvation-dependent lysosome positioning through FLCN-RILP association and active Rab34 loading. Retain this trafficking process as non-core. Loading is not detected Rab34 GEF or GDI activity, and the data do not establish a stable ternary-adapter mechanism. supported_by: - reference_id: PMID:27113757 supporting_text: FLCN promotes the peri-nuclear clustering of lysosomes following serum and amino acid withdrawal and is supported by the predominantly Golgi-associated small GTPase Rab34. - reference_id: PMID:27113757 supporting_text: Using purified recombinant proteins, we show that the FLCN-DENN domain does not act as a GEF for Rab34, but rather, loads active Rab34 onto RILP - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0034198 label: cellular response to amino acid starvation evidence_type: IDA original_reference_id: PMID:24095279 qualifier: involved_in review: summary: PMID:24095279 directly links amino-acid availability to FLCN-FNIP association/localization and RagC/D GAP function. action: ACCEPT reason: PMID:24095279 directly links amino-acid availability to FLCN-FNIP association/localization and RagC/D GAP function. This is a core starvation response, without attributing later structural states or direct amino-acid binding to this paper. supported_by: - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:31672913 supporting_text: FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding - reference_id: PMID:27113757 supporting_text: FLCN promotes the peri-nuclear clustering of lysosomes following serum and amino acid withdrawal and is supported by the predominantly Golgi-associated small GTPase Rab34. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0034198 label: cellular response to amino acid starvation evidence_type: IDA original_reference_id: PMID:27113757 qualifier: involved_in review: summary: PMID:27113757 measures nutrient-dependent FLCN/RILP/Rab34 lysosome positioning. action: ACCEPT reason: PMID:27113757 measures nutrient-dependent FLCN/RILP/Rab34 lysosome positioning. This supports the established amino-acid-starvation response while retaining the specific trafficking assay context; later Rag catalytic-state structures are separate evidence. supported_by: - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:31672913 supporting_text: FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding - reference_id: PMID:27113757 supporting_text: FLCN promotes the peri-nuclear clustering of lysosomes following serum and amino acid withdrawal and is supported by the predominantly Golgi-associated small GTPase Rab34. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0034198 label: cellular response to amino acid starvation evidence_type: IDA original_reference_id: PMID:31672913 qualifier: involved_in review: summary: PMID:31672913 demonstrates starvation-dependent lysosomal complex assembly and tests its catalytic checkpoint. action: ACCEPT reason: PMID:31672913 demonstrates starvation-dependent lysosomal complex assembly and tests its catalytic checkpoint. The response is core; the captured LFC is inhibited, not an active transition-state structure. supported_by: - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:31672913 supporting_text: FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding - reference_id: PMID:27113757 supporting_text: FLCN promotes the peri-nuclear clustering of lysosomes following serum and amino acid withdrawal and is supported by the predominantly Golgi-associated small GTPase Rab34. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0035024 label: negative regulation of Rho protein signal transduction evidence_type: IMP original_reference_id: PMID:22965878 qualifier: involved_in review: summary: PMID:22965878 measures disordered/increased RhoA signaling after FLCN perturbation and links FLCN to p0071. action: KEEP_AS_NON_CORE reason: PMID:22965878 measures disordered/increased RhoA signaling after FLCN perturbation and links FLCN to p0071. Retain contextual negative Rho signaling as non-core without assigning a direct Rho GAP, GEF or GDI molecular function to FLCN. supported_by: - reference_id: PMID:22965878 supporting_text: we found that folliculin deficiency was associated with increased expression and activity of RhoA and evidence of disordered cytokinesis - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0035556 label: intracellular signal transduction evidence_type: IDA original_reference_id: PMID:21209915 qualifier: involved_in review: summary: The broad signaling assertion in PMID:21209915 is biologically sound, but combined target evidence identifies positive TORC1 regulation (GO:1904263) as a more informative function (PMID:24095279, PMID:32612235). action: MODIFY reason: The broad signaling assertion in PMID:21209915 is biologically sound, but combined target evidence identifies positive TORC1 regulation (GO:1904263) as a more informative function (PMID:24095279, PMID:32612235). This is an evidence-based replacement, not a claimed formal ontology-child refinement of GO:0035556. The early TFE3 paper did not itself measure all later Rag mechanisms. proposed_replacement_terms: - id: GO:1904263 label: positive regulation of TORC1 signaling supported_by: - reference_id: PMID:21209915 supporting_text: FLCN inactivation was correlated with increased TFE3 transcriptional activity accompanied by its nuclear localization - reference_id: PMID:24081491 supporting_text: In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). - reference_id: PMID:24095279 - reference_id: PMID:32612235 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:24095279 - PMID:32612235 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0043065 label: positive regulation of apoptotic process evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 review: summary: FLCN perturbation and re-expression support contextual positive regulation of apoptosis. action: KEEP_AS_NON_CORE reason: PMID:21258407 shows resistance to TGF-beta-associated apoptosis in Bhd-deficient mouse ES cells, reduced BimEL induction and restoration of measured responses by Bhd re-expression or HDAC inhibition. The FLCN perturbation and re-expression evidence supports a positive regulatory contribution to apoptosis in this model, warranting non-core retention. This BP annotation does not establish an apoptosis-executioner molecular function, a chromatin enzyme activity or a TFE3 mechanism for this assay. additional_reference_ids: - PMID:21258407 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:21258407 supporting_text: BHD-deficient cells exhibited defects in cell-intrinsic apoptosis that correlated with reduced expression of the BH3-only protein Bim - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0044291 label: cell-cell contact zone evidence_type: IDA original_reference_id: PMID:22965878 qualifier: colocalizes_with review: summary: PMID:22965878 supports FLCN-p0071 colocalization and association at cell-cell junctions. action: KEEP_AS_NON_CORE reason: PMID:22965878 supports FLCN-p0071 colocalization and association at cell-cell junctions. Retain this peripheral location as non-core, without treating FLCN as an obligate structural junction component or inferring rescue of junction assembly from association alone. supported_by: - reference_id: PMID:22965878 supporting_text: Folliculin and p0071 partially co-localized at cell junctions and in mitotic cells, at the midbody during cytokinesis. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0045820 label: negative regulation of glycolysis evidence_type: IDA original_reference_id: PMID:34381247 qualifier: involved_in review: summary: PMID:34381247 directly measures human FLCN inhibition of purified LDHA and glycolytic effects in the tested cells. action: ACCEPT reason: PMID:34381247 directly measures human FLCN inhibition of purified LDHA and glycolytic effects in the tested cells. Retain negative glycolytic regulation as the process coupled to this measured molecular function, consistent with the LDHA-inhibitor core. Physiological range, endogenous stoichiometry and independent replication remain open; the synthetic inhibitory peptide is not a natural FLCN product. supported_by: - reference_id: PMID:34381247 supporting_text: Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. - reference_id: PMID:34381247 supporting_text: Together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0045892 label: negative regulation of DNA-templated transcription evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 - ensembl:ENSMUSP00000099758 review: summary: The retained GO:0000122 negative regulation of transcription by RNA polymerase II is a verified is_a child of this broad transcription term. action: TOO_GENERAL reason: The retained GO:0000122 negative regulation of transcription by RNA polymerase II is a verified is_a child of this broad transcription term. Mark TOO_GENERAL, retaining specific downstream TFE3 transcriptional regulation without assigning DNA binding to FLCN (PMID:21209915). additional_reference_ids: - PMID:21209915 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:21209915 supporting_text: FLCN inactivation was correlated with increased TFE3 transcriptional activity accompanied by its nuclear localization - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0046578 label: regulation of Ras protein signal transduction evidence_type: IDA original_reference_id: PMID:24081491 qualifier: involved_in review: summary: GO:0046578 concerns Ras-subfamily signaling; Rag GTPases are not members of that subfamily. action: MODIFY reason: GO:0046578 concerns Ras-subfamily signaling; Rag GTPases are not members of that subfamily. Replace the context with the experimentally supported GO:1904263 positive regulation of TORC1 signaling, preserving the original source. PMID:24081491 combines human depletion/localization with separately identified mouse recombinant FLCN binding experiments. This is a biological correction to the signaling route, not a claim that the original Rag experiment is false. proposed_replacement_terms: - id: GO:1904263 label: positive regulation of TORC1 signaling supported_by: - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:24081491 supporting_text: We further demonstrated that FLCN itself was selectively recruited to the surface of lysosomes after amino acid depletion and directly bound to RagA via its GTPase domain. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0046578 label: regulation of Ras protein signal transduction evidence_type: IDA original_reference_id: PMID:24095279 qualifier: involved_in review: summary: GO:0046578 concerns Ras-subfamily signaling; Rag GTPases are not members of that subfamily. action: MODIFY reason: GO:0046578 concerns Ras-subfamily signaling; Rag GTPases are not members of that subfamily. Replace the context with the experimentally supported GO:1904263 positive regulation of TORC1 signaling, preserving the original source. PMID:24095279 directly establishes partner-dependent RagC/D GAP activity. This is a biological correction to the signaling route, not a claim that the original Rag experiment is false. proposed_replacement_terms: - id: GO:1904263 label: positive regulation of TORC1 signaling supported_by: - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:24081491 supporting_text: We further demonstrated that FLCN itself was selectively recruited to the surface of lysosomes after amino acid depletion and directly bound to RagA via its GTPase domain. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0046578 label: regulation of Ras protein signal transduction evidence_type: IDA original_reference_id: PMID:31672913 qualifier: involved_in review: summary: GO:0046578 concerns Ras-subfamily signaling; Rag GTPases are not members of that subfamily. action: MODIFY reason: GO:0046578 concerns Ras-subfamily signaling; Rag GTPases are not members of that subfamily. Replace the context with the experimentally supported GO:1904263 positive regulation of TORC1 signaling, preserving the original source. PMID:31672913 resolves an inhibited complex and separately tests catalytic-residue requirements. This is a biological correction to the signaling route, not a claim that the original Rag experiment is false. proposed_replacement_terms: - id: GO:1904263 label: positive regulation of TORC1 signaling supported_by: - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:24081491 supporting_text: We further demonstrated that FLCN itself was selectively recruited to the surface of lysosomes after amino acid depletion and directly bound to RagA via its GTPase domain. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0046578 label: regulation of Ras protein signal transduction evidence_type: IDA original_reference_id: PMID:31704029 qualifier: involved_in review: summary: GO:0046578 concerns Ras-subfamily signaling; Rag GTPases are not members of that subfamily. action: MODIFY reason: GO:0046578 concerns Ras-subfamily signaling; Rag GTPases are not members of that subfamily. Replace the context with the experimentally supported GO:1904263 positive regulation of TORC1 signaling, preserving the original source. PMID:31704029 directly measures human RagC hydrolysis with FLCN-FNIP2 and R164A controls. This is a biological correction to the signaling route, not a claim that the original Rag experiment is false. proposed_replacement_terms: - id: GO:1904263 label: positive regulation of TORC1 signaling supported_by: - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:24081491 supporting_text: We further demonstrated that FLCN itself was selectively recruited to the surface of lysosomes after amino acid depletion and directly bound to RagA via its GTPase domain. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0051898 label: negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 review: summary: Mouse renal and human BHD tumor measurements support context-specific negative AKT-pathway regulation. action: KEEP_AS_NON_CORE reason: Externally recovered primary Results of PMID:19850877 show increased AKT protein/phosphorylation in late mouse renal lesions, with no corresponding mouse AKT1/2 transcript increase; human BHD tumors independently show elevated AKT pathway readouts. These pathway readouts support retaining contextual negative regulation of AKT signaling as non-core. A regulatory BP can be mediated through signaling or protein abundance; direct FLCN inhibition of the AKT enzyme is not required by this term. The molecular mechanism and wider physiological scope remain unresolved. Some Methods defer to uninspected supplementary protocols; no AKT-specific rapamycin rescue is claimed. The source-evidence guide distinguishes the recovered primary from the unchanged abstract-only normal cache. additional_reference_ids: - PMID:19850877 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:19850877 supporting_text: The PI3K-AKT pathway was activated in both human BHD renal tumors and kidney tumors in BHD(d/+) mice. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0070373 label: negative regulation of ERK1 and ERK2 cascade evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 review: summary: Mouse renal cascade measurements support context-specific negative ERK regulation. action: KEEP_AS_NON_CORE reason: Externally recovered primary Results of PMID:18182616 show increased Raf/MEK/ERK readouts after kidney-specific mouse Flcn loss in a defined postnatal model. The coordinated cascade measurements support contextual negative ERK regulation, retained as non-core. This process-level regulatory association does not require a direct kinase-inhibitor activity by FLCN. The pathway connection and tissue dependence remain unresolved; rapamycin is not presented as an ERK/AKT-specific rescue. The source-evidence guide distinguishes the recovered primary from the unchanged abstract-only normal cache. additional_reference_ids: - PMID:18182616 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:18182616 supporting_text: Targeted BHD knockout led to the activation of Raf-extracellular signal-regulated protein kinase (Erk)1/2 and Akt-mTOR pathways in the kidneys and increased expression of cell cycle proteins and cell proliferation. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0072686 label: mitotic spindle evidence_type: IDA original_reference_id: PMID:23784378 qualifier: located_in review: summary: Actual Methods and Results in PMID:23784378 support human HK2 mitotic-spindle localization of human EGFP-FLCN. action: KEEP_AS_NON_CORE reason: Actual Methods and Results in PMID:23784378 support human HK2 mitotic-spindle localization of human EGFP-FLCN. Retain this peripheral compartment as non-core, distinct from a demonstrated spindle-assembly function. Figure pixels and supplements were not independently inspected. supported_by: - reference_id: PMID:23784378 supporting_text: Our data indicate that FLCN localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0097009 label: energy homeostasis evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 - ensembl:ENSMUSP00000099758 review: summary: Adipose Flcn perturbation changes measured whole-animal energy balance. action: KEEP_AS_NON_CORE reason: PMID:27151976 measures mouse energy expenditure, intake, activity and diet responses following adipose Flcn perturbation, with AMPK-PGC1alpha-ERRalpha signaling. Direct energy-balance measurements and the metabolic pathway response support the retained energy-homeostasis association, classified as non-core because it is a tissue- and condition-dependent physiological role. Human effect sizes are not inferred. The TFE3-PGC1beta mechanism in PMID:27913603 and muscle remodeling in PMID:23150719 remain separate experimental contexts. additional_reference_ids: - PMID:23150719 - PMID:27151976 - PMID:27913603 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:23150719 supporting_text: Muscle-targeted FLCN knockout mice underwent a pronounced metabolic shift toward oxidative phosphorylation - reference_id: PMID:27151976 supporting_text: Adipoq-FLCN knockout mice exhibit increased energy expenditure and are protected from high-fat diet (HFD)-induced obesity. - reference_id: PMID:27913603 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0097009 label: energy homeostasis evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 review: summary: Adipose Flcn perturbation changes measured whole-animal energy balance. action: KEEP_AS_NON_CORE reason: PMID:27151976 measures mouse energy expenditure, intake, activity and diet responses following adipose Flcn perturbation, with AMPK-PGC1alpha-ERRalpha signaling. Direct energy-balance measurements and the metabolic pathway response support the retained energy-homeostasis association, classified as non-core because it is a tissue- and condition-dependent physiological role. Human effect sizes are not inferred. The TFE3-PGC1beta mechanism in PMID:27913603 and muscle remodeling in PMID:23150719 remain separate experimental contexts. additional_reference_ids: - PMID:23150719 - PMID:27151976 - PMID:27913603 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:23150719 supporting_text: Muscle-targeted FLCN knockout mice underwent a pronounced metabolic shift toward oxidative phosphorylation - reference_id: PMID:27151976 supporting_text: Adipoq-FLCN knockout mice exhibit increased energy expenditure and are protected from high-fat diet (HFD)-induced obesity. - reference_id: PMID:27913603 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0120163 label: negative regulation of cold-induced thermogenesis evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 - ensembl:ENSMUSP00000099758 review: summary: Retain contextual negative cold-induced thermogenesis from mouse physiology as non-core. action: KEEP_AS_NON_CORE reason: Retain contextual negative cold-induced thermogenesis from mouse physiology as non-core. PMID:27151976 tests an AMPK-PGC1alpha-ERRalpha route; PMID:27913603 independently supports Rag-TFE3-PGC1beta regulation. These are distinct mechanistic experiments, not interchangeable evidence for a single universal human thermogenic program. additional_reference_ids: - PMID:27151976 - PMID:27913603 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:27151976 supporting_text: underlying the increased resistance of Adipoq-FLCN knockout mice to cold exposure - reference_id: PMID:27913603 supporting_text: Adipose-specific deletion of FLCN relieves mTOR-dependent cytoplasmic retention of TFE3, leading to direct induction of the PGC-1 transcriptional coactivators, drivers of mitochondrial biogenesis and the browning program. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:0120163 label: negative regulation of cold-induced thermogenesis evidence_type: ISS original_reference_id: PMID:27151976 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 review: summary: The original PMID:27151976 mouse transfer concerns increased cold resistance and thermogenic physiology associated with AMPK-PGC1alpha-ERRalpha signaling after Flcn loss. action: KEEP_AS_NON_CORE reason: The original PMID:27151976 mouse transfer concerns increased cold resistance and thermogenic physiology associated with AMPK-PGC1alpha-ERRalpha signaling after Flcn loss. Retain this contextual process as non-core. Later TFE3 epistasis in PMID:27913603 is independent corroboration, not the mechanism tested in this original source. additional_reference_ids: - PMID:27913603 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:27151976 supporting_text: underlying the increased resistance of Adipoq-FLCN knockout mice to cold exposure - reference_id: PMID:27913603 supporting_text: Adipose-specific deletion of FLCN relieves mTOR-dependent cytoplasmic retention of TFE3, leading to direct induction of the PGC-1 transcriptional coactivators, drivers of mitochondrial biogenesis and the browning program. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:1901723 label: negative regulation of cell proliferation involved in kidney development evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 review: summary: Postnatal renal Flcn loss supports contextual regulation of proliferation during kidney development. action: KEEP_AS_NON_CORE reason: Postnatal kidney-specific mouse Flcn loss produces hyperproliferation and renal pathology during kidney development (PMID:18182616, PMID:18974783). The proliferation measurements in this developmental setting support retention of contextual negative regulation as non-core. Later TFEB codeletion experiments (PMID:32612235) identify a pathway contribution in their particular model. The retained BP concerns regulation of proliferation, not a newly assigned direct antimitogenic enzyme activity, and it does not imply universal suppression across tissues. additional_reference_ids: - PMID:18182616 - PMID:18974783 - PMID:32612235 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:18974783 supporting_text: BHD(flox/flox)/Ksp-Cre mice developed enlarged kidneys characterized by polycystic kidneys, hyperplasia, and cystic renal cell carcinoma. - reference_id: PMID:32612235 supporting_text: TFEB is constitutively nuclear and active in Flcn-KO kidneys and its depletion rescues mTORC1 hyperactivation. - reference_id: PMID:18182616 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:1901874 label: negative regulation of post-translational protein modification evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 - ensembl:ENSMUSP00000099758 review: summary: Actual PMID:21209915 Results distinguish FLCN-promoted TFE3 phosphorylation from FLCN-suppressed accumulation of a separate unidentified higher-mass TFE3 species. action: KEEP_AS_NON_CORE reason: Actual PMID:21209915 Results distinguish FLCN-promoted TFE3 phosphorylation from FLCN-suppressed accumulation of a separate unidentified higher-mass TFE3 species. The current mouse IMP donor has TFE3 as its input. Retain negative regulation of this unresolved modification as non-core; its chemistry is not identified, and it is not evidence for FLCN kinase/phosphatase activity or a natural splice product. additional_reference_ids: - PMID:21209915 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:21209915 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:1902532 label: negative regulation of intracellular signal transduction evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in supporting_entities: - ARBA:ARBA00027125 review: summary: Retained negative Rho signaling entails this broader intracellular-signaling term. action: TOO_GENERAL reason: Supported negative Rho signaling (PMID:22965878; GO:0035024) is formally under GO:0051058 and then this broad negative intracellular signaling term. Mark TOO_GENERAL because the narrower process remains covered. Positive Rag signaling does not refute this different branch. A complete ARBA-rule audit is not claimed. supported_by: - reference_id: PMID:22965878 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:22965878 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:1903444 label: negative regulation of brown fat cell differentiation evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 - ensembl:ENSMUSP00000099758 review: summary: PMID:27913603 supports contextual adipose-program regulation in mouse Flcn perturbation and Tfe3 codeletion experiments involving PGC1beta. action: KEEP_AS_NON_CORE reason: PMID:27913603 supports contextual adipose-program regulation in mouse Flcn perturbation and Tfe3 codeletion experiments involving PGC1beta. Retain negative brown-fat differentiation regulation as non-core. The measured adipose phenotype does not establish a universal human lineage-commitment mechanism or direct transcription-factor activity of FLCN. additional_reference_ids: - PMID:27913603 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:27913603 supporting_text: Adipose-specific deletion of FLCN relieves mTOR-dependent cytoplasmic retention of TFE3, leading to direct induction of the PGC-1 transcriptional coactivators, drivers of mitochondrial biogenesis and the browning program. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:1903444 label: negative regulation of brown fat cell differentiation evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 review: summary: PMID:27913603 supports contextual adipose-program regulation in mouse Flcn perturbation and Tfe3 codeletion experiments involving PGC1beta. action: KEEP_AS_NON_CORE reason: PMID:27913603 supports contextual adipose-program regulation in mouse Flcn perturbation and Tfe3 codeletion experiments involving PGC1beta. Retain negative brown-fat differentiation regulation as non-core. The measured adipose phenotype does not establish a universal human lineage-commitment mechanism or direct transcription-factor activity of FLCN. additional_reference_ids: - PMID:27913603 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:27913603 supporting_text: Adipose-specific deletion of FLCN relieves mTOR-dependent cytoplasmic retention of TFE3, leading to direct induction of the PGC-1 transcriptional coactivators, drivers of mitochondrial biogenesis and the browning program. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:1904263 label: positive regulation of TORC1 signaling evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - PANTHER:PTN002833743 - PomBase:SPBC24C6.08c - SGD:S000003289 - UniProtKB:Q8NFG4 review: summary: The exact positive TORC1 IBD at PTN002833743 lies on the human target lineage and includes legitimate human experimental evidence together with yeast sources. action: ACCEPT reason: The exact positive TORC1 IBD at PTN002833743 lies on the human target lineage and includes legitimate human experimental evidence together with yeast sources. Independent target GAP and TFEB-pathway experiments (PMID:24095279, PMID:32612235) support the core process. Substrate-selective results in particular models do not establish universal absence of S6K effects. supported_by: - reference_id: PMID:32612235 supporting_text: Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation - reference_id: PMID:37079666 supporting_text: The FLCN-FNIP1 complex functions as a GAP for RagC and RagD, promoting the GDP-bound state of RagC and RagD, which is required for mTOR recruitment to the lysosome - reference_id: PMID:34597140 supporting_text: This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. - reference_id: PMID:24095279 - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:24095279 - PMID:32612235 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:1904263 label: positive regulation of TORC1 signaling evidence_type: IDA original_reference_id: PMID:32612235 qualifier: involved_in review: summary: PMID:32612235 shows human FLCN-loss and Rag-mutant bypass effects on TFEB phosphorylation and a TFEB-dependent renal phenotype in mice. action: ACCEPT reason: PMID:32612235 shows human FLCN-loss and Rag-mutant bypass effects on TFEB phosphorylation and a TFEB-dependent renal phenotype in mice. This supports core positive TORC1 control. The selectivity relative to S6K/4E-BP1 is conditional on those experiments; other models show S6K effects, and direct GAP catalysis is independently established elsewhere. supported_by: - reference_id: PMID:32612235 supporting_text: Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation - reference_id: PMID:37079666 supporting_text: The FLCN-FNIP1 complex functions as a GAP for RagC and RagD, promoting the GDP-bound state of RagC and RagD, which is required for mTOR recruitment to the lysosome - reference_id: PMID:34597140 supporting_text: This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:1904263 label: positive regulation of TORC1 signaling evidence_type: IDA original_reference_id: PMID:34597140 qualifier: involved_in review: summary: PMID:34597140 links GABARAP-dependent sequestration of the FLCN-FNIP complex to TFEB regulation. action: ACCEPT reason: PMID:34597140 links GABARAP-dependent sequestration of the FLCN-FNIP complex to TFEB regulation. The direct GABARAP interface lies on FNIP1/2; the complex response supports core FLCN pathway participation without inventing a new purified FLCN-only GAP assay or native plasma-membrane localization from engineered tethering. supported_by: - reference_id: PMID:32612235 supporting_text: Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation - reference_id: PMID:37079666 supporting_text: The FLCN-FNIP1 complex functions as a GAP for RagC and RagD, promoting the GDP-bound state of RagC and RagD, which is required for mTOR recruitment to the lysosome - reference_id: PMID:34597140 supporting_text: This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:1904263 label: positive regulation of TORC1 signaling evidence_type: IDA original_reference_id: PMID:36103527 qualifier: involved_in review: summary: PMID:36103527 connects the structurally resolved active FLCN-FNIP2/Rag complex to MiT/TFE-directed TORC1 regulation. action: ACCEPT reason: PMID:36103527 connects the structurally resolved active FLCN-FNIP2/Rag complex to MiT/TFE-directed TORC1 regulation. Retain the core process with F118D, fusion and nucleotide-state experimental limits; do not assign the same catalytic behavior to every truncated natural product. supported_by: - reference_id: PMID:32612235 supporting_text: Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation - reference_id: PMID:37079666 supporting_text: The FLCN-FNIP1 complex functions as a GAP for RagC and RagD, promoting the GDP-bound state of RagC and RagD, which is required for mTOR recruitment to the lysosome - reference_id: PMID:34597140 supporting_text: This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:1904263 label: positive regulation of TORC1 signaling evidence_type: IDA original_reference_id: PMID:37079666 qualifier: involved_in review: summary: PMID:37079666 establishes AMPK phosphorylation of FNIP1 and regulation of the FLCN-dependent TFEB pathway. action: ACCEPT reason: PMID:37079666 establishes AMPK phosphorylation of FNIP1 and regulation of the FLCN-dependent TFEB pathway. This supports core positive TORC1 control without assigning AMPK kinase activity to FLCN or claiming that the selected study newly measures purified FLCN turnover. supported_by: - reference_id: PMID:32612235 supporting_text: Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation - reference_id: PMID:37079666 supporting_text: The FLCN-FNIP1 complex functions as a GAP for RagC and RagD, promoting the GDP-bound state of RagC and RagD, which is required for mTOR recruitment to the lysosome - reference_id: PMID:34597140 supporting_text: This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:1904263 label: positive regulation of TORC1 signaling evidence_type: IDA original_reference_id: PMID:39423796 qualifier: involved_in review: summary: PMID:39423796 contains actual STING/GABARAP and GDP-RagC bypass experiments that support the established FLCN pathway contribution to TORC1-TFEB control. action: ACCEPT reason: PMID:39423796 contains actual STING/GABARAP and GDP-RagC bypass experiments that support the established FLCN pathway contribution to TORC1-TFEB control. It is not merely an irrelevant partner paper. Retain the core process without claiming a new FLCN knockout, direct FLCN-STING binary interaction or purified FLCN catalytic assay in that study. supported_by: - reference_id: PMID:32612235 supporting_text: Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation - reference_id: PMID:37079666 supporting_text: The FLCN-FNIP1 complex functions as a GAP for RagC and RagD, promoting the GDP-bound state of RagC and RagD, which is required for mTOR recruitment to the lysosome - reference_id: PMID:34597140 supporting_text: This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:1905672 label: negative regulation of lysosome organization evidence_type: IDA original_reference_id: PMID:34597140 qualifier: involved_in review: summary: PMID:34597140 links GABARAP-dependent sequestration of the FLCN complex to TFEB and the lysosomal program. action: KEEP_AS_NON_CORE reason: PMID:34597140 links GABARAP-dependent sequestration of the FLCN complex to TFEB and the lysosomal program. Retain contextual negative regulation of lysosome organization as non-core; FLCN is a signaling regulator here, not a direct organelle-construction enzyme. supported_by: - reference_id: PMID:34597140 supporting_text: This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. - reference_id: PMID:39423796 supporting_text: GABARAP lipidation is known to inhibit the FLCN-FNIP-RagC/D axis, thus blocking mTORC1-mediated TFEB phosphorylation - reference_id: PMID:37079666 supporting_text: The FLCN-FNIP1 complex functions as a GAP for RagC and RagD, promoting the GDP-bound state of RagC and RagD, which is required for mTOR recruitment to the lysosome - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:1905672 label: negative regulation of lysosome organization evidence_type: IDA original_reference_id: PMID:37079666 qualifier: involved_in review: summary: PMID:37079666 links AMPK-FNIP1 regulation of FLCN and TFEB to the lysosomal program. action: KEEP_AS_NON_CORE reason: PMID:37079666 links AMPK-FNIP1 regulation of FLCN and TFEB to the lysosomal program. Retain this downstream organization phenotype as non-core. AMPK supplies the kinase activity and TFEB the transcriptional activity; neither molecular role is assigned to FLCN. supported_by: - reference_id: PMID:34597140 supporting_text: This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. - reference_id: PMID:39423796 supporting_text: GABARAP lipidation is known to inhibit the FLCN-FNIP-RagC/D axis, thus blocking mTORC1-mediated TFEB phosphorylation - reference_id: PMID:37079666 supporting_text: The FLCN-FNIP1 complex functions as a GAP for RagC and RagD, promoting the GDP-bound state of RagC and RagD, which is required for mTOR recruitment to the lysosome - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:1905672 label: negative regulation of lysosome organization evidence_type: IDA original_reference_id: PMID:39423796 qualifier: involved_in review: summary: PMID:39423796 supports STING/GABARAP/RagC-dependent control of the lysosomal program within the established FLCN pathway. action: KEEP_AS_NON_CORE reason: PMID:39423796 supports STING/GABARAP/RagC-dependent control of the lysosomal program within the established FLCN pathway. Retain contextual negative organization regulation as non-core. Its inherited background excerpt and induction of the FLCN gene are not independent demonstrations of FLCN catalytic function; the actual bypass experiments provide separate pathway evidence. supported_by: - reference_id: PMID:34597140 supporting_text: This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. - reference_id: PMID:39423796 supporting_text: GABARAP lipidation is known to inhibit the FLCN-FNIP-RagC/D axis, thus blocking mTORC1-mediated TFEB phosphorylation - reference_id: PMID:37079666 supporting_text: The FLCN-FNIP1 complex functions as a GAP for RagC and RagD, promoting the GDP-bound state of RagC and RagD, which is required for mTOR recruitment to the lysosome - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:1990877 label: FNIP-folliculin RagC/D GAP evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of supporting_entities: - PANTHER:PTN002833743 - PomBase:SPBC24C6.08c - SGD:S000003289 - UniProtKB:Q8NFG4 review: summary: The exact complex-membership IBD at PTN002833743 lies on the human target path and has yeast and human experimental grounding. action: ACCEPT reason: The exact complex-membership IBD at PTN002833743 lies on the human target path and has yeast and human experimental grounding. FLCN-FNIP complex association and paired Longin/DENN interfaces are independently supported (PMID:17028174, PMID:18403135, PMID:36103527). This is core complex membership; human self-evidence is not circular. supported_by: - reference_id: PMID:17028174 supporting_text: Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5' AMP-activated protein kinase (AMPK) - reference_id: PMID:18403135 supporting_text: C-terminally-deleted FLCN mutants, similar to those produced by naturally-occurring germline mutations in BHD patients, were unable to bind FNIP2. - reference_id: PMID:36103527 supporting_text: Conversion between active and inactive states is regulated by the RagA/B-specific GAP, GAP activity towards Rags 1 (GATOR1), and by the RagC/D-specific GAP, FLCN:FLCN-interacting protein 2 (FNIP2) - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - PMID:17028174 - PMID:18403135 - PMID:36103527 - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:1990877 label: FNIP-folliculin RagC/D GAP evidence_type: IDA original_reference_id: PMID:32612235 qualifier: part_of review: summary: Retain established FLCN-FNIP complex membership with the original PMID:32612235 cellular pathway context. action: ACCEPT reason: Retain established FLCN-FNIP complex membership with the original PMID:32612235 cellular pathway context. Earlier interaction studies and later structural work independently establish the complex; this paper is not presented as its original purified assembly experiment. supported_by: - reference_id: PMID:17028174 supporting_text: Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5' AMP-activated protein kinase (AMPK) - reference_id: PMID:18403135 supporting_text: C-terminally-deleted FLCN mutants, similar to those produced by naturally-occurring germline mutations in BHD patients, were unable to bind FNIP2. - reference_id: PMID:36103527 supporting_text: Conversion between active and inactive states is regulated by the RagA/B-specific GAP, GAP activity towards Rags 1 (GATOR1), and by the RagC/D-specific GAP, FLCN:FLCN-interacting protein 2 (FNIP2) - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:1990877 label: FNIP-folliculin RagC/D GAP evidence_type: IDA original_reference_id: PMID:36103527 qualifier: part_of review: summary: PMID:36103527 directly resolves the FLCN-FNIP2 catalytic complex using specified engineered constructs. action: ACCEPT reason: PMID:36103527 directly resolves the FLCN-FNIP2 catalytic complex using specified engineered constructs. Retain core complex membership, with those construct and nucleotide-state limits rather than assuming identical assembly of every natural product. supported_by: - reference_id: PMID:17028174 supporting_text: Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5' AMP-activated protein kinase (AMPK) - reference_id: PMID:18403135 supporting_text: C-terminally-deleted FLCN mutants, similar to those produced by naturally-occurring germline mutations in BHD patients, were unable to bind FNIP2. - reference_id: PMID:36103527 supporting_text: Conversion between active and inactive states is regulated by the RagA/B-specific GAP, GAP activity towards Rags 1 (GATOR1), and by the RagC/D-specific GAP, FLCN:FLCN-interacting protein 2 (FNIP2) - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:1990877 label: FNIP-folliculin RagC/D GAP evidence_type: IPI original_reference_id: PMID:17028174 qualifier: part_of review: summary: PMID:17028174 establishes FLCN-FNIP1 association, supporting core complex membership. action: ACCEPT reason: PMID:17028174 establishes FLCN-FNIP1 association, supporting core complex membership. Later biochemical studies identify the complex as a RagC/D GAP; that catalytic assay is not retroactively attributed to the early interaction paper. supported_by: - reference_id: PMID:17028174 supporting_text: Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5' AMP-activated protein kinase (AMPK) - reference_id: PMID:18403135 supporting_text: C-terminally-deleted FLCN mutants, similar to those produced by naturally-occurring germline mutations in BHD patients, were unable to bind FNIP2. - reference_id: PMID:36103527 supporting_text: Conversion between active and inactive states is regulated by the RagA/B-specific GAP, GAP activity towards Rags 1 (GATOR1), and by the RagC/D-specific GAP, FLCN:FLCN-interacting protein 2 (FNIP2) - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:1990877 label: FNIP-folliculin RagC/D GAP evidence_type: IPI original_reference_id: PMID:18403135 qualifier: part_of review: summary: PMID:18403135 establishes FLCN-FNIP2 association, supporting core complex membership. action: ACCEPT reason: PMID:18403135 establishes FLCN-FNIP2 association, supporting core complex membership. The interaction study is distinct from later purified RagC/D GAP assays and does not establish equivalent binding of all natural products. supported_by: - reference_id: PMID:17028174 supporting_text: Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5' AMP-activated protein kinase (AMPK) - reference_id: PMID:18403135 supporting_text: C-terminally-deleted FLCN mutants, similar to those produced by naturally-occurring germline mutations in BHD patients, were unable to bind FNIP2. - reference_id: PMID:36103527 supporting_text: Conversion between active and inactive states is regulated by the RagA/B-specific GAP, GAP activity towards Rags 1 (GATOR1), and by the RagC/D-specific GAP, FLCN:FLCN-interacting protein 2 (FNIP2) - reference_id: file:human/FLCN/FLCN-source-evidence.yaml additional_reference_ids: - file:human/FLCN/FLCN-source-evidence.yaml - term: id: GO:2000973 label: regulation of pro-B cell differentiation evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in supporting_entities: - UniProtKB:Q8QZS3 review: summary: Adult conditional Flcn loss supports a non-core pro-B differentiation regulatory association. action: KEEP_AS_NON_CORE reason: Adult ubiquitous CreER-mediated mouse Flcn deletion produces a pro-B block and peripheral B-cell loss (PMID:22709692). The specific B-lineage endpoint supports retaining the existing regulation-of-differentiation association as non-core, with moderate confidence in conservation. Survival versus differentiation and cell-autonomous versus systemic mechanisms remain unresolved. Transplantation, receptor/V(D)J, caspase, Bcl2 and rapamycin experiments in this paper concern Fnip1 and are not transferred to Flcn as rescue evidence. additional_reference_ids: - PMID:22709692 - file:human/FLCN/FLCN-source-evidence.yaml supported_by: - reference_id: PMID:22709692 supporting_text: We also demonstrate that conditional deletion of Flcn recapitulates the pro-B cell arrest of Fnip1(-/-) mice. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:17028174 title: Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. findings: [] - id: PMID:18403135 title: Identification and characterization of a novel folliculin-interacting protein FNIP2. findings: [] - id: PMID:18663353 title: Interaction of folliculin (Birt-Hogg-Dubé gene product) with a novel Fnip1-like (FnipL/Fnip2) protein. findings: [] - id: PMID:21209915 title: Inactivation of the FLCN tumor suppressor gene induces TFE3 transcriptional activity by increasing its nuclear localization. findings: - statement: FLCN inactivation was associated with nuclear localization and increased transcriptional activity of TFE3. supporting_text: FLCN inactivation was correlated with increased TFE3 transcriptional activity accompanied by its nuclear localization finding_review: review_notes: 'This excerpt does not identify the separate higher-mass TFE3 modification. Cite actual Results distinguishing that unidentified modification from phosphorylation without a new quote. Conserved original occurrence: existing_annotations[102].review.supported_by[0]. Repeated excerpts preserve provenance and are not independent experiments.' - id: PMID:22965878 title: Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis. findings: - statement: FLCN and p0071 partly colocalize at junctions and the cytokinetic midbody. supporting_text: Folliculin and p0071 partially co-localized at cell junctions and in mitotic cells, at the midbody during cytokinesis. finding_review: review_notes: 'Colocalization is not binding by itself. Binding is separately supported by inspected yeast-two-hybrid and coimmunoprecipitation experiments. Conserved original occurrence: existing_annotations[16].review.supported_by[0]. Repeated excerpts preserve provenance and are not independent experiments.' - id: PMID:23784378 title: Birt-Hogg-Dube syndrome is a novel ciliopathy. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Identifier/title and separately recovered original Methods/Results verified; normal cache remains abstract-only. Human EGFP-FLCN in MDCK, human HK2 spindle/cilium and nasal cilium observations have distinct scopes. No figure-pixel or supplementary-file inspection claimed. - id: PMID:24081491 title: Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. findings: [] - id: PMID:24095279 title: The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary demonstration that FLCN-FNIP2 is a GAP for RagC/D (human proteins, in vitro GAP assays). Checked against cached publication text. - id: PMID:25126726 title: FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation. findings: - statement: ULK1 overexpression was associated with FLCN phosphorylation, including the reported C-terminal sites. supporting_text: We reveal that the FLCN complex is regulated by ULK1 and elucidate 3 novel phosphorylation sites (Ser406, Ser537, and Ser542) within FLCN, which are induced by ULK1 overexpression. finding_review: review_notes: 'FLCN is the substrate. Ser406 versus Ser407 is unresolved. The binding row rests on coimmunoprecipitation, not this phosphorylation excerpt. Conserved original occurrence: existing_annotations[17].review.supported_by[0]. Repeated excerpts preserve provenance and are not independent experiments.' reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Identifier/title and separately recovered actual primary Methods/Results verified; normal cached full-text flag does not imply complete assay text. Lysate association, immunoprecipitated ULK1 assays, Ser406/407 ambiguity and partial triple-mutant effects limit mechanistic interpretation. - id: PMID:27113757 title: Folliculin directs the formation of a Rab34-RILP complex to control the nutrient-dependent dynamic distribution of lysosomes. findings: - statement: FLCN-DENN promotes active Rab34 loading onto RILP without detected Rab34 exchange activity in the tested assay. supporting_text: Using purified recombinant proteins, we show that the FLCN-DENN domain does not act as a GEF for Rab34, but rather, loads active Rab34 onto RILP finding_review: review_notes: 'Loading does not itself identify a binary binding assay. Association rests on separately inspected source assays; no GEF, GDI or stable ternary-adaptor mechanism. Conserved original occurrence: existing_annotations[21].review.supported_by[0]. Repeated excerpts preserve provenance and are not independent experiments.' - id: PMID:27151976 title: Chronic AMPK activation via loss of FLCN induces functional beige adipose tissue through PGC-1α/ERRα. findings: [] - id: PMID:27353360 title: The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding. findings: - statement: FLCN acts as an Hsp90 client, while its partners FNIP1 and FNIP2 act as cochaperones in the reported study. supporting_text: Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. finding_review: review_notes: 'General excerpt does not establish the row-specific partner. Preserve each existing occurrence and original row provenance; duplicates are not independent evidence. Actual IP/MS and IP support association. Purified FLCN–Hsp90 binding was negative without FNIP1. One biological finding is represented here. The repeated evidence entries below preserve the exact inherited quotation/reference occurrences for the assessment of this same finding; they are not independent observations or additional evidence strength. Occurrence ledger: existing_annotations[22].review.supported_by[0] -> references[PMID:27353360].findings[0].supporting_text; existing_annotations[23].review.supported_by[0] -> references[PMID:27353360].findings[0].finding_review.supported_by[0].supporting_text; existing_annotations[24].review.supported_by[0] -> references[PMID:27353360].findings[0].finding_review.supported_by[1].supporting_text; existing_annotations[25].review.supported_by[0] -> references[PMID:27353360].findings[0].finding_review.supported_by[2].supporting_text; existing_annotations[26].review.supported_by[0] -> references[PMID:27353360].findings[0].finding_review.supported_by[3].supporting_text; existing_annotations[27].review.supported_by[0] -> references[PMID:27353360].findings[0].finding_review.supported_by[4].supporting_text; existing_annotations[28].review.supported_by[0] -> references[PMID:27353360].findings[0].finding_review.supported_by[5].supporting_text; existing_annotations[29].review.supported_by[0] -> references[PMID:27353360].findings[0].finding_review.supported_by[6].supporting_text; existing_annotations[30].review.supported_by[0] -> references[PMID:27353360].findings[0].finding_review.supported_by[7].supporting_text; existing_annotations[31].review.supported_by[0] -> references[PMID:27353360].findings[0].finding_review.supported_by[8].supporting_text.' supported_by: - reference_id: PMID:27353360 supporting_text: Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. - reference_id: PMID:27353360 supporting_text: Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. - reference_id: PMID:27353360 supporting_text: Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. - reference_id: PMID:27353360 supporting_text: Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. - reference_id: PMID:27353360 supporting_text: Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. - reference_id: PMID:27353360 supporting_text: Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. - reference_id: PMID:27353360 supporting_text: Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. - reference_id: PMID:27353360 supporting_text: Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. - reference_id: PMID:27353360 supporting_text: Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. - id: PMID:29848618 title: GATOR1-dependent recruitment of FLCN-FNIP to lysosomes coordinates Rag GTPase heterodimer nucleotide status in response to amino acids. findings: [] - id: PMID:31672913 title: Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Identifier/title and selected actual primary structure and biochemical evidence verified. Arg164 is catalytically required; the inhibited LFC structure does not depict active arginine insertion. - id: PMID:31704029 title: Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Identifier/title and selected primary Methods/Results verified. Direct human RagC hydrolysis and strong R164A loss support GAP activity; the captured structure is an intermediate rather than a transition-state insertion. - id: PMID:32612235 title: A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dubé syndrome. findings: - statement: Active RagC or RagD mutants restore TFEB phosphorylation in FLCN-deficient cells. supporting_text: Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation finding_review: review_notes: 'Positive Rag/TOR evidence does not support the negative-Rho entailment used for this broad term. Retain the excerpt with its actual finding; row103 uses Rho evidence and the official ontology path. Conserved original occurrence: existing_annotations[103].review.supported_by[0]. Repeated excerpts preserve provenance and are not independent experiments.' - statement: TFEB depletion rescues mTORC1 hyperactivation in Flcn-knockout kidneys. supporting_text: TFEB is constitutively nuclear and active in Flcn-KO kidneys and its depletion rescues mTORC1 hyperactivation. finding_review: review_notes: 'This inherited excerpt documents the renal TFEB-feedback context, not the human flow-induced ciliary mechanism. One biological finding is represented here. The repeated evidence entries below preserve the exact inherited quotation/reference occurrences for the assessment of this same finding; they are not independent observations or additional evidence strength. Occurrence ledger: existing_annotations[71].review.supported_by[0] -> references[PMID:32612235].findings[1].supporting_text; existing_annotations[72].review.supported_by[0] -> references[PMID:32612235].findings[1].finding_review.supported_by[0].supporting_text; existing_annotations[73].review.supported_by[0] -> references[PMID:32612235].findings[1].finding_review.supported_by[1].supporting_text.' supported_by: - reference_id: PMID:32612235 supporting_text: TFEB is constitutively nuclear and active in Flcn-KO kidneys and its depletion rescues mTORC1 hyperactivation. - reference_id: PMID:32612235 supporting_text: TFEB is constitutively nuclear and active in Flcn-KO kidneys and its depletion rescues mTORC1 hyperactivation. - statement: The studied Flcn-knockout kidneys have increased RagC/RagD and other TFEB targets. supporting_text: Finally, the levels of RagC and RagD were increased, as well as the levels of other previously described TFEB targets finding_review: review_notes: 'This inherited excerpt documents the renal TFEB-feedback context, not the human flow-induced ciliary mechanism. One biological finding is represented here. The repeated evidence entries below preserve the exact inherited quotation/reference occurrences for the assessment of this same finding; they are not independent observations or additional evidence strength. Occurrence ledger: existing_annotations[71].review.supported_by[1] -> references[PMID:32612235].findings[2].supporting_text; existing_annotations[72].review.supported_by[1] -> references[PMID:32612235].findings[2].finding_review.supported_by[0].supporting_text; existing_annotations[73].review.supported_by[1] -> references[PMID:32612235].findings[2].finding_review.supported_by[1].supporting_text.' supported_by: - reference_id: PMID:32612235 supporting_text: Finally, the levels of RagC and RagD were increased, as well as the levels of other previously described TFEB targets - reference_id: PMID:32612235 supporting_text: Finally, the levels of RagC and RagD were increased, as well as the levels of other previously described TFEB targets reference_review: relevance: HIGH correctness: VERIFIED review_notes: Identifier/title and selected primary experiments verified. Human FLCN-loss/Rag-bypass TFEB assays and mouse Flcn/Tfeb renal epistasis support pathway regulation. TFEB selectivity relative to S6K/4E-BP1 is specific to tested conditions, not a universal negative. - id: PMID:34381247 title: The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Identifier/title and separately recovered actual primary Methods/Results verified. Purified human FLCN/LDHA inhibition and tested-cell glycolytic effects support a direct molecular capacity; physiological generality and independent replication remain open. - id: PMID:34597140 title: GABARAP sequesters the FLCN-FNIP tumor suppressor complex to couple autophagy with lysosomal biogenesis. findings: [] - id: PMID:36103527 title: Structural basis for FLCN RagC GAP activation in MiT-TFE substrate-selective mTORC1 regulation. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Structure of the GAP-competent FLCN-FNIP2-Rag state. Checked against cached publication text. - id: PMID:37079666 title: Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: AMPK phosphorylation of FNIP1 inhibits FLCN-FNIP1 GAP activity to activate TFEB/TFE3. Checked against cached publication text. - id: PMID:39423796 title: A TBK1-independent primordial function of STING in lysosomal biogenesis. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Identifier/title and selected actual primary experiments verified through independent consultation. STING/GABARAP and GDP-RagC bypass inform the FLCN pathway; not merely a passing discussion mention, but not a new FLCN knockout, binary STING interaction or purified FLCN catalytic assay. - id: PMID:19850877 title: Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2. findings: - statement: A distinct mouse Bhd null allele was associated with early embryonic lethality and visceral-endoderm defects. supporting_text: BHD homozygous null (BHD(d/d)) mice displayed early embryonic lethality at E5.5-E6.5, showing defects in the visceral endoderm. finding_review: review_notes: 'Corroborating PMID19850877 evidence, not current mouse donor PMID21258407; separate alleles and no untested TFE3 lethality mechanism. Conserved original occurrence: existing_annotations[3].review.supported_by[0]. Repeated excerpts preserve provenance and are not independent experiments.' reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Identifier/title and selected original Results verified. Distinct mouse null-allele embryonic findings and renal AKT evidence include human BHD tumors; this is not the current PMID:21258407 embryo donor. Some assay Methods defer to uninspected supplements. - id: PMID:18182616 title: 'Kidney-targeted Birt-Hogg-Dube gene inactivation in a mouse model: Erk1/2 and Akt-mTOR activation, cell hyperproliferation, and polycystic kidneys.' findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Mouse donor for ERK and kidney proliferation ISS transfers; abstract-only in cache. Checked against cached publication text. - id: PMID:18974783 title: Deficiency of FLCN in mouse kidney led to development of polycystic kidneys and renal neoplasia. findings: [] - id: PMID:21258407 title: Loss of the Birt-Hogg-Dubé tumor suppressor results in apoptotic resistance due to aberrant TGFβ-mediated transcription. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Mouse donor for TGF-beta and apoptosis annotations. Checked against cached publication text. - id: PMID:22709692 title: The folliculin-FNIP1 pathway deleted in human Birt-Hogg-Dubé syndrome is required for murine B-cell development. findings: - statement: Conditional adult mouse Flcn deletion produces a pro-B block resembling the Fnip1-null phenotype. supporting_text: We also demonstrate that conditional deletion of Flcn recapitulates the pro-B cell arrest of Fnip1(-/-) mice. finding_review: review_notes: 'Separate B-cell evidence from PMID22709692, not the current PMID21258407 donor for broad hemopoiesis. This experiment is directly about Flcn; partner rescue data are not transferred. Conserved original occurrence: existing_annotations[66].review.supported_by[0]. Repeated excerpts preserve provenance and are not independent experiments.' - id: PMID:23150719 title: Regulation of mitochondrial oxidative metabolism by tumor suppressor FLCN. findings: [] - id: PMID:27913603 title: The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue. findings: [] - id: PMID:27072130 title: Tumor Suppressor Folliculin Regulates mTORC1 through Primary Cilia. findings: - statement: The authors propose a ciliary FLCN–LKB1 recruitment model connected to AMPK activation. supporting_text: it is conceivable that FLCN recruits LKB1 through primary cilia before targeting it to basal bodies for AMPK activation. finding_review: review_notes: 'Inherited excerpt explicitly presents a model, not a localization measurement. Independent PMID23784378 supports ciliary localization; no direct LKB1 transport or enzyme function is inferred. One biological finding is represented here. The repeated evidence entries below preserve the exact inherited quotation/reference occurrences for the assessment of this same finding; they are not independent observations or additional evidence strength. Occurrence ledger: existing_annotations[56].review.supported_by[1] -> references[PMID:27072130].findings[0].supporting_text; existing_annotations[57].review.supported_by[1] -> references[PMID:27072130].findings[0].finding_review.supported_by[0].supporting_text; existing_annotations[58].review.supported_by[1] -> references[PMID:27072130].findings[0].finding_review.supported_by[1].supporting_text.' supported_by: - reference_id: PMID:27072130 supporting_text: it is conceivable that FLCN recruits LKB1 through primary cilia before targeting it to basal bodies for AMPK activation. - reference_id: PMID:27072130 supporting_text: it is conceivable that FLCN recruits LKB1 through primary cilia before targeting it to basal bodies for AMPK activation. - id: file:human/FLCN/FLCN-source-evidence.yaml title: FLCN source evidence, assay boundaries, phylogenetic replay and conservation policy findings: [] core_functions: - description: Partner-dependent GTPase-activating activity for RagC/D in the FLCN-FNIP1/2 complex. FLCN supplies the catalytic Arg164 contribution, converting RagC/D toward the GDP-bound state that supports mTORC1 phosphorylation and cytoplasmic retention of TFEB/TFE3. Nutrient-dependent lysosomal recruitment, inhibitory-complex assembly and activation regulate this activity; effects on other mTORC1 substrates depend on cellular conditions. molecular_function: id: GO:0005096 label: GTPase activator activity directly_involved_in: - id: GO:1904263 label: positive regulation of TORC1 signaling - id: GO:0034198 label: cellular response to amino acid starvation locations: - id: GO:0005765 label: lysosomal membrane - id: GO:0005829 label: cytosol in_complex: id: GO:1990877 label: FNIP-folliculin RagC/D GAP supported_by: - reference_id: PMID:24095279 supporting_text: Moreover, we identified the FLCN-FNIP complex as a potent GTPase activating protein (GAP) for RagC/D that interacts with the Rag heterodimer in an amino acid-sensitive fashion and localizes to the lysosomal surface upon amino acid starvation. - reference_id: PMID:31672913 supporting_text: First, we identified Arg164 of FLCN as a catalytically required arginine residue for GAP activity. - reference_id: PMID:31704029 supporting_text: Furthermore, we identified the catalytic residue necessary for the GAP activity, which leads us to interpret our structure as an on-pathway intermediate. - reference_id: PMID:32612235 supporting_text: Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation - reference_id: PMID:36103527 supporting_text: Conversion between active and inactive states is regulated by the RagA/B-specific GAP, GAP activity towards Rags 1 (GATOR1), and by the RagC/D-specific GAP, FLCN:FLCN-interacting protein 2 (FNIP2) - reference_id: file:human/FLCN/FLCN-source-evidence.yaml - description: Direct binding and uncompetitive inhibition of human LDHA, demonstrated with purified proteins and accompanied by reduced glycolytic activity in tested cells. This measured molecular capacity is distinct from the Rag GAP function; its physiological range and behavior at endogenous stoichiometry require further testing. Synthetic inhibitory-loop constructs are not natural FLCN products. molecular_function: id: GO:0160193 label: L-lactate dehydrogenase inhibitor activity directly_involved_in: - id: GO:0045820 label: negative regulation of glycolytic process locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: PMID:34381247 supporting_text: Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. - reference_id: PMID:34381247 supporting_text: Together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis. - reference_id: file:human/FLCN/FLCN-source-evidence.yaml suggested_questions: - question: How broadly does the directly measured LDHA-inhibitory activity operate at endogenous FLCN:LDHA stoichiometry, independently of FNIP1/2 and Rag signaling? - question: Which FLCN-dependent developmental and B-cell phenotypes reflect lineage-autonomous differentiation, survival or intercellular signals, and which mechanisms are conserved in humans? - question: What is the chemistry of the unidentified higher-mass TFE3 modification suppressed by FLCN, distinct from the phosphorylation promoted by FLCN? - question: Do the three natural FLCN products differ in partner assembly, localization and catalytic activity? Canonical Arg164 and synthetic-peptide results cannot establish the functions of the truncated products. - question: Under which conditions does endogenous FLCN occupy a nuclear pool, and does that pool have an activity distinct from cytosolic/lysosomal signaling? suggested_experiments: - description: Compare endogenous-level wild-type and R164A FLCN restoration for RagC hydrolysis, TFEB localization, LDHA activity and lactate production, with independent FNIP and LDHA interaction controls. experiment_type: structure-function rescue hypothesis: LDHA inhibition and RagC/D GAP activity are separable molecular capacities. - description: Combine lineage-restricted Flcn deletion with survival measurements, differentiation trajectories and matched restoration, testing TFEB/TFE3 dependence separately in each tissue. experiment_type: conditional genetics and rescue hypothesis: Distinct survival and differentiation mechanisms contribute to the contextual developmental phenotypes. - description: Express sequence-verified natural FLCN products individually at matched levels and assay FNIP assembly, RagC/D turnover, LDHA inhibition and localization. experiment_type: product-resolved functional comparison hypothesis: Truncation and alternative sequence segments alter functions independently rather than retaining all canonical activities.