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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: FLCN-dependent repression of TFE3 target transcription is supported by human loss/restoration experiments (PMID:21209915). 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. Supporting Evidence: PMID:21209915 Conversely, wildtype FLCN suppressed GPNMB expression in FLCN-null cells. PMID:21209915 FLCN inactivation was correlated with increased TFE3 transcriptional activity accompanied by its nuclear localization PMID:24081491 In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: The combined electronic mouse/rule transfer agrees with FLCN-dependent repression of TFE3 target transcription in human cells (PMID:21209915). 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. Supporting Evidence: PMID:21209915 Conversely, wildtype FLCN suppressed GPNMB expression in FLCN-null cells. PMID:21209915 FLCN inactivation was correlated with increased TFE3 transcriptional activity accompanied by its nuclear localization PMID:24081491 In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:21209915 Inactivation of the FLCN tumor suppressor gene induces TFE3 ... | KEEP AS NON CORE | Summary: Human FLCN restoration and knockdown experiments support repression of TFE3-dependent transcription (PMID:21209915). 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. Supporting Evidence: PMID:21209915 Conversely, wildtype FLCN suppressed GPNMB expression in FLCN-null cells. PMID:21209915 FLCN inactivation was correlated with increased TFE3 transcriptional activity accompanied by its nuclear localization PMID:24081491 In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0001701 in utero embryonic development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse developmental and differentiation phenotypes support a non-core ortholog association. 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. |
| GO:0004857 enzyme inhibitor activity | IDA PMID:34381247 The tumor suppressor folliculin inhibits lactate dehydrogena... | MODIFY | Summary: Purified human FLCN directly inhibits human LDHA, including kinetic and inhibitory-loop experiments in PMID:34381247. 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 219β228 peptide is not a natural FLCN product; independent physiological replication and the behavior of the truncated natural products remain open. Proposed replacements: L-lactate dehydrogenase inhibitor activity Supporting Evidence: PMID:34381247 Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005096 GTPase activator activity | IDA PMID:24095279 The folliculin tumor suppressor is a GAP for the RagC/D GTPa... | ACCEPT | Summary: PMID:24095279 directly measures partner-dependent FLCN-FNIP2 GAP activity with RagC/D specificity; isolated subunits were inactive under the tested conditions. 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. Supporting Evidence: PMID:24095279 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. PMID:31672913 First, we identified Arg164 of FLCN as a catalytically required arginine residue for GAP activity. PMID:31704029 Furthermore, we identified the catalytic residue necessary for the GAP activity, which leads us to interpret our structure as an on-pathway intermediate. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005096 GTPase activator activity | IDA PMID:31672913 Structural mechanism of a Rag GTPase activation checkpoint b... | ACCEPT | Summary: PMID:31672913 uses biochemical assays and Arg164 mutagenesis to establish FLCN catalytic contribution to RagC/D GAP activity. 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. Supporting Evidence: PMID:24095279 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. PMID:31672913 First, we identified Arg164 of FLCN as a catalytically required arginine residue for GAP activity. PMID:31704029 Furthermore, we identified the catalytic residue necessary for the GAP activity, which leads us to interpret our structure as an on-pathway intermediate. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005096 GTPase activator activity | IDA PMID:31704029 Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Comp... | ACCEPT | Summary: PMID:31704029 directly measures RagC hydrolysis with purified human FLCN-FNIP2 and strong loss of activity with R164A. 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. Supporting Evidence: PMID:24095279 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. PMID:31672913 First, we identified Arg164 of FLCN as a catalytically required arginine residue for GAP activity. PMID:31704029 Furthermore, we identified the catalytic residue necessary for the GAP activity, which leads us to interpret our structure as an on-pathway intermediate. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005096 GTPase activator activity | IDA PMID:32612235 A substrate-specific mTORC1 pathway underlies Birt-Hogg-DubΓ©... | ACCEPT | Summary: FLCN RagC/D GAP activity is independently established by purified assays (PMID:24095279, PMID:31704029). 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. Supporting Evidence: PMID:24095279 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. PMID:31672913 First, we identified Arg164 of FLCN as a catalytically required arginine residue for GAP activity. PMID:31704029 Furthermore, we identified the catalytic residue necessary for the GAP activity, which leads us to interpret our structure as an on-pathway intermediate. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005096 GTPase activator activity | IDA PMID:36103527 Structural basis for FLCN RagC GAP activation in MiT-TFE sub... | ACCEPT | Summary: PMID:36103527 resolves an active FLCN-FNIP2/Rag catalytic complex and tests catalytic contributions. 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. Supporting Evidence: PMID:24095279 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. PMID:31672913 First, we identified Arg164 of FLCN as a catalytically required arginine residue for GAP activity. PMID:31704029 Furthermore, we identified the catalytic residue necessary for the GAP activity, which leads us to interpret our structure as an on-pathway intermediate. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005096 GTPase activator activity | IDA PMID:37079666 Induction of lysosomal and mitochondrial biogenesis by AMPK ... | ACCEPT | Summary: PMID:37079666 demonstrates AMPK/FNIP1 control of the FLCN-dependent TFEB pathway. 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). Supporting Evidence: PMID:24095279 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. PMID:31672913 First, we identified Arg164 of FLCN as a catalytically required arginine residue for GAP activity. PMID:31704029 Furthermore, we identified the catalytic residue necessary for the GAP activity, which leads us to interpret our structure as an on-pathway intermediate. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005096 GTPase activator activity | IEA GO_REF:0000002 | ACCEPT | Summary: The InterPro electronic assignment agrees with direct target-specific RagC/D GAP assays (PMID:24095279, PMID:31704029). 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. Supporting Evidence: PMID:24095279 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. PMID:31672913 First, we identified Arg164 of FLCN as a catalytically required arginine residue for GAP activity. PMID:31704029 Furthermore, we identified the catalytic residue necessary for the GAP activity, which leads us to interpret our structure as an on-pathway intermediate. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005515 protein binding | IPI PMID:17028174 Folliculin encoded by the BHD gene interacts with a binding ... | KEEP AS NON CORE | Summary: PMID:17028174 establishes FLCN-FNIP1 association by interaction and coimmunoprecipitation experiments. 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. Supporting Evidence: PMID:17028174 Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5' AMP-activated protein kinase (AMPK) file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005515 protein binding | IPI PMID:18403135 Identification and characterization of a novel folliculin-in... | KEEP AS NON CORE | Summary: PMID:18403135 supports FLCN association with FNIP1 alongside the characterization of FNIP2. 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. Supporting Evidence: PMID:17028174 Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5' AMP-activated protein kinase (AMPK) file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005515 protein binding | IPI PMID:18403135 Identification and characterization of a novel folliculin-in... | KEEP AS NON CORE | Summary: PMID:18403135 directly characterizes FNIP2 and its association with FLCN. 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. Supporting Evidence: PMID:18403135 C-terminally-deleted FLCN mutants, similar to those produced by naturally-occurring germline mutations in BHD patients, were unable to bind FNIP2. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005515 protein binding | IPI PMID:18663353 Interaction of folliculin (Birt-Hogg-DubΓ© gene product) with... | KEEP AS NON CORE | Summary: The accessible PMID:18663353 abstract reports FLCN-FnipL/FNIP2 interaction, while its full body remains inaccessible. 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. Supporting Evidence: PMID:18403135 C-terminally-deleted FLCN mutants, similar to those produced by naturally-occurring germline mutations in BHD patients, were unable to bind FNIP2. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005515 protein binding | IPI PMID:22965878 Folliculin interacts with p0071 (plakophilin-4) and deficien... | KEEP AS NON CORE | Summary: PMID:22965878 supports FLCN-p0071/PKP4 association by yeast two-hybrid and coimmunoprecipitation experiments. 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. |
| GO:0005515 protein binding | IPI PMID:25126726 FLCN, a novel autophagy component, interacts with GABARAP an... | KEEP AS NON CORE | Summary: PMID:25126726 reports coimmunoprecipitation of FLCN with ULK1, stronger for kinase-inactive K46I than wild type. 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. |
| GO:0005515 protein binding | IPI PMID:25126726 FLCN, a novel autophagy component, interacts with GABARAP an... | KEEP AS NON CORE | Summary: PMID:25126726 supports FLCN-GABARAP association with cell-lysate GST pull-down and coimmunoprecipitation assays. 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. Supporting Evidence: PMID:25126726 our findings demonstrate that FLCN interacts with a second integral component of the autophagy machinery, GABA(A) receptor-associated protein (GABARAP). file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005515 protein binding | IPI PMID:25126726 FLCN, a novel autophagy component, interacts with GABARAP an... | KEEP AS NON CORE | Summary: PMID:25126726 supports a GABARAP-associated FLCN complex in the FNIP1 context recorded in this row. 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). Supporting Evidence: PMID:25126726 our findings demonstrate that FLCN interacts with a second integral component of the autophagy machinery, GABA(A) receptor-associated protein (GABARAP). file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005515 protein binding | IPI PMID:25126726 FLCN, a novel autophagy component, interacts with GABARAP an... | KEEP AS NON CORE | Summary: PMID:25126726 supports a GABARAP-associated FLCN complex in the FNIP2 context recorded in this row. 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). Supporting Evidence: PMID:25126726 our findings demonstrate that FLCN interacts with a second integral component of the autophagy machinery, GABA(A) receptor-associated protein (GABARAP). file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005515 protein binding | IPI PMID:27113757 Folliculin directs the formation of a Rab34-RILP complex to ... | KEEP AS NON CORE | Summary: PMID:27113757 supports FLCN-RILP association and FLCN-DENN-dependent loading of active Rab34 onto RILP. 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. |
| GO:0005515 protein binding | IPI PMID:27353360 The FNIP co-chaperones decelerate the Hsp90 chaperone cycle ... | KEEP AS NON CORE | Summary: PMID:27353360 supports FLCN association with AHSA1 in the interaction/proteomic chaperone-complex experiments. 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. |
| GO:0005515 protein binding | IPI PMID:27353360 The FNIP co-chaperones decelerate the Hsp90 chaperone cycle ... | KEEP AS NON CORE | Summary: PMID:27353360 supports FLCN association with HSP90AA1/Hsp90 alpha in the interaction/proteomic chaperone-complex experiments. 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. |
| GO:0005515 protein binding | IPI PMID:27353360 The FNIP co-chaperones decelerate the Hsp90 chaperone cycle ... | KEEP AS NON CORE | Summary: PMID:27353360 supports FLCN association with STIP1 in the interaction/proteomic chaperone-complex experiments. 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. |
| GO:0005515 protein binding | IPI PMID:27353360 The FNIP co-chaperones decelerate the Hsp90 chaperone cycle ... | KEEP AS NON CORE | Summary: PMID:27353360 supports FLCN association with PPP5C in the interaction/proteomic chaperone-complex experiments. 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. |
| GO:0005515 protein binding | IPI PMID:27353360 The FNIP co-chaperones decelerate the Hsp90 chaperone cycle ... | KEEP AS NON CORE | Summary: PMID:27353360 supports FLCN association with CCT2 in the interaction/proteomic chaperone-complex experiments. 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. |
| GO:0005515 protein binding | IPI PMID:27353360 The FNIP co-chaperones decelerate the Hsp90 chaperone cycle ... | KEEP AS NON CORE | Summary: PMID:27353360 supports FLCN association with PTGES3 in the interaction/proteomic chaperone-complex experiments. 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. |
| GO:0005515 protein binding | IPI PMID:27353360 The FNIP co-chaperones decelerate the Hsp90 chaperone cycle ... | KEEP AS NON CORE | Summary: PMID:27353360 supports FLCN association with CDC37 in the interaction/proteomic chaperone-complex experiments. 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. |
| GO:0005515 protein binding | IPI PMID:27353360 The FNIP co-chaperones decelerate the Hsp90 chaperone cycle ... | KEEP AS NON CORE | Summary: PMID:27353360 supports FLCN association with FNIP1 in the interaction/proteomic chaperone-complex experiments. 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. |
| GO:0005515 protein binding | IPI PMID:27353360 The FNIP co-chaperones decelerate the Hsp90 chaperone cycle ... | KEEP AS NON CORE | Summary: PMID:27353360 supports FLCN association with FNIP2 in the interaction/proteomic chaperone-complex experiments. 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. |
| GO:0005515 protein binding | IPI PMID:27353360 The FNIP co-chaperones decelerate the Hsp90 chaperone cycle ... | KEEP AS NON CORE | Summary: PMID:27353360 supports FLCN association with STUB1 in the interaction/proteomic chaperone-complex experiments. 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. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Nuclear localization is a peripheral, context-dependent pool. 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. Supporting Evidence: PMID:17028174 FLCN also localized in the nucleus. PMID:18663353 FnipL/Fnip2 and Flcn were located together in the cytoplasm in a reticular pattern, although solely expressed Flcn was found mainly in the nucleus. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005634 nucleus | IDA PMID:17028174 Folliculin encoded by the BHD gene interacts with a binding ... | KEEP AS NON CORE | Summary: Nuclear localization is a peripheral, context-dependent pool. 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. Supporting Evidence: PMID:17028174 FLCN also localized in the nucleus. PMID:18663353 FnipL/Fnip2 and Flcn were located together in the cytoplasm in a reticular pattern, although solely expressed Flcn was found mainly in the nucleus. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005634 nucleus | IDA PMID:18663353 Interaction of folliculin (Birt-Hogg-DubΓ© gene product) with... | KEEP AS NON CORE | Summary: Nuclear localization is a peripheral, context-dependent pool. 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. Supporting Evidence: PMID:17028174 FLCN also localized in the nucleus. PMID:18663353 FnipL/Fnip2 and Flcn were located together in the cytoplasm in a reticular pattern, although solely expressed Flcn was found mainly in the nucleus. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Nuclear localization is a peripheral, context-dependent pool. 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. Supporting Evidence: PMID:17028174 FLCN also localized in the nucleus. PMID:18663353 FnipL/Fnip2 and Flcn were located together in the cytoplasm in a reticular pattern, although solely expressed Flcn was found mainly in the nucleus. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005737 cytoplasm | IDA PMID:17028174 Folliculin encoded by the BHD gene interacts with a binding ... | MODIFY | Summary: The broad cytoplasmic localization in PMID:17028174 is valid. 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 replacements: cytosol lysosomal membrane Supporting Evidence: PMID:17028174 HA-FNIP1 and FLAG-FLCN, transiently cotransfected into HeLa cells, colocalized in the cytoplasm with a reticular pattern PMID:24095279 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. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005737 cytoplasm | IDA PMID:18663353 Interaction of folliculin (Birt-Hogg-DubΓ© gene product) with... | MODIFY | Summary: The broad cytoplasmic localization in PMID:18663353 is valid. 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 replacements: cytosol lysosomal membrane Supporting Evidence: PMID:17028174 HA-FNIP1 and FLAG-FLCN, transiently cotransfected into HeLa cells, colocalized in the cytoplasm with a reticular pattern PMID:24095279 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. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005737 cytoplasm | IDA PMID:22965878 Folliculin interacts with p0071 (plakophilin-4) and deficien... | MODIFY | Summary: The broad cytoplasmic localization in PMID:22965878 is valid. 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 replacements: cytosol lysosomal membrane Supporting Evidence: PMID:17028174 HA-FNIP1 and FLAG-FLCN, transiently cotransfected into HeLa cells, colocalized in the cytoplasm with a reticular pattern PMID:24095279 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. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005764 lysosome | TAS PMID:25126726 FLCN, a novel autophagy component, interacts with GABARAP an... | ACCEPT | Summary: Lysosome is an informative core organelle location, retained under the repository root-organelle exception even though lysosomal membrane is also annotated. 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. Supporting Evidence: PMID:24081491 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. PMID:29848618 FLCN is recruited to lysosomes during amino acid starvation, where it interacts with RagA/B as a heterodimeric complex with FLCN-interacting proteins (FNIPs). file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005765 lysosomal membrane | IDA PMID:24081491 Recruitment of folliculin to lysosomes supports the amino ac... | ACCEPT | Summary: PMID:24081491 distinguishes overexpressed mouse FLCN/FNIP1 from independently CRISPR-tagged endogenous human FLCN. 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. Supporting Evidence: PMID:24081491 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. PMID:31672913 FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding PMID:29848618 FLCN is recruited to lysosomes during amino acid starvation, where it interacts with RagA/B as a heterodimeric complex with FLCN-interacting proteins (FNIPs). file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005765 lysosomal membrane | IDA PMID:24095279 The folliculin tumor suppressor is a GAP for the RagC/D GTPa... | ACCEPT | Summary: PMID:24095279 demonstrates dynamic lysosomal association of the FLCN-FNIP complex alongside partner-dependent RagC/D GAP activity. 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. Supporting Evidence: PMID:24081491 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. PMID:31672913 FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding PMID:29848618 FLCN is recruited to lysosomes during amino acid starvation, where it interacts with RagA/B as a heterodimeric complex with FLCN-interacting proteins (FNIPs). file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005765 lysosomal membrane | IDA PMID:27113757 Folliculin directs the formation of a Rab34-RILP complex to ... | ACCEPT | Summary: PMID:27113757 supports FLCN association with the lysosomal membrane in its RILP/Rab34 trafficking experiments. 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. Supporting Evidence: PMID:24081491 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. PMID:31672913 FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding PMID:29848618 FLCN is recruited to lysosomes during amino acid starvation, where it interacts with RagA/B as a heterodimeric complex with FLCN-interacting proteins (FNIPs). file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005765 lysosomal membrane | IDA PMID:29848618 GATOR1-dependent recruitment of FLCN-FNIP to lysosomes coord... | ACCEPT | 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. 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. Supporting Evidence: PMID:24081491 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. PMID:31672913 FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding PMID:29848618 FLCN is recruited to lysosomes during amino acid starvation, where it interacts with RagA/B as a heterodimeric complex with FLCN-interacting proteins (FNIPs). file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005765 lysosomal membrane | IDA PMID:31672913 Structural mechanism of a Rag GTPase activation checkpoint b... | ACCEPT | Summary: PMID:31672913 supports starvation-dependent assembly and recruitment of the lysosomal folliculin complex. 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. Supporting Evidence: PMID:24081491 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. PMID:31672913 FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding PMID:29848618 FLCN is recruited to lysosomes during amino acid starvation, where it interacts with RagA/B as a heterodimeric complex with FLCN-interacting proteins (FNIPs). file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt subcellular-location mapping is corroborated by direct human lysosomal recruitment experiments (PMID:24081491, PMID:29848618). 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. Supporting Evidence: PMID:24081491 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. PMID:31672913 FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding PMID:29848618 FLCN is recruited to lysosomes during amino acid starvation, where it interacts with RagA/B as a heterodimeric complex with FLCN-interacting proteins (FNIPs). file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005813 centrosome | IDA PMID:23784378 Birt-Hogg-Dube syndrome is a novel ciliopathy. | KEEP AS NON CORE | Summary: Actual Methods and Results in PMID:23784378 identify human EGFP-FLCN at centrosomes in MDCK host cells, with separate endogenous mouse IMCD3 observations. 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. Supporting Evidence: PMID:23784378 Our data indicate that FLCN localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005813 centrosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Actual Methods and Results in PMID:23784378 identify human EGFP-FLCN at centrosomes in MDCK host cells, with separate endogenous mouse IMCD3 observations. 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. Supporting Evidence: PMID:23784378 Our data indicate that FLCN localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005819 spindle | IEA GO_REF:0000044 | MODIFY | Summary: The observed specific compartment is the mitotic spindle in human HK2 cells expressing EGFP-FLCN (PMID:23784378). 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 replacements: mitotic spindle Supporting Evidence: PMID:23784378 Our data indicate that FLCN localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: The positive cytosol IBD at PTN002833743 lies on the exact human target path, with legitimate human experimental grounding. 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. Supporting Evidence: PMID:24095279 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. PMID:31672913 FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Retain the original Human Protein Atlas IDA context for a well-supported core cytosolic pool. 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. Supporting Evidence: PMID:24095279 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. PMID:31672913 FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005829 cytosol | IDA PMID:24081491 Recruitment of folliculin to lysosomes supports the amino ac... | ACCEPT | Summary: PMID:24081491 shows diffuse basal signal from endogenous-locus tagged human FLCN and starvation/refeeding-dependent redistribution. 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. Supporting Evidence: PMID:24095279 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. PMID:31672913 FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005829 cytosol | IDA PMID:24095279 The folliculin tumor suppressor is a GAP for the RagC/D GTPa... | ACCEPT | Summary: PMID:24095279 supports a dynamic cytosolic FLCN-FNIP pool that redistributes with amino-acid availability. 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. Supporting Evidence: PMID:24095279 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. PMID:31672913 FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005829 cytosol | IDA PMID:29848618 GATOR1-dependent recruitment of FLCN-FNIP to lysosomes coord... | ACCEPT | Summary: Knockout controls in the actual primary PMID:29848618 validate endogenous human cytoplasmic FLCN staining and its regulated recruitment. 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. Supporting Evidence: PMID:24095279 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. PMID:31672913 FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005829 cytosol | IDA PMID:31672913 Structural mechanism of a Rag GTPase activation checkpoint b... | ACCEPT | Summary: PMID:31672913 supports cytosolic FLCN and regulated movement into the lysosomal complex. 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. Supporting Evidence: PMID:24095279 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. PMID:31672913 FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: The electronic cytosol assignment agrees with direct endogenous human localization and dynamic recruitment (PMID:24081491, PMID:29848618). 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. Supporting Evidence: PMID:24095279 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. PMID:31672913 FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005929 cilium | IDA PMID:23784378 Birt-Hogg-Dube syndrome is a novel ciliopathy. | KEEP AS NON CORE | Summary: PMID:23784378 supports ciliary localization in human HK2 and nasal epithelial experiments, with separate tagged and other-species assays. 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. Supporting Evidence: PMID:23784378 Our data indicate that FLCN localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005929 cilium | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: PMID:23784378 supports ciliary localization in human HK2 and nasal epithelial experiments, with separate tagged and other-species assays. 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. Supporting Evidence: PMID:23784378 Our data indicate that FLCN localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0005929 cilium | TAS PMID:25126726 FLCN, a novel autophagy component, interacts with GABARAP an... | KEEP AS NON CORE | Summary: PMID:23784378 supports ciliary localization in human HK2 and nasal epithelial experiments, with separate tagged and other-species assays. 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. Supporting Evidence: PMID:23784378 Our data indicate that FLCN localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0007043 cell-cell junction assembly | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Junction organization and barrier assays support contextual junction-assembly involvement. 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. Supporting Evidence: PMID:22965878 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. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0007043 cell-cell junction assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Junction organization and barrier assays support contextual junction-assembly involvement. 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. Supporting Evidence: PMID:22965878 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. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0009267 cellular response to starvation | IDA PMID:24095279 The folliculin tumor suppressor is a GAP for the RagC/D GTPa... | MODIFY | Summary: The perturbation in PMID:24095279 is amino-acid starvation, with regulated FLCN-FNIP localization and Rag association. 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 replacements: cellular response to amino acid starvation Supporting Evidence: PMID:24095279 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. PMID:31672913 FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0009267 cellular response to starvation | IDA PMID:31672913 Structural mechanism of a Rag GTPase activation checkpoint b... | MODIFY | Summary: PMID:31672913 examines amino-acid-starvation-dependent lysosomal complex assembly and its catalytic checkpoint. 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 replacements: cellular response to amino acid starvation Supporting Evidence: PMID:24095279 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. PMID:31672913 FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0010508 positive regulation of autophagy | IDA PMID:25126726 FLCN, a novel autophagy component, interacts with GABARAP an... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:25126726 Here, we identify that loss of FLCN moderately impairs basal autophagic flux, while re-expression of FLCN rescues autophagy. PMID:25126726 our findings demonstrate that FLCN interacts with a second integral component of the autophagy machinery, GABA(A) receptor-associated protein (GABARAP). file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0010508 positive regulation of autophagy | IMP PMID:25126726 FLCN, a novel autophagy component, interacts with GABARAP an... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:25126726 Here, we identify that loss of FLCN moderately impairs basal autophagic flux, while re-expression of FLCN rescues autophagy. PMID:25126726 our findings demonstrate that FLCN interacts with a second integral component of the autophagy machinery, GABA(A) receptor-associated protein (GABARAP). file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0019899 enzyme binding | IPI PMID:34381247 The tumor suppressor folliculin inhibits lactate dehydrogena... | MODIFY | Summary: PMID:34381247 goes beyond FLCN-LDHA association to direct inhibition of purified human LDHA. 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 replacements: L-lactate dehydrogenase inhibitor activity Supporting Evidence: PMID:34381247 Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0030097 hemopoiesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse embryoid-body hematopoietic endpoints support a non-core differentiation association. 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. |
| GO:0030496 midbody | IDA PMID:22965878 Folliculin interacts with p0071 (plakophilin-4) and deficien... | KEEP AS NON CORE | Summary: PMID:22965878 includes endogenous HaCat midbody staining, restored FTC133 cells and HeLa bimolecular fluorescence complementation. 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. Supporting Evidence: PMID:22965878 Folliculin and p0071 partially co-localized at cell junctions and in mitotic cells, at the midbody during cytokinesis. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0030511 positive regulation of transforming growth factor beta receptor signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:21258407 In aggregate, this work identifies a specific tumor suppressive mechanism for BHD in regulating TGFΞ²-dependent transcription and apoptosis file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0030511 positive regulation of transforming growth factor beta receptor signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:21258407 In aggregate, this work identifies a specific tumor suppressive mechanism for BHD in regulating TGFΞ²-dependent transcription and apoptosis file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0032006 regulation of TOR signaling | ISS GO_REF:0000024 | TOO GENERAL | Summary: Specific positive and negative TOR processes both entail broad TOR regulation. 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. Supporting Evidence: PMID:32612235 Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation PMID:37079666 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 file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0032007 negative regulation of TOR signaling | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: FLCN supports context-specific suppression of TOR signaling in flow and renal models. 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. Supporting Evidence: file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0032007 negative regulation of TOR signaling | NAS PMID:17028174 Folliculin encoded by the BHD gene interacts with a binding ... | KEEP AS NON CORE | Summary: FLCN supports context-specific suppression of TOR signaling in flow and renal models. 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. |
| GO:0032007 negative regulation of TOR signaling | NAS PMID:31672913 Structural mechanism of a Rag GTPase activation checkpoint b... | KEEP AS NON CORE | Summary: FLCN supports context-specific suppression of TOR signaling in flow and renal models. 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. |
| GO:0032008 positive regulation of TOR signaling | IDA PMID:24081491 Recruitment of folliculin to lysosomes supports the amino ac... | MODIFY | Summary: Refine positive TOR regulation to GO:1904263 positive regulation of TORC1 signaling, the supported RagC/D-dependent branch. 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 replacements: positive regulation of TORC1 signaling Supporting Evidence: PMID:24081491 In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). PMID:24095279 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. PMID:32612235 Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0032008 positive regulation of TOR signaling | IDA PMID:24095279 The folliculin tumor suppressor is a GAP for the RagC/D GTPa... | MODIFY | Summary: Refine positive TOR regulation to GO:1904263 positive regulation of TORC1 signaling, the supported RagC/D-dependent branch. 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 replacements: positive regulation of TORC1 signaling Supporting Evidence: PMID:24081491 In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). PMID:24095279 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. PMID:32612235 Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0032008 positive regulation of TOR signaling | IDA PMID:31672913 Structural mechanism of a Rag GTPase activation checkpoint b... | MODIFY | Summary: Refine positive TOR regulation to GO:1904263 positive regulation of TORC1 signaling, the supported RagC/D-dependent branch. 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 replacements: positive regulation of TORC1 signaling Supporting Evidence: PMID:24081491 In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). PMID:24095279 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. PMID:32612235 Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0032008 positive regulation of TOR signaling | IDA PMID:31704029 Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Comp... | MODIFY | Summary: Refine positive TOR regulation to GO:1904263 positive regulation of TORC1 signaling, the supported RagC/D-dependent branch. 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 replacements: positive regulation of TORC1 signaling Supporting Evidence: PMID:24081491 In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). PMID:24095279 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. PMID:32612235 Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0032008 positive regulation of TOR signaling | IEA GO_REF:0000117 | MODIFY | Summary: Refine positive TOR regulation to GO:1904263 positive regulation of TORC1 signaling, the supported RagC/D-dependent branch. 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 replacements: positive regulation of TORC1 signaling Supporting Evidence: PMID:24081491 In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). PMID:24095279 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. PMID:32612235 Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0032008 positive regulation of TOR signaling | ISS GO_REF:0000024 | MODIFY | Summary: Refine positive TOR regulation to GO:1904263 positive regulation of TORC1 signaling, the supported RagC/D-dependent branch. 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 replacements: positive regulation of TORC1 signaling Supporting Evidence: PMID:24081491 In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). PMID:24095279 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. PMID:32612235 Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0032418 lysosome localization | IDA PMID:27113757 Folliculin directs the formation of a Rab34-RILP complex to ... | KEEP AS NON CORE | Summary: PMID:27113757 supports starvation-dependent lysosome positioning through FLCN-RILP association and active Rab34 loading. 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. Supporting Evidence: PMID:27113757 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. PMID:27113757 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 file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0034198 cellular response to amino acid starvation | IDA PMID:24095279 The folliculin tumor suppressor is a GAP for the RagC/D GTPa... | ACCEPT | Summary: PMID:24095279 directly links amino-acid availability to FLCN-FNIP association/localization and RagC/D GAP function. 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. Supporting Evidence: PMID:24095279 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. PMID:31672913 FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding PMID:27113757 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. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0034198 cellular response to amino acid starvation | IDA PMID:27113757 Folliculin directs the formation of a Rab34-RILP complex to ... | ACCEPT | Summary: PMID:27113757 measures nutrient-dependent FLCN/RILP/Rab34 lysosome positioning. 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. Supporting Evidence: PMID:24095279 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. PMID:31672913 FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding PMID:27113757 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. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0034198 cellular response to amino acid starvation | IDA PMID:31672913 Structural mechanism of a Rag GTPase activation checkpoint b... | ACCEPT | Summary: PMID:31672913 demonstrates starvation-dependent lysosomal complex assembly and tests its catalytic checkpoint. 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. Supporting Evidence: PMID:24095279 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. PMID:31672913 FLCN clustered on LAMP2-positive lysosomes in amino acid-depleted conditions and became dispersed in the cytosol upon refeeding PMID:27113757 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. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0035024 negative regulation of Rho protein signal transduction | IMP PMID:22965878 Folliculin interacts with p0071 (plakophilin-4) and deficien... | KEEP AS NON CORE | Summary: PMID:22965878 measures disordered/increased RhoA signaling after FLCN perturbation and links FLCN to p0071. 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. Supporting Evidence: PMID:22965878 we found that folliculin deficiency was associated with increased expression and activity of RhoA and evidence of disordered cytokinesis file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0035556 intracellular signal transduction | IDA PMID:21209915 Inactivation of the FLCN tumor suppressor gene induces TFE3 ... | MODIFY | 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). 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 replacements: positive regulation of TORC1 signaling Supporting Evidence: PMID:21209915 FLCN inactivation was correlated with increased TFE3 transcriptional activity accompanied by its nuclear localization PMID:24081491 In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0043065 positive regulation of apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: FLCN perturbation and re-expression support contextual positive regulation of apoptosis. 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. Supporting Evidence: PMID:21258407 BHD-deficient cells exhibited defects in cell-intrinsic apoptosis that correlated with reduced expression of the BH3-only protein Bim file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0044291 cell-cell contact zone | IDA PMID:22965878 Folliculin interacts with p0071 (plakophilin-4) and deficien... | KEEP AS NON CORE | Summary: PMID:22965878 supports FLCN-p0071 colocalization and association at cell-cell junctions. 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. Supporting Evidence: PMID:22965878 Folliculin and p0071 partially co-localized at cell junctions and in mitotic cells, at the midbody during cytokinesis. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0045820 negative regulation of glycolysis | IDA PMID:34381247 The tumor suppressor folliculin inhibits lactate dehydrogena... | ACCEPT | Summary: PMID:34381247 directly measures human FLCN inhibition of purified LDHA and glycolytic effects in the tested cells. 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. Supporting Evidence: PMID:34381247 Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. PMID:34381247 Together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0045892 negative regulation of DNA-templated transcription | IEA GO_REF:0000107 | TOO GENERAL | Summary: The retained GO:0000122 negative regulation of transcription by RNA polymerase II is a verified is_a child of this broad transcription term. 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). Supporting Evidence: PMID:21209915 FLCN inactivation was correlated with increased TFE3 transcriptional activity accompanied by its nuclear localization file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0046578 regulation of Ras protein signal transduction | IDA PMID:24081491 Recruitment of folliculin to lysosomes supports the amino ac... | MODIFY | Summary: GO:0046578 concerns Ras-subfamily signaling; Rag GTPases are not members of that subfamily. 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 replacements: positive regulation of TORC1 signaling Supporting Evidence: PMID:24095279 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. PMID:24081491 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. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0046578 regulation of Ras protein signal transduction | IDA PMID:24095279 The folliculin tumor suppressor is a GAP for the RagC/D GTPa... | MODIFY | Summary: GO:0046578 concerns Ras-subfamily signaling; Rag GTPases are not members of that subfamily. 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 replacements: positive regulation of TORC1 signaling Supporting Evidence: PMID:24095279 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. PMID:24081491 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. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0046578 regulation of Ras protein signal transduction | IDA PMID:31672913 Structural mechanism of a Rag GTPase activation checkpoint b... | MODIFY | Summary: GO:0046578 concerns Ras-subfamily signaling; Rag GTPases are not members of that subfamily. 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 replacements: positive regulation of TORC1 signaling Supporting Evidence: PMID:24095279 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. PMID:24081491 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. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0046578 regulation of Ras protein signal transduction | IDA PMID:31704029 Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Comp... | MODIFY | Summary: GO:0046578 concerns Ras-subfamily signaling; Rag GTPases are not members of that subfamily. 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 replacements: positive regulation of TORC1 signaling Supporting Evidence: PMID:24095279 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. PMID:24081491 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. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse renal and human BHD tumor measurements support context-specific negative AKT-pathway regulation. 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. Supporting Evidence: PMID:19850877 The PI3K-AKT pathway was activated in both human BHD renal tumors and kidney tumors in BHD(d/+) mice. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0070373 negative regulation of ERK1 and ERK2 cascade | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse renal cascade measurements support context-specific negative ERK regulation. 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. Supporting Evidence: PMID:18182616 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. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0072686 mitotic spindle | IDA PMID:23784378 Birt-Hogg-Dube syndrome is a novel ciliopathy. | KEEP AS NON CORE | Summary: Actual Methods and Results in PMID:23784378 support human HK2 mitotic-spindle localization of human EGFP-FLCN. 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. Supporting Evidence: PMID:23784378 Our data indicate that FLCN localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0097009 energy homeostasis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Adipose Flcn perturbation changes measured whole-animal energy balance. 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. Supporting Evidence: PMID:23150719 Muscle-targeted FLCN knockout mice underwent a pronounced metabolic shift toward oxidative phosphorylation PMID:27151976 Adipoq-FLCN knockout mice exhibit increased energy expenditure and are protected from high-fat diet (HFD)-induced obesity. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0097009 energy homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Adipose Flcn perturbation changes measured whole-animal energy balance. 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. Supporting Evidence: PMID:23150719 Muscle-targeted FLCN knockout mice underwent a pronounced metabolic shift toward oxidative phosphorylation PMID:27151976 Adipoq-FLCN knockout mice exhibit increased energy expenditure and are protected from high-fat diet (HFD)-induced obesity. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0120163 negative regulation of cold-induced thermogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain contextual negative cold-induced thermogenesis from mouse physiology 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. Supporting Evidence: PMID:27151976 underlying the increased resistance of Adipoq-FLCN knockout mice to cold exposure PMID:27913603 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. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:0120163 negative regulation of cold-induced thermogenesis | ISS PMID:27151976 Chronic AMPK activation via loss of FLCN induces functional ... | KEEP AS NON CORE | Summary: The original PMID:27151976 mouse transfer concerns increased cold resistance and thermogenic physiology associated with AMPK-PGC1alpha-ERRalpha signaling after Flcn loss. 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. Supporting Evidence: PMID:27151976 underlying the increased resistance of Adipoq-FLCN knockout mice to cold exposure PMID:27913603 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. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:1901723 negative regulation of cell proliferation involved in kidney development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Postnatal renal Flcn loss supports contextual regulation of proliferation during kidney development. 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. Supporting Evidence: PMID:18974783 BHD(flox/flox)/Ksp-Cre mice developed enlarged kidneys characterized by polycystic kidneys, hyperplasia, and cystic renal cell carcinoma. PMID:32612235 TFEB is constitutively nuclear and active in Flcn-KO kidneys and its depletion rescues mTORC1 hyperactivation. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:1901874 negative regulation of post-translational protein modification | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Actual PMID:21209915 Results distinguish FLCN-promoted TFE3 phosphorylation from FLCN-suppressed accumulation of a separate unidentified higher-mass TFE3 species. 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. |
| GO:1902532 negative regulation of intracellular signal transduction | IEA GO_REF:0000117 | TOO GENERAL | Summary: Retained negative Rho signaling entails this broader intracellular-signaling term. 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. |
| GO:1903444 negative regulation of brown fat cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: PMID:27913603 supports contextual adipose-program regulation in mouse Flcn perturbation and Tfe3 codeletion experiments involving PGC1beta. 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. Supporting Evidence: PMID:27913603 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. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:1903444 negative regulation of brown fat cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: PMID:27913603 supports contextual adipose-program regulation in mouse Flcn perturbation and Tfe3 codeletion experiments involving PGC1beta. 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. Supporting Evidence: PMID:27913603 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. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:1904263 positive regulation of TORC1 signaling | IBA GO_REF:0000033 | ACCEPT | Summary: The exact positive TORC1 IBD at PTN002833743 lies on the human target lineage and includes legitimate human experimental evidence together with yeast sources. 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. Supporting Evidence: PMID:32612235 Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation PMID:37079666 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 PMID:34597140 This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:1904263 positive regulation of TORC1 signaling | IDA PMID:32612235 A substrate-specific mTORC1 pathway underlies Birt-Hogg-DubΓ©... | ACCEPT | Summary: PMID:32612235 shows human FLCN-loss and Rag-mutant bypass effects on TFEB phosphorylation and a TFEB-dependent renal phenotype in mice. 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. Supporting Evidence: PMID:32612235 Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation PMID:37079666 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 PMID:34597140 This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:1904263 positive regulation of TORC1 signaling | IDA PMID:34597140 GABARAP sequesters the FLCN-FNIP tumor suppressor complex to... | ACCEPT | Summary: PMID:34597140 links GABARAP-dependent sequestration of the FLCN-FNIP complex to TFEB regulation. 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. Supporting Evidence: PMID:32612235 Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation PMID:37079666 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 PMID:34597140 This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:1904263 positive regulation of TORC1 signaling | IDA PMID:36103527 Structural basis for FLCN RagC GAP activation in MiT-TFE sub... | ACCEPT | Summary: PMID:36103527 connects the structurally resolved active FLCN-FNIP2/Rag complex to MiT/TFE-directed TORC1 regulation. 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. Supporting Evidence: PMID:32612235 Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation PMID:37079666 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 PMID:34597140 This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:1904263 positive regulation of TORC1 signaling | IDA PMID:37079666 Induction of lysosomal and mitochondrial biogenesis by AMPK ... | ACCEPT | Summary: PMID:37079666 establishes AMPK phosphorylation of FNIP1 and regulation of the FLCN-dependent TFEB pathway. 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. Supporting Evidence: PMID:32612235 Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation PMID:37079666 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 PMID:34597140 This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:1904263 positive regulation of TORC1 signaling | IDA PMID:39423796 A TBK1-independent primordial function of STING in lysosomal... | ACCEPT | Summary: PMID:39423796 contains actual STING/GABARAP and GDP-RagC bypass experiments that support the established FLCN pathway contribution to TORC1-TFEB control. 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. Supporting Evidence: PMID:32612235 Importantly, expression of active RagCS75L or RagDS77L mutants in FLCN KO cells rescued TFEB phosphorylation PMID:37079666 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 PMID:34597140 This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. file:human/FLCN/FLCN-source-evidence.yaml |
| GO:1905672 negative regulation of lysosome organization | IDA PMID:34597140 GABARAP sequesters the FLCN-FNIP tumor suppressor complex to... | KEEP AS NON CORE | Summary: PMID:34597140 links GABARAP-dependent sequestration of the FLCN complex to TFEB and the lysosomal program. 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. Supporting Evidence: PMID:34597140 This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. PMID:39423796 GABARAP lipidation is known to inhibit the FLCN-FNIP-RagC/D axis, thus blocking mTORC1-mediated TFEB phosphorylation PMID:37079666 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 file:human/FLCN/FLCN-source-evidence.yaml |
| GO:1905672 negative regulation of lysosome organization | IDA PMID:37079666 Induction of lysosomal and mitochondrial biogenesis by AMPK ... | KEEP AS NON CORE | Summary: PMID:37079666 links AMPK-FNIP1 regulation of FLCN and TFEB to the lysosomal program. 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. Supporting Evidence: PMID:34597140 This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. PMID:39423796 GABARAP lipidation is known to inhibit the FLCN-FNIP-RagC/D axis, thus blocking mTORC1-mediated TFEB phosphorylation PMID:37079666 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 file:human/FLCN/FLCN-source-evidence.yaml |
| GO:1905672 negative regulation of lysosome organization | IDA PMID:39423796 A TBK1-independent primordial function of STING in lysosomal... | KEEP AS NON CORE | Summary: PMID:39423796 supports STING/GABARAP/RagC-dependent control of the lysosomal program within the established FLCN pathway. 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. Supporting Evidence: PMID:34597140 This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. PMID:39423796 GABARAP lipidation is known to inhibit the FLCN-FNIP-RagC/D axis, thus blocking mTORC1-mediated TFEB phosphorylation PMID:37079666 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 file:human/FLCN/FLCN-source-evidence.yaml |
| GO:1990877 FNIP-folliculin RagC/D GAP | IBA GO_REF:0000033 | ACCEPT | Summary: The exact complex-membership IBD at PTN002833743 lies on the human target path and has yeast and human experimental grounding. 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. Supporting Evidence: PMID:17028174 Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5' AMP-activated protein kinase (AMPK) PMID:18403135 C-terminally-deleted FLCN mutants, similar to those produced by naturally-occurring germline mutations in BHD patients, were unable to bind FNIP2. PMID:36103527 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) file:human/FLCN/FLCN-source-evidence.yaml |
| GO:1990877 FNIP-folliculin RagC/D GAP | IDA PMID:32612235 A substrate-specific mTORC1 pathway underlies Birt-Hogg-DubΓ©... | ACCEPT | Summary: Retain established FLCN-FNIP complex membership with the original PMID:32612235 cellular pathway context. 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. Supporting Evidence: PMID:17028174 Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5' AMP-activated protein kinase (AMPK) PMID:18403135 C-terminally-deleted FLCN mutants, similar to those produced by naturally-occurring germline mutations in BHD patients, were unable to bind FNIP2. PMID:36103527 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) file:human/FLCN/FLCN-source-evidence.yaml |
| GO:1990877 FNIP-folliculin RagC/D GAP | IDA PMID:36103527 Structural basis for FLCN RagC GAP activation in MiT-TFE sub... | ACCEPT | Summary: PMID:36103527 directly resolves the FLCN-FNIP2 catalytic complex using specified engineered constructs. 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. Supporting Evidence: PMID:17028174 Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5' AMP-activated protein kinase (AMPK) PMID:18403135 C-terminally-deleted FLCN mutants, similar to those produced by naturally-occurring germline mutations in BHD patients, were unable to bind FNIP2. PMID:36103527 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) file:human/FLCN/FLCN-source-evidence.yaml |
| GO:1990877 FNIP-folliculin RagC/D GAP | IPI PMID:17028174 Folliculin encoded by the BHD gene interacts with a binding ... | ACCEPT | Summary: PMID:17028174 establishes FLCN-FNIP1 association, supporting core complex membership. 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. Supporting Evidence: PMID:17028174 Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5' AMP-activated protein kinase (AMPK) PMID:18403135 C-terminally-deleted FLCN mutants, similar to those produced by naturally-occurring germline mutations in BHD patients, were unable to bind FNIP2. PMID:36103527 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) file:human/FLCN/FLCN-source-evidence.yaml |
| GO:1990877 FNIP-folliculin RagC/D GAP | IPI PMID:18403135 Identification and characterization of a novel folliculin-in... | ACCEPT | Summary: PMID:18403135 establishes FLCN-FNIP2 association, supporting core complex membership. 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. Supporting Evidence: PMID:17028174 Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5' AMP-activated protein kinase (AMPK) PMID:18403135 C-terminally-deleted FLCN mutants, similar to those produced by naturally-occurring germline mutations in BHD patients, were unable to bind FNIP2. PMID:36103527 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) file:human/FLCN/FLCN-source-evidence.yaml |
| GO:2000973 regulation of pro-B cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Adult conditional Flcn loss supports a non-core pro-B differentiation regulatory association. 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. Supporting Evidence: PMID:22709692 We also demonstrate that conditional deletion of Flcn recapitulates the pro-B cell arrest of Fnip1(-/-) mice. file:human/FLCN/FLCN-source-evidence.yaml |
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Download this section (compressed HTML)Q: How broadly does the directly measured LDHA-inhibitory activity operate at endogenous FLCN:LDHA stoichiometry, independently of FNIP1/2 and Rag signaling?
Q: Which FLCN-dependent developmental and B-cell phenotypes reflect lineage-autonomous differentiation, survival or intercellular signals, and which mechanisms are conserved in humans?
Q: What is the chemistry of the unidentified higher-mass TFE3 modification suppressed by FLCN, distinct from the phosphorylation promoted by FLCN?
Q: 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.
Q: Under which conditions does endogenous FLCN occupy a nuclear pool, and does that pool have an activity distinct from cytosolic/lysosomal signaling?
Experiment: 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.
Hypothesis: LDHA inhibition and RagC/D GAP activity are separable molecular capacities.
Type: structure-function rescue
Experiment: Combine lineage-restricted Flcn deletion with survival measurements, differentiation trajectories and matched restoration, testing TFEB/TFE3 dependence separately in each tissue.
Hypothesis: Distinct survival and differentiation mechanisms contribute to the contextual developmental phenotypes.
Type: conditional genetics and rescue
Experiment: Express sequence-verified natural FLCN products individually at matched levels and assay FNIP assembly, RagC/D turnover, LDHA inhibition and localization.
Hypothesis: Truncation and alternative sequence segments alter functions independently rather than retaining all canonical activities.
Type: product-resolved functional comparison
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