id: A0A8C4MM62
gene_symbol: FLCN
taxon:
  id: NCBITaxon:9793
  label: Equus asinus
status: COMPLETE
description: Assessment of 5 ProtNLM2 GO predictions for donkey folliculin (A0A8C4MM62), a full-length
  ortholog of human FLCN (94.64% identity, same PANTHER subfamily PTHR31441:SF2, catalytic Arg-164 conserved)
  whose core function is RagC/RagD GAP activity with FNIP1/2, driving mTORC1 phosphorylation of TFEB and
  TFE3. One prediction is correct and absent from the donkey GOA record (enzyme inhibitor activity, from
  direct LDHA inhibition by human FLCN). Two are incorrect because they restate knockout phenotypes as
  participation in a process (in utero embryonic development, cell-cell junction assembly), the same grounds
  on which the human FLCN review marks these terms over-annotated. Two are uncertain because FLCN acts upstream
  of them only indirectly or through a generic consequence of its specific mTORC1 role (transforming growth
  factor beta receptor signalling pathway, positive regulation of protein phosphorylation). ProtNLM2 emitted
  no non-GO function-text or subcellular-location output for this accession in the frozen snapshot.
source_documents:
- genes/EQUAS/FLCN/FLCN-uniprot.txt
- genes/EQUAS/FLCN/FLCN-goa.tsv
- genes/EQUAS/FLCN/FLCN-ai-review.yaml
- genes/human/FLCN/FLCN-ai-review.yaml
- genes/EQUAS/FLCN/FLCN-bioinformatics/human_Q8NFG4-uniprot.txt
- genes/EQUAS/FLCN/FLCN-bioinformatics/mouse_Q8QZS3-uniprot.txt
- genes/EQUAS/FLCN/FLCN-bioinformatics/RESULTS.md
- projects/PROTNLM_EVALUATION/donkey40/donkey40-predictions.tsv
predictions:
- source_method: ProtNLM2
  source_version: UniProt API snapshot 2026-10-14
  predicted_term:
    id: GO:0007179
    label: transforming growth factor beta receptor signaling pathway
  predicted_term_type: GO_BP
  review:
    assessment: UNC
    confidence_score: 1
    summary: The experimental evidence (Bhd-null mouse cells and a FLCN-null human renal cancer line) shows
      that FLCN loss reduces TGF-beta-dependent transcription and alters expression of TGF-beta pathway genes,
      which supports at most regulation of the pathway, not participation in it. FLCN is a cytoplasmic and
      lysosomal Rag GAP with no reported role as a component of TGF-beta receptor signalling, and the effect
      is thought to be indirect, via TFE3/TFEB deregulation. The donkey GOA record carries positive regulation
      of TGF-beta receptor signalling, which the donkey review leaves UNDECIDED and the human review keeps
      as non-core; regulation of a pathway is not an is_a child of the pathway, so the prediction is not
      a less precise form of that term. The evidence neither establishes nor refutes direct involvement.
    supported_by:
    - reference_id: PMID:21258407
      supporting_text: results instead from reduced Bim transcription associated with a
        general loss of TGFβ-mediated transcription and chromatin modifications
    - reference_id: PMID:20573232
      supporting_text: We identified genes that were differentially expressed in the cell lines with or
        without wild-type FLCN, many of which are involved in TGF-beta signaling
- source_method: ProtNLM2
  source_version: UniProt API snapshot 2026-10-14
  predicted_term:
    id: GO:0004857
    label: enzyme inhibitor activity
  predicted_term_type: GO_MF
  review:
    assessment: COR
    confidence_score: 2
    summary: Human FLCN binds lactate dehydrogenase A directly and acts as an uncompetitive inhibitor (PMID:34381247,
      human IDA to this term; the human review prefers the more specific child L-lactate dehydrogenase inhibitor
      activity, GO:0160193, and treats it as non-core). The donkey protein is a full-length ortholog in the
      same PANTHER subfamily at 94.64% identity, and the term is absent from the donkey GOA record, which
      carries only GTPase activator activity as MF. The finding comes from a single laboratory and the inhibitory
      region was not mapped residue by residue, so the transfer rests on orthology.
    supported_by:
    - reference_id: PMID:34381247
      supporting_text: we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive
        inhibitor of LDHA
    - reference_id: file:EQUAS/FLCN/FLCN-bioinformatics/RESULTS.md
      supporting_text: The donkey sequence A0A8C4MM62 (578 residues) aligns to human Q8NFG4 (579 residues)
        with 94.64% identity across 578 paired residues.
- source_method: ProtNLM2
  source_version: UniProt API snapshot 2026-10-14
  predicted_term:
    id: GO:0001934
    label: positive regulation of protein phosphorylation
  predicted_term_type: GO_BP
  review:
    assessment: UNC
    confidence_score: 1
    summary: FLCN loss abolishes mTORC1 phosphorylation of TFE3 and TFEB while leaving S6K and 4E-BP1 phosphorylation
      intact, because FLCN GAP activity on RagC is needed to recruit these substrates to the lysosome. The
      effect is therefore real but substrate-specific and mediated through mTORC1, and it is already captured
      more informatively by positive regulation of TORC1 signalling (GO:1904263), which the donkey GOA record
      carries and the donkey review accepts. GO:1904263 is not a descendant of GO:0001934 (OLS4 ancestry),
      so the prediction is not simply less precise. Neither human FLCN, FNIP1, RagC nor RagD carries this
      term or its descendants in GOA, indicating that regulators of this pathway are conventionally annotated
      to TORC1 signalling rather than to generic protein phosphorylation. The prediction is defensible but
      uninformative, and cannot be scored as clearly correct or incorrect.
    supported_by:
    - reference_id: PMID:35358174
      supporting_text: loss of the mTORC1 regulator
        folliculin (FLCN) renders mTORC1 specifically incompetent to phosphorylate TFE3
    - reference_id: file:EQUAS/FLCN/FLCN-bioinformatics/human_Q8NFG4-uniprot.txt
      supporting_text: "Acts as a key component for non-\nCC       canonical mTORC1-dependent control of the MiT/TFE factors TFEB and\nCC       TFE3"
- source_method: ProtNLM2
  source_version: UniProt API snapshot 2026-10-14
  predicted_term:
    id: GO:0001701
    label: in utero embryonic development
  predicted_term_type: GO_BP
  review:
    assessment: NPI
    confidence_score: 0
    summary: Homozygous Flcn knockout mice die at 5.5-6.5 dpc, which shows that FLCN is necessary for embryonic
      development, not that it performs a step of it. The human FLCN review marks this term over-annotated
      on exactly these grounds; the mouse source is a phenotype-based IMP and the lethality is most plausibly
      a downstream consequence of unrestrained TFE3 activity. FLCN's activity is Rag GAP-mediated control
      of mTORC1, and no developmental-process mechanism has been shown. The term is absent from the donkey
      GOA record. The prediction converts a knockout phenotype into process participation, so it is scored
      as incorrect.
    supported_by:
    - reference_id: file:EQUAS/FLCN/FLCN-bioinformatics/mouse_Q8QZS3-uniprot.txt
      supporting_text: Embryonic lethality at 5.5-6.5 dpc
- source_method: ProtNLM2
  source_version: UniProt API snapshot 2026-10-14
  predicted_term:
    id: GO:0007043
    label: cell-cell junction assembly
  predicted_term_type: GO_BP
  review:
    assessment: NPI
    confidence_score: 0
    summary: The only experimental basis is a knockdown study in mouse renal collecting-duct cells, in which
      FLCN or p0071 deficiency caused tight junction defects and E-cadherin mislocalization, and FLCN only
      partially co-localized with p0071 at junctions. This shows that FLCN deficiency perturbs junctions,
      not that FLCN participates in junction assembly, and the human FLCN review marks the term over-annotated
      on these grounds. No mechanism linking FLCN Rag GAP activity directly to junction assembly is known.
      The term is absent from the donkey GOA record.
    supported_by:
    - reference_id: PMID:22965878
      supporting_text: Deficiency of folliculin and of p0071 resulted in
        tight junction defects and mislocalization of E-cadherin in mouse inner
        medullary collecting duct-3 renal tubular cells.
    - reference_id: PMID:22965878
      supporting_text: Folliculin and p0071 partially co-localized at cell
        junctions and in mitotic cells
references:
- id: file:EQUAS/FLCN/FLCN-bioinformatics/human_Q8NFG4-uniprot.txt
  title: UniProt Swiss-Prot record for human FLCN (Q8NFG4)
  findings: []
- id: file:EQUAS/FLCN/FLCN-bioinformatics/mouse_Q8QZS3-uniprot.txt
  title: UniProt Swiss-Prot record for mouse Flcn (Q8QZS3)
  findings: []
- id: file:EQUAS/FLCN/FLCN-bioinformatics/RESULTS.md
  title: 'FLCN: donkey-human sequence comparison'
  findings: []
- id: PMID:34381247
  title: The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect.
  findings: []
- id: PMID:21258407
  title: Loss of the Birt-Hogg-Dubé tumor suppressor results in apoptotic resistance due to aberrant TGFβ-mediated
    transcription.
  findings: []
- id: PMID:20573232
  title: Tumor suppressor FLCN inhibits tumorigenesis of a FLCN-null renal cancer cell line and regulates
    expression of key molecules in TGF-beta signaling.
  findings: []
- id: PMID:35358174
  title: Folliculin promotes substrate-selective mTORC1 activity by activating RagC to recruit TFE3.
  findings: []
- id: PMID:22965878
  title: Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA
    signalling, epithelial polarization and cytokinesis.
  findings: []