fem-3

id: Q8I8U6
gene_symbol: fem-3
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:6238
  label: Caenorhabditis briggsae
description: >-
  FEM-3 is a terminal sex-determination regulator that promotes male cell fate in the
  nematode Caenorhabditis briggsae. In XO animals it directs male somatic differentiation
  in all tissues, and in XX hermaphrodites it specifies the early germ cells to adopt the
  sperm fate before the switch to oogenesis. FEM-3 acts together with FEM-1 and FEM-2 as a
  substrate-recognition module of a CUL-2 (Cullin-2) RING E3 ubiquitin-ligase complex that
  ubiquitinates the transcription factor TRA-1 (the Gli-family terminal repressor of male
  development), targeting it for proteasomal degradation; loss of FEM activity leaves TRA-1
  active and feminizes the animal. FEM-3 activity is antagonized upstream by the membrane
  receptor TRA-2, which binds FEM-3 directly to repress its male-promoting function. The
  FEM-3 protein is the most rapidly diverging protein known in Caenorhabditis, and its
  interaction surface with TRA-2 coevolves in a strictly species-specific manner, making
  the gene a notable example of rapid coevolution within a conserved developmental pathway.
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Orthology-based (GO_REF:0000107) transfer from the C. elegans ortholog FEM-1/FEM-3
      complex context. FEM proteins act as the cytoplasmic/peri-nuclear substrate-recognition
      module of the CUL-2 ligase that degrades TRA-1; a cytoplasmic location is consistent with
      this role but is a broad cellular-component term and not the core function.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0007530
    label: sex determination
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Correct but high-level parent of the gene's specific role. The experimentally supported
      and more informative term is male sex determination (GO:0030238)/male somatic sex
      determination (GO:0019102); this general term is retained as non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0008287
    label: protein serine/threonine phosphatase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: >-
      Almost certainly an over-propagated electronic annotation. FEM-2 is the PP2C-type
      protein serine/threonine phosphatase of the FEM module; FEM-3 itself is not a phosphatase
      and there is no evidence it is a structural part of a phosphatase complex. The biologically
      relevant complex for FEM-3 is the CUL-2 RING E3 ubiquitin-ligase complex (GO:0031462). This
      term appears to result from transfer of an interactor's (FEM-2) annotation.
    action: REMOVE
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Over-general and mechanistically indirect. FEM-3 promotes degradation of the TRA-1
      transcriptional repressor, which derepresses male target genes, but FEM-3 is not itself a
      transcriptional regulator; the downstream gene-expression effect is a consequence of
      proteolytic regulation of TRA-1. Best captured by the male sex-determination process terms
      rather than by a generic positive-regulation-of-gene-expression term.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0019102
    label: male somatic sex determination
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Consistent with the orthologous family and independently supported experimentally in
      C. briggsae (see the IMP annotation from PMID:12477393). FEM-3 directs male somatic
      differentiation in all tissues of XO animals. Core process.
    action: ACCEPT
- term:
    id: GO:0019903
    label: protein phosphatase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Reflects the documented physical interaction between FEM-3 and the PP2C phosphatase FEM-2
      within the FEM module (transferred from the C. elegans ortholog). This is a genuine binding
      partner, but the binding is in service of assembling the substrate-recognition module of the
      CUL-2 ligase; it is a supporting molecular interaction rather than the core molecular
      function. Retained as non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0030238
    label: male sex determination
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Accurate and central to FEM-3 function; FEM-3 is a male-promoting (masculinizing) gene whose
      loss feminizes the animal. Supported both by orthology and by the C. briggsae RNAi/epistasis
      data in PMID:12477393. Core process.
    action: ACCEPT
- term:
    id: GO:0031462
    label: Cul2-RING ubiquitin ligase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: >-
      Correct and biologically central. FEM-3 (with FEM-1 and FEM-2) is part of the CUL-2-based
      RING E3 ubiquitin-ligase complex (CUL-2/ELC-1/RBX/FEM-1/FEM-2/FEM-3) that ubiquitinates TRA-1.
      This is the defining complex for the gene's molecular role.
    action: ACCEPT
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: >-
      True but uninformative root-level complex term; subsumed by the specific Cul2-RING ubiquitin
      ligase complex (GO:0031462) annotation. Retained as non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0042006
    label: masculinization of hermaphroditic germ-line
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Strongly supported by the biology: in XX hermaphrodites FEM-3 specifies the first germ cells
      to become sperm (the transient spermatogenic program), a masculinization of the hermaphrodite
      germ line. Consistent with the C. elegans ortholog and with the conserved fem-3 function shown
      in PMID:12477393. Core germline aspect of the male-promoting role.
    action: ACCEPT
- term:
    id: GO:0060282
    label: positive regulation of oocyte development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Directionally wrong, not merely over-general. FEM-3 promotes the sperm fate and is
      antagonistic to oogenesis; gain-of-function fem-3 alleles in C. elegans cause excess sperm and
      failure of the sperm-to-oocyte switch (masculinized germ line), i.e. they suppress, not promote,
      oocyte development. The positive-regulation directionality contradicts FEM-3's established
      germline role and should be removed rather than retained as over-general.
    action: REMOVE
- term:
    id: GO:0071168
    label: protein localization to chromatin
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      No support for a direct chromatin-localization role for FEM-3. FEM-3 acts in the cytoplasm as a
      ubiquitin-ligase substrate-recognition component; any effect on a chromatin-associated factor
      (TRA-1) is via proteolysis, not by mediating its localization to chromatin. Likely an
      over-propagated electronic annotation.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:1904146
    label: positive regulation of meiotic cell cycle process involved in oocyte maturation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Directionally wrong and not supported by FEM-3's established role; FEM-3 promotes
      spermatogenesis and antagonizes oocyte/oogenesis programs rather than positively regulating
      oocyte meiotic maturation. The positive-regulation directionality contradicts FEM-3 biology
      and should be removed.
    action: REMOVE
- term:
    id: GO:1905936
    label: regulation of germ cell proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Not a recognized core function of FEM-3, which acts in germline sex (fate) determination rather
      than in regulating germ cell proliferation per se. Plausibly a peripheral/indirect effect at most;
      treated as non-core given the weak (electronic, orthology-transferred) evidence.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12477393
  qualifier: enables
  review:
    summary: >-
      Experimentally supported physical interaction (IPI; WITH UniProtKB:Q17307, C. briggsae TRA-2):
      Haag et al. showed FEM-3 binds TRA-2 in a strictly species-specific manner. The binding itself is
      real and important, but the bare 'protein binding' term is uninformative. The interaction underlies
      FEM-3's role as a substrate-recognition/adaptor component; the specific function is better expressed
      by the ubiquitin ligase-substrate adaptor activity captured in core_functions.
    action: MARK_AS_OVER_ANNOTATED
    proposed_replacement_terms:
    - id: GO:1990756
      label: ubiquitin ligase-substrate adaptor activity
- term:
    id: GO:0019102
    label: male somatic sex determination
  evidence_type: IMP
  original_reference_id: PMID:12477393
  qualifier: involved_in
  review:
    summary: >-
      Experimentally supported in C. briggsae by RNAi (IMP): Haag et al. used RNA interference to show
      that the male-promoting function of fem-3 and its epistatic relationship with the upstream
      repressor tra-2 are conserved across C. elegans, C. briggsae and C. remanei. This is the strongest,
      species-specific evidence for FEM-3's core role and should be retained.
    action: ACCEPT
- term:
    id: GO:1990756
    label: ubiquitin ligase-substrate adaptor activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Proposed molecular-function annotation capturing FEM-3's role as a substrate-recognition/adaptor
      component of the CUL-2 RING E3 ubiquitin-ligase complex that targets TRA-1 for ubiquitination
      (with FEM-1 and FEM-2). This is the informative MF replacement for the bare 'protein binding' (IPI)
      annotation and is supported by orthology to C. elegans FEM-3 and by the established CUL-2/FEM
      degradation machinery for TRA-1.
    action: NEW
core_functions:
- description: >-
    Substrate-recognition (adaptor) subunit of the FEM module of a CUL-2 RING E3 ubiquitin-ligase
    complex; bridges the male-determination substrate TRA-1 to the ligase for ubiquitination and
    proteasomal degradation, and binds the upstream regulator TRA-2.
  molecular_function:
    id: GO:1990756
    label: ubiquitin ligase-substrate adaptor activity
  supported_by:
  - reference_id: PMID:12477393
    supporting_text: >-
      the FEM-3 protein interacts with TRA-2 in each species, but in a strictly species-specific manner
  in_complex:
    id: GO:0031462
    label: Cul2-RING ubiquitin ligase complex
- description: >-
    Promotes male somatic and germline cell fate; required for male differentiation in XO animals and
    for specification of the early sperm fate in the XX hermaphrodite germ line.
  molecular_function:
    id: GO:1990756
    label: ubiquitin ligase-substrate adaptor activity
  supported_by:
  - reference_id: PMID:12477393
    supporting_text: >-
      the male-promoting function of fem-3 and its epistatic relationship with its female-promoting
      upstream repressor, tra-2, are conserved
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to
    orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: PMID:12477393
  title: Rapid coevolution of the nematode sex-determining genes fem-3 and tra-2.
  findings:
  - statement: >-
      RNAi in C. elegans, C. briggsae and C. remanei shows the male-promoting function of fem-3 and its
      epistatic relationship with the upstream repressor tra-2 are conserved across all three species.
    reference_section_type: ABSTRACT
    supporting_text: >-
      the male-promoting function of fem-3 and its epistatic relationship with its female-promoting
      upstream repressor, tra-2, are conserved
  - statement: >-
      FEM-3 binds TRA-2 directly, but the interaction is strictly species-specific and the FEM-3/TRA-2
      interface is rapidly coevolving.
    reference_section_type: ABSTRACT
    supporting_text: >-
      the FEM-3 protein interacts with TRA-2 in each species, but in a strictly species-specific manner
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified (Haag, Wang, Kimble, Curr Biol 2002). Cached entry is abstract-only; abstract
      directly supports the conserved male-promoting function of C. briggsae fem-3 (IMP) and the
      species-specific FEM-3-TRA-2 interaction (IPI). Provides the experimental basis for the
      male sex-determination and TRA-2-binding annotations.