id: Q8N3Y1
gene_symbol: FBXW8
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXW8 (FBW8, FBX29) is an F-box/WD40-repeat protein that serves as the
  substrate-recognition subunit of a distinctive vertebrate-specific
  cullin-RING ubiquitin ligase. Unlike most F-box proteins, which assemble into
  the canonical SCF (SKP1-CUL1) ligase, FBXW8 is the exclusive F-box partner of
  CUL7, forming the CUL7-RING(FBXW8) (CRL7(FBXW8)) complex composed of CUL7,
  SKP1, RBX1 and FBXW8. Structural and biochemical work shows that CUL7 binds
  FBXW8 through an unusual F-box-independent mode and that, within CRL7(FBXW8),
  the RBX1 RING domain is held in an orientation incompatible with charging
  E2~ubiquitin/E2~NEDD8; the complex therefore lacks intrinsic catalytic
  activity and instead acts as a substrate receptor that couples, via
  SKP1-FBXW8, to a separately neddylated CUL1-RBX1 catalytic module that
  performs ubiquitin transfer. As an adaptor, FBXW8 selects substrates for
  polyubiquitination and proteasomal degradation. Documented substrates include
  insulin receptor substrate 1 (IRS1), recognized after S6-kinase
  phosphorylation in an mTOR-dependent manner (linking FBXW8 to insulin/IGF-1
  signaling and cellular senescence); the Golgi stacking protein
  GORASP1/GRASP65, whose degradation, together with the scaffold OBSL1 that
  localizes CUL7(FBXW8) to the Golgi, controls Golgi morphology and dendrite
  patterning in neurons; the Ste20-family kinase MAP4K1/HPK1, recognized when
  autophosphorylated; phosphorylated cyclin D1 (CCND1), recognized after
  ERK/MAPK-dependent Thr286 phosphorylation and degraded in the cytoplasm during
  S phase; the chromatin-associated MRFAP1, degraded around anaphase-telophase;
  and adipose triglyceride lipase (ATGL/PNPLA2), K48-polyubiquitinated by a
  Golgi-localized CUL7-FBXW8 complex to restrain lipolysis. FBXW8 carries a
  polybasic N-terminal region that binds Golgi phosphatidylinositol 4-phosphate
  (PtdIns4P), coupling intracellular glucose status to recruitment of the
  CUL7-FBXW8 ligase to the Golgi. FBXW8 is also an
  associated component of the CUL7-OBSL1-CCDC8 "3M complex" implicated in
  microtubule and genome integrity and growth (3M syndrome), and is required in
  mouse models for placental development and fetal growth. FBXW8 is a
  cytoplasmic protein that also localizes to the perinuclear region and Golgi
  apparatus.
alternative_products:
- name: '1'
  id: Q8N3Y1-1
- name: '2'
  id: Q8N3Y1-2
  sequence_note: VSP_008501
existing_annotations:
- term:
    id: GO:0060271
    label: cilium assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) assignment of cilium assembly involvement, inferred from the FBXW family. Human FBXW8 has no direct experimental evidence for ciliogenesis (that role is documented for its paralog FBXW5 via kinesin-13 degradation).
    action: KEEP_AS_NON_CORE
    reason: Plausible family-level inference but unsupported by direct human FBXW8 evidence; the well-characterized functions are CUL7-dependent degradation of IRS1, GORASP1, HPK1 and cyclin D1.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Substrate-recognition component of the Cul7-RING(FBXW8) ubiquitin ligase complex
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of protein ubiquitination, the general process FBXW8 participates in as a substrate-recognition adaptor of CRL7(FBXW8).
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the SCF/CUL7-dependent proteasomal catabolic process annotations are more specific.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: mediates the ubiquitination and subsequent proteasomal degradation of target proteins
- term:
    id: GO:0031467
    label: Cul7-RING ubiquitin ligase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic assignment of CUL7-RING complex membership, the core complex for FBXW8 as the exclusive F-box partner of CUL7.
    action: ACCEPT
    reason: Core complex; FBXW8 is the substrate-recognition subunit of CRL7(FBXW8), supported by IDA and structural evidence.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Component of the Cul7-RING(FBXW8) complex consisting of CUL7, RBX1, SKP1 and FBXW8
- term:
    id: GO:0005814
    label: centriole
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) assignment of centriolar localization/activity, inferred from family members. Human FBXW8 evidence places it in cytoplasm/perinuclear/Golgi; CUL7 (its partner) has reported centrosomal localization within the 3M complex.
    action: KEEP_AS_NON_CORE
    reason: Family-level inference; centrosomal association is documented for the CUL7-OBSL1-CCDC8 3M complex but direct FBXW8 centriolar activity is not established in human.
    supported_by:
    - reference_id: PMID:24793695
      supporting_text: regulate the level and centrosomal localization of CUL7
- term:
    id: GO:0036064
    label: ciliary basal body
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic assignment of ciliary basal body activity, inferred from the family. Not directly supported for human FBXW8.
    action: KEEP_AS_NON_CORE
    reason: Family-level inference without direct human FBXW8 evidence; documented FBXW8 localizations are cytoplasm, perinuclear region and Golgi.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, perinuclear region {ECO:0000269|PubMed:21572988}.'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic assignment of cytoplasmic localization, consistent with the experimentally documented cytoplasmic localization of FBXW8.
    action: ACCEPT
    reason: Correct core localization with experimental support.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:17205132}.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of Golgi localization from UniProt subcellular location, consistent with the experimentally documented Golgi localization where FBXW8 (CUL7) controls Golgi morphology.
    action: ACCEPT
    reason: Correct localization; CUL7(FBXW8) localizes to the Golgi complex and regulates Golgi morphology, supported by IDA.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Golgi apparatus {ECO:0000269|PubMed:21572988}.
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of perinuclear localization from UniProt subcellular location, consistent with documented perinuclear/Golgi localization.
    action: ACCEPT
    reason: Correct localization with experimental support.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, perinuclear region {ECO:0000269|PubMed:21572988}.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15070733
  qualifier: enables
  review:
    summary: IntAct interaction with SKP1 (P63208), the adaptor linking FBXW8 into the CRL7 complex. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the FBXW8-SKP1 interaction but bare protein binding is uninformative; complex membership is captured by the CUL7-RING/SCF complex annotations.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: 'Q8N3Y1; P63208: SKP1; NbExp=6; IntAct=EBI-914770, EBI-307486'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17314511
  qualifier: enables
  review:
    summary: TAP/MudPIT interaction capturing FBXW8 association with MYC (P01106). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: 'Q8N3Y1; P01106: MYC; NbExp=3; IntAct=EBI-914770, EBI-447544'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27705803
  qualifier: enables
  review:
    summary: Polycomb complexome AP-MS map capturing an FBXW8 interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: 'Q8N3Y1; P63208: SKP1; NbExp=6; IntAct=EBI-914770, EBI-307486'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Cell-specific interactome capturing an FBXW8 interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: 'Q8N3Y1; P63208: SKP1; NbExp=6; IntAct=EBI-914770, EBI-307486'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-map study capturing an FBXW8 interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: 'Q8N3Y1; P63208: SKP1; NbExp=6; IntAct=EBI-914770, EBI-307486'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Ortholog-based assignment of cytosolic site of action, consistent with the documented cytosolic localization (phospho-Ser85-dependent for IRS1 ubiquitination).
    action: ACCEPT
    reason: Correct localization; FBXW8 acts in the cytosol/cytoplasm, consistent with experimental evidence.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Note=Localizes to the cytosol when phosphorylated at Ser-85, promoting IRS1 ubiquitination.
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based assignment of ubiquitin-dependent catabolism, the core biological process for FBXW8 as a substrate receptor directing targets to degradation.
    action: ACCEPT
    reason: Correct core biological process; FBXW8 directs substrates (IRS1, cyclin D1, HPK1) to ubiquitin-dependent degradation. The more specific proteasome-mediated/SCF-dependent catabolic process annotations are also present.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: mediates the ubiquitination and subsequent proteasomal degradation of target proteins
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Combined automated assignment of protein ubiquitination, redundant with the IBA/IDA ubiquitination annotations.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; redundant with more specific catabolic-process annotations.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: Ortholog-based assignment of SCF complex membership. FBXW8's defining complex is CRL7(FBXW8)/CUL7-RING; however, structural data show its catalytic coupling occurs via SKP1-FBXW8 to a CUL1-RBX1 module, so an SCF/CUL1 association is justified.
    action: KEEP_AS_NON_CORE
    reason: The primary, well-defined complex is CUL7-RING(FBXW8); SCF/CUL1 membership reflects the catalytic-coupling partnership rather than the canonical receptor assembly.
    supported_by:
    - reference_id: PMID:35982156
      supporting_text: CRL7 serves as a substrate receptor linked via SKP1-FBXW8 to a neddylated CUL1-RBX1 catalytic module mediating ubiquitination
- term:
    id: GO:0031467
    label: Cul7-RING ubiquitin ligase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: Ortholog-based assignment of CUL7-RING complex membership, the defining core complex of FBXW8.
    action: ACCEPT
    reason: Core complex; redundant with IDA and structural evidence.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Component of the Cul7-RING(FBXW8) complex consisting of CUL7, RBX1, SKP1 and FBXW8
- term:
    id: GO:0032436
    label: positive regulation of proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based assignment of positive regulation of proteasomal catabolism, consistent with FBXW8 driving substrate degradation. Somewhat redundant with the direct catabolic-process annotations.
    action: KEEP_AS_NON_CORE
    reason: Correct in spirit (FBXW8 promotes substrate degradation) but the direct proteasome-mediated catabolic process annotations are more accurate; FBXW8 directly mediates rather than regulates degradation.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: mediates the ubiquitination and subsequent proteasomal degradation of target proteins
- term:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ortholog-based assignment of substrate-adaptor activity, the core molecular function of FBXW8 as the substrate-recognition subunit of CRL7(FBXW8).
    action: ACCEPT
    reason: Core molecular function; FBXW8 is the substrate-specific adaptor that recognizes IRS1, GORASP1, HPK1 and cyclin D1, supported by IDA.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Substrate-recognition component of the Cul7-RING(FBXW8) ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence (HPA) evidence for cytosolic localization, consistent with the documented cytoplasmic/cytosolic localization.
    action: ACCEPT
    reason: Correct localization with direct experimental support.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:17205132}.
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:35982156
  qualifier: part_of
  review:
    summary: ComplexPortal/NAS assertion of SCF complex membership, reflecting the structural finding that CRL7(FBXW8) couples via SKP1-FBXW8 to a CUL1-RBX1 catalytic module. FBXW8 binds CUL1 through its F-box/SKP1 and CUL7 through F-box-independent regions, bridging a multi-cullin Rbx1-Cul1-Skp1-Fbxw8-Cul7-Rbx1 assembly.
    action: KEEP_AS_NON_CORE
    reason: Justified by the catalytic-coupling partnership with CUL1-RBX1 but the primary receptor complex is CUL7-RING(FBXW8). FBXW8 is the substrate receptor; ubiquitin transfer is catalyzed by the neddylated CUL1-RBX1 module, consistent with the adaptor (not catalytic) nature of F-box proteins.
    supported_by:
    - reference_id: PMID:35982156
      supporting_text: CRL7 serves as a substrate receptor linked via SKP1-FBXW8 to a neddylated CUL1-RBX1 catalytic module mediating ubiquitination
    - reference_id: file:human/FBXW8/FBXW8-deep-research-falcon.md
      supporting_text: CUL7 binds FBXW8 in an F-box-independent mode; CRL7^FBXW8 alone lacks auto-neddylation/ubiquitination activity; catalytic coupling occurs to CUL1-RBX1
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:35982156
  qualifier: involved_in
  review:
    summary: ComplexPortal/NAS assertion of SCF-dependent proteasomal catabolism, consistent with FBXW8 directing substrates to degradation through a CUL1-coupled catalytic module.
    action: ACCEPT
    reason: Core biological process; FBXW8 directs substrates to proteasomal degradation, with ubiquitin transfer catalyzed via a coupled CUL1-RBX1 module.
    supported_by:
    - reference_id: PMID:35982156
      supporting_text: CRL7 serves as a substrate receptor linked via SKP1-FBXW8 to a neddylated CUL1-RBX1 catalytic module mediating ubiquitination
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:18498745
  qualifier: is_active_in
  review:
    summary: Direct evidence that FBXW8 (CUL7 complex) acts in the cytoplasm to target IRS1 for degradation.
    action: ACCEPT
    reason: Correct cytoplasmic site of action with direct experimental support.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:17205132}.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:17205132
  qualifier: is_active_in
  review:
    summary: Direct evidence that the majority of FBXW8 is expressed in the cytoplasm where it mediates cyclin D1 degradation.
    action: ACCEPT
    reason: Correct cytoplasmic site of action with direct experimental support.
    supported_by:
    - reference_id: PMID:17205132
      supporting_text: The majority of FBXW8 is expressed in the cytoplasm during G1 and S phase
- term:
    id: GO:0031467
    label: Cul7-RING ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:17205132
  qualifier: part_of
  review:
    summary: Direct evidence that FBXW8 is a component of the CUL7-RING E3 ligase that ubiquitinates cyclin D1. Core complex.
    action: ACCEPT
    reason: Core complex membership with direct experimental support.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Component of the Cul7-RING(FBXW8) complex consisting of CUL7, RBX1, SKP1 and FBXW8
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:17205132
  qualifier: involved_in
  review:
    summary: Direct evidence that FBXW8 mediates cyclin D1 degradation via the proteasome. Core biological process.
    action: ACCEPT
    reason: Core biological process with direct experimental support.
    supported_by:
    - reference_id: PMID:17205132
      supporting_text: This is mediated by phosphorylation at Thr286 through the activity of the Ras/Raf/MEK/ERK cascade and the F-box protein FBXW8, which is an E3 ligase
- term:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:17205132
  qualifier: enables
  review:
    summary: Direct evidence that FBXW8 functions as the substrate-recognition adaptor for cyclin D1. Core molecular function.
    action: ACCEPT
    reason: Core molecular function with direct experimental support.
    supported_by:
    - reference_id: PMID:17205132
      supporting_text: Increased cyclin D1 degradation is linked to association with FBXW8 in the cytoplasm
- term:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:24362026
  qualifier: enables
  review:
    summary: Direct evidence that FBXW8 recognizes and binds autophosphorylated MAP4K1/HPK1 as a substrate adaptor. Core molecular function.
    action: ACCEPT
    reason: Core molecular function with direct experimental support.
    supported_by:
    - reference_id: PMID:24362026
      supporting_text: We found that the CUL7/Fbxw8 ubiquitin ligase targeted HPK1 for degradation via the 26 S proteasome. The ubiquitination of HPK1 required its kinase activity and autophosphorylation
- term:
    id: GO:0046627
    label: negative regulation of insulin receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:18498745
  qualifier: involved_in
  review:
    summary: Direct evidence that FBXW8 (CUL7 complex) degrades IRS1, negatively regulating insulin/IGF-1 signaling.
    action: ACCEPT
    reason: Supported core biological role; CUL7(FBXW8) targets IRS1 for degradation, dampening downstream AKT/MEK-ERK signaling.
    supported_by:
    - reference_id: PMID:18498745
      supporting_text: we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:18498745
  qualifier: is_active_in
  review:
    summary: Direct evidence that FBXW8 acts in the cytosol for IRS1 ubiquitination.
    action: ACCEPT
    reason: Correct cytosolic site of action with direct experimental support.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Note=Localizes to the cytosol when phosphorylated at Ser-85, promoting IRS1 ubiquitination.
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:18498745
  qualifier: involved_in
  review:
    summary: Direct evidence that FBXW8 (CUL7 complex) targets IRS1 for ubiquitin-dependent degradation. Core biological process.
    action: ACCEPT
    reason: Core biological process with direct experimental support.
    supported_by:
    - reference_id: PMID:18498745
      supporting_text: a key role for the CUL7 E3 in targeting IRS-1 for degradation
- term:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:18498745
  qualifier: enables
  review:
    summary: Direct evidence that FBXW8 is the substrate-targeting subunit recognizing IRS1. Core molecular function.
    action: ACCEPT
    reason: Core molecular function with direct experimental support.
    supported_by:
    - reference_id: PMID:18498745
      supporting_text: the Cullin 7 (CUL7) E3 ubiquitin ligase complex containing the Fbw8-substrate-targeting subunit
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18498745
  qualifier: enables
  review:
    summary: IntAct interaction(s) from the IRS1 degradation study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real complex/substrate interactions but bare protein binding is uninformative; substrate relationship captured by the catabolic-process annotations.
    supported_by:
    - reference_id: PMID:18498745
      supporting_text: the Cullin 7 (CUL7) E3 ubiquitin ligase complex containing the Fbw8-substrate-targeting subunit
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24362026
  qualifier: enables
  review:
    summary: IntAct interaction with MAP4K1/HPK1 from the HPK1 degradation study; a real substrate interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally meaningful FBXW8-HPK1 substrate interaction but bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:24362026
      supporting_text: Wild-type protein phosphatase 4 (PP4), but not the phosphatase-dead PP4 mutant, PP4-RL, inhibits the interaction of Fbxw8 with HPK1
- term:
    id: GO:0008283
    label: cell population proliferation
  evidence_type: IDA
  original_reference_id: PMID:24362026
  qualifier: involved_in
  review:
    summary: Evidence that FBXW8-mediated HPK1 degradation promotes pancreatic cancer cell proliferation.
    action: KEEP_AS_NON_CORE
    reason: A downstream physiological consequence of FBXW8 substrate degradation rather than a core molecular/biological function; relevant to cancer biology.
    supported_by:
    - reference_id: PMID:24362026
      supporting_text: CUL7/Fbxw8 ubiquitin ligase promotes pancreatic cancer cell proliferation
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:24362026
  qualifier: involved_in
  review:
    summary: Direct evidence that FBXW8 promotes ubiquitination of HPK1. The general ubiquitination process.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the proteasome-mediated catabolic process annotation is more specific.
    supported_by:
    - reference_id: PMID:24362026
      supporting_text: We found that the CUL7/Fbxw8 ubiquitin ligase targeted HPK1 for degradation via the 26 S proteasome
- term:
    id: GO:0031467
    label: Cul7-RING ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:18498745
  qualifier: part_of
  review:
    summary: Direct evidence that FBXW8 is a component of the CUL7-RING ligase targeting IRS1. Core complex.
    action: ACCEPT
    reason: Core complex membership with direct experimental support.
    supported_by:
    - reference_id: PMID:18498745
      supporting_text: the Cullin 7 (CUL7) E3 ubiquitin ligase complex containing the Fbw8-substrate-targeting subunit, Skp1, and the ROC1 RING finger protein
- term:
    id: GO:0031467
    label: Cul7-RING ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:24362026
  qualifier: part_of
  review:
    summary: Direct evidence that FBXW8 is a component of the CUL7-RING ligase targeting HPK1. Core complex.
    action: ACCEPT
    reason: Core complex membership with direct experimental support.
    supported_by:
    - reference_id: PMID:24362026
      supporting_text: We found that the CUL7/Fbxw8 ubiquitin ligase targeted HPK1 for degradation via the 26 S proteasome
- term:
    id: GO:1990393
    label: 3M complex
  evidence_type: IDA
  original_reference_id: PMID:24793695
  qualifier: colocalizes_with
  review:
    summary: Evidence that FBXW8 is an associated component of the CUL7-OBSL1-CCDC8 3M complex implicated in microtubule and genome integrity.
    action: ACCEPT
    reason: Supported; FBXW8 associates with the 3M complex (via CUL7), which functions in microtubule/genome integrity and growth (3M syndrome).
    supported_by:
    - reference_id: PMID:24793695
      supporting_text: CUL7, OBSL1, and CCDC8 proteins form a 3M complex that functions in maintaining microtubule and genome integrity and normal development
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21572988
  qualifier: enables
  review:
    summary: IntAct interactions from the OBSL1-CUL7(FBXW8) Golgi/dendrite study (e.g. OBSL1, GORASP1). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real complex/substrate interactions (OBSL1, GORASP1) but bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:21572988
      supporting_text: OBSL1 forms a physical complex with the scaffold protein Cul7 and thereby localizes Cul7 at the Golgi apparatus
- term:
    id: GO:0007030
    label: Golgi organization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity transfer of Golgi organization involvement, supported directly in human by the OBSL1-CUL7(FBXW8)/GORASP1 study.
    action: ACCEPT
    reason: Supported core role; CUL7(FBXW8) regulates Golgi morphology via GORASP1 degradation (also IGI-supported in PMID:21572988).
    supported_by:
    - reference_id: PMID:21572988
      supporting_text: Inhibition of Cul7(Fbxw8) also dramatically impairs the morphology of the Golgi complex, leading to deficient secretory trafficking in neurons
- term:
    id: GO:0007030
    label: Golgi organization
  evidence_type: IGI
  original_reference_id: PMID:21572988
  qualifier: involved_in
  review:
    summary: Genetic-interaction evidence (with OBSL1/GORASP1) that CUL7(FBXW8) controls Golgi morphology. Core biological role.
    action: ACCEPT
    reason: Supported core biological role with genetic-interaction evidence.
    supported_by:
    - reference_id: PMID:21572988
      supporting_text: Inhibition of Cul7(Fbxw8) also dramatically impairs the morphology of the Golgi complex, leading to deficient secretory trafficking in neurons
- term:
    id: GO:0050775
    label: positive regulation of dendrite morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity transfer of positive regulation of dendrite morphogenesis, supported directly in human/rat by the CUL7(FBXW8) neuronal study.
    action: ACCEPT
    reason: Supported core role in neurons; CUL7(FBXW8) is selectively required for dendrite growth and elaboration.
    supported_by:
    - reference_id: PMID:21572988
      supporting_text: Cul7(Fbxw8) is selectively required for the growth and elaboration of dendrites but not axons in primary neurons and in the developing rat cerebellum in vivo
- term:
    id: GO:0050775
    label: positive regulation of dendrite morphogenesis
  evidence_type: IDA
  original_reference_id: PMID:21572988
  qualifier: involved_in
  review:
    summary: Direct evidence that CUL7(FBXW8) promotes dendrite growth and elaboration in neurons.
    action: ACCEPT
    reason: Supported core role in neuronal morphogenesis with direct experimental support.
    supported_by:
    - reference_id: PMID:21572988
      supporting_text: Cul7(Fbxw8) is selectively required for the growth and elaboration of dendrites but not axons in primary neurons and in the developing rat cerebellum in vivo
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:21572988
  qualifier: located_in
  review:
    summary: Direct evidence that CUL7(FBXW8) localizes to the Golgi complex in brain neurons.
    action: ACCEPT
    reason: Correct localization with direct experimental support.
    supported_by:
    - reference_id: PMID:21572988
      supporting_text: the E3 ubiquitin ligase Cul7(Fbxw8) localizes to the Golgi complex in mammalian brain neurons
- term:
    id: GO:0031467
    label: Cul7-RING ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:21572988
  qualifier: part_of
  review:
    summary: Direct evidence that FBXW8 is a component of the CUL7-RING ligase in the Golgi/dendrite study. Core complex.
    action: ACCEPT
    reason: Core complex membership with direct experimental support.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Component of the Cul7-RING(FBXW8) complex consisting of CUL7, RBX1, SKP1 and FBXW8
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:21572988
  qualifier: located_in
  review:
    summary: Direct evidence for perinuclear/Golgi localization of CUL7(FBXW8) in neurons.
    action: ACCEPT
    reason: Correct localization with direct experimental support.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, perinuclear region {ECO:0000269|PubMed:21572988}.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952618
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization within CRL neddylation reactions. Consistent with documented cytoplasmic localization.
    action: ACCEPT
    reason: Correct localization, consistent with experimental evidence; CRL-cycle Reactome events are pathway-context annotations.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:17205132}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952620
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization within CRL neddylation reactions. Consistent with documented cytoplasmic localization.
    action: ACCEPT
    reason: Correct localization, redundant with other localization annotations.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:17205132}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955241
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (CAND1 binding to CRL). Consistent with documented cytoplasmic localization.
    action: ACCEPT
    reason: Correct localization, redundant with other localization annotations.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:17205132}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955289
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (COMMD-CAND1 displacement). Consistent with documented cytoplasmic localization.
    action: ACCEPT
    reason: Correct localization, redundant with other localization annotations.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:17205132}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956040
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (COP9 signalosome deneddylation). Consistent with documented cytoplasmic localization.
    action: ACCEPT
    reason: Correct localization, redundant with other localization annotations.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:17205132}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956200
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (DCUN1D3 binding to CRL1). Consistent with documented cytoplasmic localization.
    action: ACCEPT
    reason: Correct localization, redundant with other localization annotations.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:17205132}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983140
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (Ub transfer to substrate). Consistent with documented cytoplasmic localization.
    action: ACCEPT
    reason: Correct localization, redundant with other localization annotations.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:17205132}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983147
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (E3 release from polyubiquitinated substrate). Consistent with documented cytoplasmic localization.
    action: ACCEPT
    reason: Correct localization, redundant with other localization annotations.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:17205132}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983156
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (polyubiquitination of substrate). Consistent with documented cytoplasmic localization.
    action: ACCEPT
    reason: Correct localization, redundant with other localization annotations.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:17205132}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983157
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (E3 interaction with substrate and E2-Ub). Consistent with documented cytoplasmic localization.
    action: ACCEPT
    reason: Correct localization, redundant with other localization annotations.
    supported_by:
    - reference_id: file:human/FBXW8/FBXW8-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:17205132}.
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:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:15070733
  title: M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Source of an FBXW8-SKP1 (P63208) generic F-box/SCF IntAct contact; the paper is about Wee1/beta-TrCP.
- id: PMID:17205132
  title: A critical role for FBXW8 and MAPK in cyclin D1 degradation and cancer cell proliferation.
  findings:
  - statement: FBXW8 mediates cytoplasmic degradation of cyclin D1 phosphorylated at Thr286 via the Ras/Raf/MEK/ERK cascade; FBXW8 depletion accumulates cyclin D1 and impairs cancer cell proliferation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; establishes FBXW8 as the substrate receptor for phospho-cyclin D1 and its cytoplasmic localization.
- id: PMID:17314511
  title: Large-scale identification of c-MYC-associated proteins using a combined TAP/MudPIT approach.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput MYC-interactome (TAP/MudPIT); source of an FBXW8-MYC bare protein binding annotation.
- id: PMID:18498745
  title: The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation.
  findings:
  - statement: The CUL7(FBXW8) E3 ligase (CUL7, FBXW8, SKP1, ROC1/RBX1) targets IRS1 for ubiquitin-dependent degradation in an mTOR/p70-S6-kinase-dependent manner; Cul7-/- cells accumulate IRS1 with increased AKT and MEK/ERK signaling and undergo senescence-like phenotypes.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; establishes the IRS1 substrate and the negative regulation of insulin/IGF-1 signaling.
- id: PMID:21572988
  title: An OBSL1-Cul7Fbxw8 ubiquitin ligase signaling mechanism regulates Golgi morphology and dendrite patterning.
  findings:
  - statement: CUL7(FBXW8) localizes to the Golgi (via OBSL1) and is required for Golgi morphology, secretory trafficking, and dendrite (not axon) elaboration in neurons; the Golgi stacking protein GRASP65/GORASP1 is a physiological substrate.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract only in cache (full_text_available false); IDA/IGI annotations rely on full text read by curators. Source of Golgi organization, dendrite morphogenesis, GORASP1 substrate and Golgi/perinuclear localization.
- id: PMID:24362026
  title: The CUL7/F-box and WD repeat domain containing 8 (CUL7/Fbxw8) ubiquitin ligase promotes degradation of hematopoietic progenitor kinase 1.
  findings:
  - statement: CUL7(FBXW8) recognizes autophosphorylated MAP4K1/HPK1 and targets it for 26S proteasomal degradation, a process antagonized by PP4 dephosphorylation of HPK1 Thr355; this promotes pancreatic cancer cell proliferation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; establishes the HPK1 substrate and the proliferation link.
- id: PMID:24793695
  title: The 3M complex maintains microtubule and genome integrity.
  findings:
  - statement: CUL7, OBSL1 and CCDC8 form a 3M complex (with which FBXW8 associates via CUL7) that maintains microtubule and genome integrity; CUL7 depletion causes microtubule defects, prometaphase arrest, tetraploidy and mitotic death.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text available; supports the 3M complex association annotation. The microtubule/genome roles are primarily CUL7/OBSL1/CCDC8-centric.
- id: PMID:27705803
  title: A High-Density Map for Navigating the Human Polycomb Complexome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: AP-MS complexome map; source of a bare protein binding annotation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Cell-specific interactome; source of a bare protein binding annotation.
- id: PMID:35982156
  title: Structure of CRL7(FBXW8) reveals coupling with CUL1-RBX1/ROC1 for multi-cullin-RING E3-catalyzed ubiquitin ligation.
  findings:
  - statement: Cryo-EM shows CUL7 binds FBXW8 in an F-box-independent mode; within CRL7(FBXW8) the RBX1 RING is held incompatible with E2~Ub/E2~NEDD8 binding, so the complex lacks intrinsic catalytic activity and instead acts as a substrate receptor coupled via SKP1-FBXW8 to a neddylated CUL1-RBX1 catalytic module.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; defines the mechanistic basis for FBXW8 as a substrate receptor coupled to CUL1-RBX1 catalysis - key for the SCF vs CUL7 complex annotations.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal cell-map study; source of a bare protein binding annotation.
- id: file:human/FBXW8/FBXW8-deep-research-falcon.md
  title: Falcon deep research report for human FBXW8
  findings:
  - statement: Cryo-EM and reconstitution show CRL7(FBXW8) is an atypical multi-cullin E3 in which CUL7-FBXW8 recruits substrate while a neddylated CUL1-RBX1 module provides catalytic activity; recombinant CRL7(FBXW8) alone lacks auto-neddylation and ubiquitination activity.
    supporting_text: CUL7 binds FBXW8 in an F-box-independent mode; CRL7^FBXW8 alone lacks auto-neddylation/ubiquitination activity; catalytic coupling occurs to CUL1-RBX1
  - statement: A Golgi-localized CUL7-FBXW8 complex directly binds adipose triglyceride lipase (ATGL/PNPLA2) and mediates its K48-linked polyubiquitylation and proteasomal degradation, restraining lipolysis; glucose depletion lowers Golgi PtdIns4P and reduces this degradation.
    supporting_text: Golgi-localized CUL7-FBXW8 directly interacts with ATGL and mediates K48-linked polyubiquitylation/proteasomal degradation
  - statement: FBXW8 contains a polybasic N-terminal region that binds Golgi PtdIns4P, providing a phosphoinositide-sensing recruitment mechanism that couples intracellular glucose status to assembly of the CUL7-FBXW8 ligase at the Golgi.
    supporting_text: FBXW8 has a polybasic N-terminal region binding Golgi PtdIns4P; glucose deprivation lowers Golgi PtdIns4P, reduces FBXW8/CUL7 assembly at Golgi, stabilizes ATGL, and increases lipolysis
  - statement: FBXW8 (in CUL7/FBXW8) promotes degradation of the nuclear chromatin-associated protein MRFAP1 specifically around anaphase-telophase, with FBXW8 overexpression increasing MRFAP1 polyubiquitination and knockdown prolonging its half-life.
    supporting_text: Cul7/FBXW8 promotes MRFAP1 degradation during anaphase-telophase; FBXW8 overexpression increases polyubiquitination and knockdown prolongs half-life
  - statement: FBXW8 is essential in mouse models for mid-to-late placental development and fetal growth; Fbxw8 knockout causes intrauterine growth retardation and placental structural defects, with Fbxw8-null phenotypes milder than Cul7-null lethality.
    supporting_text: Loss causes intrauterine growth retardation, small placentas, reduced spongiotrophoblast/labyrinth abnormalities; placental defect depends on fetal genotype
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'Falcon synthesis of FBXW8 primary literature; the multi-cullin CRL7-CUL1 coupling, cyclin D1, HPK1, IRS1 and GORASP1 substrates and Golgi/cytoplasmic localization cross-check against UniProt Q8N3Y1 and cached PMID:17205132/PMID:18498745/PMID:21572988/PMID:24362026/PMID:35982156. New substrate leads (ATGL/PtdIns4P axis from Ding 2024 Nat Cell Biol; MRFAP1 from Li 2017; PDCoV N) are from single primary papers not yet in GOA and are treated as supporting context, not a basis to overrule curated annotations.'
- id: Reactome:R-HSA-8952618
  title: AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8952620
  title: NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8955241
  title: CAND1 binds cytosolic CRL E3 ubiquitin ligases
  findings: []
- id: Reactome:R-HSA-8955289
  title: COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956040
  title: COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956200
  title: MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-983140
  title: Transfer of Ub from E2 to substrate and release of E2
  findings: []
- id: Reactome:R-HSA-983147
  title: Release of E3 from polyubiquitinated substrate
  findings: []
- id: Reactome:R-HSA-983156
  title: Polyubiquitination of substrate
  findings: []
- id: Reactome:R-HSA-983157
  title: Interaction of E3 with substrate and E2-Ub complex
  findings: []
core_functions:
- description: Substrate-recognition subunit of the vertebrate-specific CUL7-RING(FBXW8) (CRL7(FBXW8)) E3 ubiquitin ligase; selects phosphorylation-marked substrates - IRS1 (after S6-kinase/mTOR phosphorylation), MAP4K1/HPK1 (autophosphorylated), and phospho-cyclin D1 - for polyubiquitination and proteasomal degradation, with ubiquitin transfer catalyzed via a coupled CUL1-RBX1 module.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:18498745
    supporting_text: the Cullin 7 (CUL7) E3 ubiquitin ligase complex containing the Fbw8-substrate-targeting subunit
  - reference_id: PMID:35982156
    supporting_text: CRL7 serves as a substrate receptor linked via SKP1-FBXW8 to a neddylated CUL1-RBX1 catalytic module mediating ubiquitination
  directly_involved_in:
  - id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
- description: Golgi-localized CUL7(FBXW8) substrate receptor. Scaffolded at the Golgi by OBSL1, it mediates degradation of the Golgi stacking protein GORASP1/GRASP65 to control Golgi morphology, secretory trafficking and dendrite elaboration in neurons; recruited to the Golgi via a polybasic N-terminal region that binds Golgi PtdIns4P, it also K48-polyubiquitinates adipose triglyceride lipase (ATGL/PNPLA2) to restrain lipolysis in a glucose-responsive manner.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005794
    label: Golgi apparatus
  supported_by:
  - reference_id: PMID:21572988
    supporting_text: we identify the Golgi protein Grasp65 as a novel and physiologically relevant substrate of Cul7(Fbxw8) in the control of Golgi and dendrite morphogenesis in neurons
  - reference_id: file:human/FBXW8/FBXW8-deep-research-falcon.md
    supporting_text: Golgi-localized CUL7-FBXW8 directly interacts with ATGL and mediates K48-linked polyubiquitylation/proteasomal degradation
  directly_involved_in:
  - id: GO:0007030
    label: Golgi organization
- description: Negative regulator of insulin/IGF-1 signaling as the substrate receptor that targets IRS1 for CUL7-dependent ubiquitin-mediated degradation, dampening downstream AKT and MEK/ERK pathway activation.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:18498745
    supporting_text: a key role for the CUL7 E3 in targeting IRS-1 for degradation
  directly_involved_in:
  - id: GO:0046627
    label: negative regulation of insulin receptor signaling pathway
proposed_new_terms: []
suggested_questions:
- question: Given that CRL7(FBXW8) lacks intrinsic catalytic activity and couples to a separate CUL1-RBX1 module, how is this two-cullin assembly regulated, and which substrates require the coupled module versus other catalytic partners?
- question: How do the phosphorylation states of substrates (IRS1, HPK1, cyclin D1) and of FBXW8 itself (Ser85 by mTORC2) coordinate the timing and subcellular site (cytosol vs Golgi) of FBXW8-dependent degradation?
- question: What determines whether an FBXW8-attached K48 polyubiquitin chain routes a substrate to proteasomal degradation (e.g. ATGL, cyclin D1) versus selective autophagy (as reported for viral nucleocapsid), and is PtdIns4P-dependent Golgi recruitment a general feature for membrane-proximal substrates?
suggested_experiments:
- description: Reconstitute the full CRL7(FBXW8)-CUL1-RBX1 coupled ligase in vitro with neddylation machinery and phosphorylated substrates (IRS1, HPK1, cyclin D1, GORASP1, ATGL) to confirm the requirement for the CUL1-RBX1 catalytic module and map ubiquitination sites/chain linkages.
- description: Perform FBXW8 degron-depletion combined with quantitative phosphoproteomics and ubiquitinomics in neuronal, hepatocyte/adipocyte, and cancer cell models to define the endogenous substrate repertoire and dissect the Golgi/dendrite, lipolysis (ATGL/PtdIns4P), and insulin-signaling functions.
- description: Mutate the FBXW8 polybasic N-terminal region to abolish Golgi PtdIns4P binding and test, with cell fractionation and ubiquitination assays, whether Golgi recruitment is required selectively for ATGL/GORASP1 turnover but dispensable for cytosolic substrates (IRS1, HPK1, cyclin D1).