id: P57775 gene_symbol: FBXW4 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXW4 (dactylin; SHFM3) is a member of the F-box/WD40 (FBXW) family of proteins. Its 412-residue product contains an N-terminal F-box motif (approximately residues 25-71) and a C-terminal beta-propeller built from roughly six WD40 repeats. F-box proteins function as the interchangeable substrate-recognition subunits of SCF (SKP1-CUL1-F-box)-type cullin-RING E3 ubiquitin ligase complexes: the F-box motif docks the protein onto SKP1/CUL1, while the WD40 propeller recognizes (typically phosphorylated) substrate proteins and presents them for ubiquitination by the RBX1-bound E2, committing them to proteasomal degradation. Affinity-purification studies confirm that FBXW4 assembles, in an F-box-dependent manner, with the canonical SCF core subunits SKP1, CUL1 and RBX1 and with COP9 signalosome subunits (which deneddylate and regulate cullin-RING ligases), and that FBXW4 associates with ubiquitinated cellular proteins in a manner enhanced by proteasome inhibition - establishing it as a bona fide SCF substrate receptor engaged in ubiquitin-dependent turnover. Its physiological substrates, however, remain undefined. FBXW4 is broadly expressed (including brain, kidney, lung and liver) and is recurrently mutated, deleted, or under-expressed across human cancers, suggesting a candidate tumor-suppressor role. The human gene maps to chromosome 10q24.3 within the critical region for split-hand/foot malformation type 3 (SHFM3), and the orthologous gene is disrupted in the mouse dactylaplasia (Dac) mutant, which fails to maintain the apical ectodermal ridge and truncates the autopod. SHFM3 is most often associated with tandem/discontinuous genomic duplications at 10q24 that perturb a shared cis-regulatory neighborhood and alter expression of FBXW4 and several neighboring genes (e.g. BTRC, POLL, LBX1) rather than with coding mutations in FBXW4 itself, so FBXW4's precise contribution to limb development and its physiological ubiquitination substrates remain incompletely defined. existing_annotations: - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of review: summary: Phylogenetic (PAN-GO) assignment of SCF complex membership, consistent with FBXW4's F-box motif that docks F-box proteins onto SKP1/CUL1. Now directly corroborated by FBXW4-specific affinity-purification data showing F-box-dependent assembly with SKP1, CUL1 and RBX1. action: ACCEPT reason: Core localization/assembly role for an F-box protein; supported by the F-box domain, the documented SKP1 interaction, and direct biochemical co-purification of FBXW4 with the SCF core (SKP1/CUL1/RBX1) and COP9 signalosome in an F-box-dependent manner. additional_reference_ids: - file:human/FBXW4/FBXW4-deep-research-falcon.md supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex - reference_id: file:human/FBXW4/FBXW4-deep-research-falcon.md supporting_text: FBXW4 co-purifies/interacts with **SKP1, CUL1, RBX1** and multiple **COP9 signalosome (COPS)** subunits, and these interactions are **F-box dependent** - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic assignment of involvement in SCF-dependent proteasomal degradation, the canonical process for F-box substrate-receptor proteins. FBXW4-specific data show it engages ubiquitinated proteins in a proteasome-inhibitor- and F-box-dependent manner, supporting genuine participation in ubiquitin-dependent turnover. action: ACCEPT reason: Core biological process for an F-box protein acting as an SCF substrate receptor; consistent with the UniProt function statement and with direct evidence that FBXW4 associates with ubiquitinated cellular proteins (increased by MG132) in an F-box-dependent manner. additional_reference_ids: - file:human/FBXW4/FBXW4-deep-research-falcon.md supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: Probably recognizes and binds to some phosphorylated proteins and promotes their ubiquitination and degradation - reference_id: file:human/FBXW4/FBXW4-deep-research-falcon.md supporting_text: FBXW4 interacts with **ubiquitinated cellular proteins**, and the interaction increases with **proteasome inhibition (MG132)** in an **F-box-dependent** manner, consistent with substrate engagement in ubiquitin-dependent turnover pathways - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22632967 qualifier: enables review: summary: IntAct interaction captured against SKP1 (UniProtKB:P63208) in a cyclin F/SCF study; records the functionally important FBXW4-SKP1 association. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the real FBXW4-SKP1 interaction (the WITH/FROM target is P63208/SKP1), which underpins SCF assembly, but bare protein binding is uninformative per curation guidelines. supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: 'P57775; P63208: SKP1; NbExp=3; IntAct=EBI-2372268, EBI-307486' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27705803 qualifier: enables review: summary: IntAct interaction against SKP1 (UniProtKB:P63208) from a Polycomb complexome map; supports FBXW4-SKP1 association. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the FBXW4-SKP1 interaction (WITH/FROM P63208/SKP1) relevant to SCF assembly, but bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: 'P57775; P63208: SKP1; NbExp=3; IntAct=EBI-2372268, EBI-307486' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 qualifier: enables review: summary: High-throughput interactome interaction against PRKN/Parkin isoform (UniProtKB:O60260-5) from a neurodegenerative-disease interactome study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a high-throughput interaction (WITH/FROM O60260-5/PRKN); bare protein binding is uninformative and not a core function. supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: 'P57775; O60260-5: PRKN; NbExp=3; IntAct=EBI-2372268, EBI-21251460' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: IntAct interaction against SKP1 (UniProtKB:P63208) from a cell-specific interactome map; supports FBXW4-SKP1 association. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the FBXW4-SKP1 interaction (WITH/FROM P63208/SKP1) relevant to SCF assembly, but bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: 'P57775; P63208: SKP1; NbExp=3; IntAct=EBI-2372268, EBI-307486' - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:34445249 qualifier: part_of review: summary: ComplexPortal (CPX-7761) curated assignment of FBXW4 to an SCF E3 ubiquitin ligase complex variant. action: ACCEPT reason: Correct core assembly annotation; FBXW4 is the substrate-receptor subunit of an SCF complex variant (ComplexPortal CPX-7761), consistent with SKP1 binding. supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:34445249 qualifier: involved_in review: summary: ComplexPortal-derived assignment of involvement in SCF-dependent proteasomal degradation, the canonical process for an SCF substrate receptor. action: ACCEPT reason: Correct core biological process; redundant with the IBA assignment of the same term. supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: promotes their ubiquitination and degradation - term: id: GO:0060173 label: limb development evidence_type: NAS original_reference_id: PMID:10471509 qualifier: involved_in review: summary: Author-stated involvement in limb development, based on disruption of the orthologous gene (dactylin) in the mouse dactylaplasia mutant, which truncates the autopod via failure to maintain the apical ectodermal ridge. action: KEEP_AS_NON_CORE reason: Genetically well-supported developmental association (dactylaplasia mouse; SHFM3 locus) but the molecular mechanism and direct FBXW4 substrates in limb patterning are not established; this is a pleiotropic developmental role rather than a demonstrated direct molecular function. supported_by: - reference_id: PMID:10471509 supporting_text: this report demonstrates the importance of this gene family in vertebrate embryonic development - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952618 qualifier: located_in review: summary: Reactome pathway-level cytosol localization for FBXW4 within generic CRL1/SCF neddylation and ubiquitination reactions. action: KEEP_AS_NON_CORE reason: Plausible cytosolic localization for an SCF subunit, but derived from generic CRL pathway reactions rather than FBXW4-specific localization data; the dactylin/SHFM3 literature implies action in developing tissues without resolving compartment. supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952620 qualifier: located_in review: summary: Reactome pathway-level cytosol localization (NEDD8:AcM-UBE2M binds CRL1) propagated to FBXW4 as an SCF subunit. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific. supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955241 qualifier: located_in review: summary: Reactome pathway-level cytosol localization (CAND1 binds cytosolic CRL ligases) propagated to FBXW4. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific. supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955289 qualifier: located_in review: summary: Reactome pathway-level cytosol localization (COMMDs displace CAND1) propagated to FBXW4. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific. supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956040 qualifier: located_in review: summary: Reactome pathway-level cytosol localization (COP9 signalosome deneddylates CRLs) propagated to FBXW4. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific. supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956200 qualifier: located_in review: summary: Reactome pathway-level cytosol localization (MyrG-DCUN1D3 binds CRL1) propagated to FBXW4. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific. supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983140 qualifier: located_in review: summary: Reactome pathway-level cytosol localization (transfer of Ub from E2 to substrate) propagated to FBXW4. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific. supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983147 qualifier: located_in review: summary: Reactome pathway-level cytosol localization (release of E3 from polyubiquitinated substrate) propagated to FBXW4. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific. supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983156 qualifier: located_in review: summary: Reactome pathway-level cytosol localization (polyubiquitination of substrate) propagated to FBXW4. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific. supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983157 qualifier: located_in review: summary: Reactome pathway-level cytosol localization (interaction of E3 with substrate and E2-Ub complex) propagated to FBXW4. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific. supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex - term: id: GO:0030326 label: embryonic limb morphogenesis evidence_type: NAS original_reference_id: PMID:10405324 qualifier: involved_in review: summary: Author-stated putative involvement in limb morphogenesis from the original cloning paper, based on FBXW4 mapping to the SHFM3 critical region at 10q24.3. action: KEEP_AS_NON_CORE reason: Reflects a candidate-gene/positional inference (SHFM3 critical region) rather than a demonstrated molecular mechanism; developmental role is non-core and the direct substrates in limb morphogenesis are unknown. supported_by: - reference_id: PMID:10405324 supporting_text: likely to be involved in key signaling pathways crucial for normal limb development, make it a promising candidate gene for SHFM3 - term: id: GO:0000151 label: ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:10945468 qualifier: part_of review: summary: Author-stated membership in a ubiquitin ligase complex, based on FBXW4 being an F-box/WD40 protein of the SCF family. A more general parent of the specific SCF complex term. action: ACCEPT reason: Correct but generic; subsumed by the more specific GO:0019005 (SCF ubiquitin ligase complex). Consistent with the F-box family role. supported_by: - reference_id: PMID:10945468 supporting_text: F-box proteins are critical components of the SCF ubiquitin-protein ligase complex and are involved in substrate recognition and recruitment for ubiquitination - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:10945468 qualifier: involved_in review: summary: Author-stated involvement in ubiquitin-dependent protein catabolism, a parent of the specific SCF-dependent proteasomal process. action: ACCEPT reason: Correct but generic; the more specific GO:0031146 better captures FBXW4's role as an SCF substrate receptor. supported_by: - reference_id: PMID:10945468 supporting_text: their distinct role in ubiquitin-dependent protein degradation references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: PMID:10405324 title: A novel human gene encoding an F-box/WD40 containing protein maps in the SHFM3 critical region on 10q24. findings: - statement: Cloning of human Dactylin/FBXW4, an F-box/WD40 protein at 10q24.3 within the SHFM3 critical region; expressed in brain, kidney, lung and liver; proposed as a candidate gene for split hand/foot malformation acting via ubiquitination of signaling-pathway proteins in limb development. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified original cloning; source of the SHFM3-locus and embryonic limb morphogenesis annotations. Limb role is positional/candidate-gene based, not a demonstrated molecular mechanism. - id: PMID:10471509 title: A novel member of the F-box/WD40 gene family, encoding dactylin, is disrupted in the mouse dactylaplasia mutant. findings: - statement: Positional cloning of the mouse dactylaplasia (Dac) gene identifies dactylin (Fbxw4 ortholog); Dac disrupts maintenance of the apical ectodermal ridge and truncates the autopod, resembling human SHFM, demonstrating the importance of the F-box/WD40 family in vertebrate limb development. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified; genetic basis for the limb development annotation via the dactylaplasia mouse. - id: PMID:10945468 title: cDNA cloning and expression analysis of new members of the mammalian F-box protein family. findings: - statement: Cloning of 10 mammalian F-box proteins including FBWD4 (FBXW4) which contains WD40-repeat domains; F-box proteins are substrate-recognition components of SCF ubiquitin-protein ligase complexes with distinct roles in ubiquitin-dependent degradation. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified family cloning paper; source of generic ubiquitin ligase complex and ubiquitin-dependent catabolic process annotations. - id: PMID:22632967 title: Cyclin F-mediated degradation of ribonucleotide reductase M2 controls genome integrity and DNA repair. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Study of SCF(cyclin F); the FBXW4 GOA annotation from this PMID is an IntAct interaction against SKP1 (WITH/FROM P63208), not a claim about cyclin F or RRM2. Source of a bare protein binding annotation. - id: PMID:27705803 title: A High-Density Map for Navigating the Human Polycomb Complexome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput complexome map; FBXW4 annotation is an IntAct interaction against SKP1 (WITH/FROM P63208). - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput interactome; FBXW4 annotation is an interaction against a PRKN/Parkin isoform (WITH/FROM O60260-5). Bare protein binding, non-core. - 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; FBXW4 annotation is an IntAct interaction against SKP1 (WITH/FROM P63208). - id: PMID:34445249 title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability. findings: - statement: Review of SCF (SKP1-CUL1-F-box) complex biology; provides the basis for ComplexPortal assignment of FBXW4 to an SCF E3 ubiquitin ligase complex variant and to SCF-dependent proteasomal degradation. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified SCF review; basis for ComplexPortal SCF complex and SCF-dependent catabolic process 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: [] - id: file:human/FBXW4/FBXW4-deep-research-falcon.md title: Falcon deep research report for human FBXW4 findings: - statement: FBXW4 assembles with the canonical SCF core (SKP1, CUL1, RBX1) and with COP9 signalosome subunits in an F-box-dependent manner, providing direct biochemical evidence (beyond family inference) that it is an SCF substrate-recognition subunit rather than an enzyme or transporter. supporting_text: FBXW4 co-purifies/interacts with **SKP1, CUL1, RBX1** and multiple **COP9 signalosome (COPS)** subunits, and these interactions are **F-box dependent** - statement: FBXW4 associates with ubiquitinated cellular proteins, and this association increases upon proteasome inhibition in an F-box-dependent way, consistent with substrate engagement in ubiquitin-dependent turnover. supporting_text: FBXW4 interacts with **ubiquitinated cellular proteins**, and the interaction increases with **proteasome inhibition (MG132)** in an **F-box-dependent** manner, consistent with substrate engagement in ubiquitin-dependent turnover pathways - statement: The endogenous substrate(s) of SCF(FBXW4) remain undefined; the primary biochemical study frames substrate identification as a future direction. supporting_text: 'The specific endogenous **substrate(s)** targeted by SCF^FBXW4 remain insufficiently defined in the retrieved evidence; the 2013 study frames substrate identification as a future direction' - statement: FBXW4 is recurrently mutated, lost, and under-expressed across human cancers, consistent with a possible tumor-suppressor role, though causal substrates/pathways are unclear. supporting_text: FBXW4 is mutated, lost, and under-expressed in human cancers, and argue this pattern is consistent with a potential **tumor suppressor** role, though definitive causal substrates/pathways remain unclear - statement: SHFM3 at 10q24 is best explained as a cis-regulatory / multi-gene misexpression disorder; recurrent duplications include FBXW4 with neighboring genes, and enhancer perturbation in mouse alters Fbxw4 expression rather than acting through an FBXW4 coding mutation. supporting_text: SVs likely perturb **cis-regulatory elements**, **3D chromatin architecture**, and/or coordinated expression of multiple genes in the region reference_review: relevance: HIGH correctness: VERIFIED review_notes: Falcon synthesis grounded chiefly in Lockwood et al. 2013 (PLoS ONE, doi:10.1371/journal.pone.0063610), which provides the first direct biochemical evidence that FBXW4 is an SCF substrate receptor (F-box-dependent assembly with SKP1/CUL1/RBX1 and the COP9 signalosome; MG132-dependent association with ubiquitinated proteins). Cross-checked against UniProt P57775 SUBUNIT/FUNCTION statements and ComplexPortal CPX-7761. SHFM3 cis-regulatory-neighborhood model is consistent with the UniProt SHFM3 disease note and the prior SHFM3 cloning/mapping literature already cited in this review. core_functions: - description: Substrate-recognition (substrate-adaptor) subunit of an SCF (SKP1-CUL1-F-box) cullin-RING E3 ubiquitin ligase complex, docking via its F-box motif onto SKP1/CUL1 and using its WD40 propeller to recruit substrates and bridge them to the ligase for SCF-dependent proteasomal degradation. FBXW4 itself is not catalytic; the ubiquitin-transfer/RING activity resides on the RBX1 subunit of the assembled SCF complex. Direct physiological substrates of SCF(FBXW4) remain undefined. supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex - reference_id: PMID:10945468 supporting_text: F-box proteins are critical components of the SCF ubiquitin-protein ligase complex and are involved in substrate recognition and recruitment for ubiquitination - reference_id: file:human/FBXW4/FBXW4-deep-research-falcon.md supporting_text: FBXW4 co-purifies/interacts with **SKP1, CUL1, RBX1** and multiple **COP9 signalosome (COPS)** subunits, and these interactions are **F-box dependent** locations: - id: GO:0005829 label: cytosol directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process proposed_new_terms: - proposed_name: ubiquitin-like ligase-substrate adaptor activity proposed_definition: Bridging a substrate to a ubiquitin-like protein ligase, as performed by an SCF F-box substrate-recognition subunit that binds both SKP1/the ligase scaffold and the substrate to facilitate the substrate's ubiquitination. This corresponds to the existing GO term GO:1990756, which is not currently in FBXW4's annotation set. justification: FBXW4 assembles with the SCF core (SKP1/CUL1/RBX1) and the COP9 signalosome in an F-box-dependent manner and associates with ubiquitinated proteins in a proteasome-inhibitor-dependent way, consistent with a substrate-adaptor molecular function rather than catalysis (which is RBX1's). Adding GO:1990756 would give FBXW4 an informative molecular-function term in place of the uninformative bare protein binding annotations. proposed_parent: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: file:human/FBXW4/FBXW4-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex - reference_id: file:human/FBXW4/FBXW4-deep-research-falcon.md supporting_text: FBXW4 co-purifies/interacts with **SKP1, CUL1, RBX1** and multiple **COP9 signalosome (COPS)** subunits, and these interactions are **F-box dependent** suggested_questions: - question: What are the direct, phosphorylation-dependent ubiquitination substrates recognized by the FBXW4 WD40 propeller, and which signaling pathways (e.g. Wnt) do they belong to? - question: Given that SHFM3 is associated with a tandem duplication at 10q24 rather than FBXW4 coding mutations, is the limb phenotype due to altered FBXW4 dosage, a neighboring gene, or a regulatory element, and what is FBXW4's direct molecular contribution? suggested_experiments: - description: Affinity purification of tagged FBXW4 with SKP1/CUL1/RBX1 followed by mass spectrometry of co-purifying and ubiquitinated proteins, in limb-bud-derived or epithelial cells, to identify physiological SCF(FBXW4) substrates. - description: Reconstitute SCF(FBXW4) in vitro with SKP1, CUL1, RBX1 and an E2 and test ubiquitination of candidate developmental-signaling substrates, comparing wild-type to F-box-deletion FBXW4 to confirm substrate-adaptor activity.