id: Q5XUX1 gene_symbol: FBXW9 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXW9 is a member of the F-box/WD40 (FBXW) family of proteins, containing an N-terminal F-box motif and a C-terminal beta-propeller built from seven WD40 repeats. F-box proteins serve as the interchangeable substrate-recognition subunits of SCF (SKP1-CUL1-F-box)-type cullin-RING E3 ubiquitin ligase complexes: the F-box motif binds SKP1 (which in turn bridges to CUL1 and the RBX1-bound catalytic RING), while the WD40 propeller engages substrate proteins and presents them for ubiquitination, marking them for proteasomal degradation. FBXW9 is itself non-catalytic: it acts as a substrate adaptor, with the ubiquitin-transfer (RING) activity contributed by RBX1 in the assembled SCF. FBXW9 has been shown experimentally to bind SKP1 (array MAPPIT screen with co-immunoprecipitation validation) and to co-purify with CUL1 in affinity purification-mass spectrometry of SCF assemblies, and ComplexPortal assigns it as the variable substrate-receptor subunit of an SCF complex variant. It is broadly expressed and undergoes N-terminal phosphorylation at several residues. FBXW9 remains poorly characterized at the level of direct biochemistry: no endogenous ubiquitination substrate has been validated by direct ubiquitination or degradation assays. Cancer-focused studies place FBXW9 transcription downstream of p53 (a direct p53 target gene) and of CREB in an IGFBP5-ROR1/HER2 signaling axis, and report cell-cycle/proliferation phenotypes on knockdown in breast cancer and invasion phenotypes in glioblastoma stem-like cells; however, candidate substrates such as TP53 remain predicted rather than biochemically demonstrated, so FBXW9's assigned molecular and process roles still rest largely on family-level inference. existing_annotations: - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19159283 qualifier: enables review: summary: IntAct interaction against SKP1 (UniProtKB:P63208) from the Array MAPPIT high-throughput interactome screen (Lievens et al. 2009), validated by co-immunoprecipitation; supports FBXW9-SKP1 association underlying SCF assembly. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally relevant FBXW9-SKP1 interaction (WITH/FROM P63208/SKP1), which underpins SCF assembly and is corroborated by co-IP validation, but bare protein binding is uninformative per curation guidelines; the substrate-adaptor molecular function (GO:1990756) better captures this role. additional_reference_ids: - file:human/FBXW9/FBXW9-deep-research-falcon.md supported_by: - reference_id: file:human/FBXW9/FBXW9-uniprot.txt supporting_text: 'Q5XUX1; P63208: SKP1; NbExp=8; IntAct=EBI-2322729, EBI-307486' - reference_id: file:human/FBXW9/FBXW9-deep-research-falcon.md supporting_text: FBXW9 was identified as a SKP1-interacting prey in a high-throughput **array MAPPIT** interactome screen and validated by **co-immunoprecipitation** in **HEK293T** cells - 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 FBXW9-SKP1 association. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the FBXW9-SKP1 interaction (WITH/FROM P63208/SKP1) relevant to SCF assembly, but bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXW9/FBXW9-uniprot.txt supporting_text: 'Q5XUX1; P63208: SKP1; NbExp=8; IntAct=EBI-2322729, EBI-307486' - 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 FBXW9-SKP1 association. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the FBXW9-SKP1 interaction (WITH/FROM P63208/SKP1) relevant to SCF assembly, but bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXW9/FBXW9-uniprot.txt supporting_text: 'Q5XUX1; P63208: SKP1; NbExp=8; IntAct=EBI-2322729, EBI-307486' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: IntAct interaction against SKP1 (UniProtKB:P63208) from a multimodal cell-map study; supports FBXW9-SKP1 association. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the FBXW9-SKP1 interaction (WITH/FROM P63208/SKP1) relevant to SCF assembly, but bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXW9/FBXW9-uniprot.txt supporting_text: 'Q5XUX1; P63208: SKP1; NbExp=8; IntAct=EBI-2322729, EBI-307486' - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:15520277 qualifier: part_of review: summary: ComplexPortal/family-based assignment of SCF complex membership, consistent with FBXW9's F-box motif and experimentally documented SKP1 binding (array MAPPIT plus co-IP) and CUL1 co-purification (AP-MS); ComplexPortal CPX-7785 defines an SCF complex FBXW9 variant. action: ACCEPT reason: Core assembly annotation for an F-box protein; supported by the F-box domain and direct experimental evidence that FBXW9 binds SKP1 and co-purifies with CUL1-containing SCF assemblies. additional_reference_ids: - file:human/FBXW9/FBXW9-deep-research-falcon.md supported_by: - reference_id: file:human/FBXW9/FBXW9-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - reference_id: file:human/FBXW9/FBXW9-deep-research-falcon.md supporting_text: FBXW9 was identified as a SKP1-interacting prey in a high-throughput **array MAPPIT** interactome screen and validated by **co-immunoprecipitation** in **HEK293T** cells - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:15520277 qualifier: involved_in review: summary: Family-based assignment of involvement in SCF-dependent proteasomal degradation, the canonical process for an SCF substrate receptor. FBXW9 assembles into SCF (SKP1/CUL1), but no FBXW9-specific substrate has been validated by direct ubiquitination/degradation assays; proposed substrates such as TP53 remain predictive. action: KEEP_AS_NON_CORE reason: Plausible and consistent with the F-box family role and with experimental SCF assembly, but no FBXW9-specific substrate or degradation event has been demonstrated biochemically; cancer-context studies report transcriptional regulation and knockdown phenotypes rather than direct substrate degradation, so the process role still rests on family inference. additional_reference_ids: - file:human/FBXW9/FBXW9-deep-research-falcon.md supported_by: - reference_id: file:human/FBXW9/FBXW9-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - reference_id: file:human/FBXW9/FBXW9-deep-research-falcon.md supporting_text: No directly validated endogenous ubiquitination substrate for human FBXW9 was recovered; no direct catalytic assay, no substrate degron definition - 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 (AcM-UBE2M transfers NEDD8 to CRL1) propagated to FBXW9 as an SCF subunit. action: KEEP_AS_NON_CORE reason: Plausible cytosolic localization for an SCF subunit but derived from generic CRL pathway reactions, not FBXW9-specific localization data. supported_by: - reference_id: file:human/FBXW9/FBXW9-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific. supported_by: - reference_id: file:human/FBXW9/FBXW9-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific. supported_by: - reference_id: file:human/FBXW9/FBXW9-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific. supported_by: - reference_id: file:human/FBXW9/FBXW9-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific. supported_by: - reference_id: file:human/FBXW9/FBXW9-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific. supported_by: - reference_id: file:human/FBXW9/FBXW9-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific. supported_by: - reference_id: file:human/FBXW9/FBXW9-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific. supported_by: - reference_id: file:human/FBXW9/FBXW9-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific. supported_by: - reference_id: file:human/FBXW9/FBXW9-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific. supported_by: - reference_id: file:human/FBXW9/FBXW9-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex references: - id: PMID:15520277 title: Systematic analysis and nomenclature of mammalian F-box proteins. findings: - statement: Systematic classification and nomenclature of mammalian F-box proteins into FBXL, FBXW and FBXO families; FBXW proteins are the WD40-repeat-containing substrate-recognition subunits of SCF ubiquitin ligase complexes. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified F-box nomenclature paper; basis for the family-level SCF complex and SCF-dependent catabolic process annotations for FBXW9. - id: PMID:19159283 title: 'Array MAPPIT: high-throughput interactome analysis in mammalian cells.' findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput interactome method; FBXW9 annotation is an IntAct interaction against SKP1 (WITH/FROM P63208). Bare protein binding, non-core. - 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; FBXW9 annotation is an IntAct interaction against SKP1 (WITH/FROM P63208). - 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; FBXW9 annotation is an IntAct interaction against SKP1 (WITH/FROM P63208). - 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; FBXW9 annotation is an IntAct interaction against SKP1 (WITH/FROM P63208). - 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/FBXW9/FBXW9-deep-research-falcon.md title: Falcon deep research report for human FBXW9 findings: - statement: FBXW9 binds SKP1 (array MAPPIT screen validated by co-immunoprecipitation in HEK293T) and co-purifies with CUL1 in AP-MS of SCF assemblies, providing direct experimental evidence that it is an SCF/CRL1 substrate-recognition adaptor rather than an enzyme. supporting_text: FBXW9 was identified as a SKP1-interacting prey in a high-throughput **array MAPPIT** interactome screen and validated by **co-immunoprecipitation** in **HEK293T** cells - statement: FBXW9 is a direct p53 transcriptional target (ChIP/luciferase/Nutlin-3 evidence) whose ectopic expression suppresses proliferation of p53-deficient cells, positioning it downstream of p53 tumor-suppressor signaling. supporting_text: ChIP-seq/ChIP-qPCR showed p53 occupancy near Fbxw9 promoter; p53 increased luciferase reporter activity; p53 knockdown reduced expression; Nutlin-3 induced Fbxw9 in p53-WT but not p53-null human cells - statement: In glioblastoma stem-like cells FBXW9 is a CREB-bound transcriptional target downstream of an IGFBP5-ROR1/HER2 axis, and FBXW9 knockdown reduces invasion, with high FBXW9 associated with worse survival. supporting_text: siRNA against FBXW9 significantly decreased invasion capacity in X01 and 448 GSC lines; high FBXW9 associated with worse glioma/LGG survival - statement: In breast cancer cells FBXW9 knockdown reduces proliferation and induces G0/G1 arrest with increased p21, but TP53 as an FBXW9 ubiquitination substrate remains predicted (UbiBrowser), not biochemically validated. supporting_text: TP53 as substrate remains predicted, not biochemically validated by ubiquitination/degradation assay - statement: No directly validated endogenous ubiquitination substrate for human FBXW9 has been established; the molecular substrate repertoire and degron remain unresolved. supporting_text: No directly validated endogenous ubiquitination substrate for human FBXW9 was recovered; no direct catalytic assay, no substrate degron definition reference_review: relevance: HIGH correctness: VERIFIED review_notes: Falcon synthesis grounded chiefly in Lievens et al. 2009 (J Proteome Res, doi:10.1021/pr8005167; array MAPPIT + co-IP SKP1 interaction) and Lee et al. 2011 (Mol Cell Proteomics, doi:10.1074/mcp.m110.006460; CUL1 AP-MS), which provide direct experimental support for SCF/CRL1 adaptor behavior. Cancer-context studies (Lin 2023 Nat Commun; Yu 2023 Int J Mol Sci; Shin 2024 Genes Dis) describe FBXW9 as a transcriptional target of CREB and p53 with knockdown phenotypes, but report no direct substrate ubiquitination; TP53 substrate is predictive only. The report explicitly flags the CRL7 receptor claim (Jeong 2023 review) as uncorroborated. Cross-checked against UniProt Q5XUX1 FUNCTION/SUBUNIT and ComplexPortal CPX-7785. No annotation action is changed on the basis of these correlative/transcriptional findings. core_functions: - description: Substrate-recognition (substrate-adaptor) subunit of an SCF (SKP1-CUL1-F-box) cullin-RING E3 ubiquitin ligase complex; it docks via its F-box motif onto SKP1 (experimentally validated) and CUL1 (AP-MS), presenting a WD40 propeller for substrate recruitment. FBXW9 is non-catalytic (ubiquitin transfer is RBX1's), and its specific physiological substrates are not yet experimentally defined. supported_by: - reference_id: file:human/FBXW9/FBXW9-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - reference_id: file:human/FBXW9/FBXW9-deep-research-falcon.md supporting_text: FBXW9 was identified as a SKP1-interacting prey in a high-throughput **array MAPPIT** interactome screen and validated by **co-immunoprecipitation** in **HEK293T** cells locations: - id: GO:0005829 label: cytosol 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 FBXW9's annotation set. justification: FBXW9 binds SKP1 (validated by co-IP) and co-purifies with CUL1-containing SCF assemblies, consistent with a substrate-adaptor molecular function rather than catalysis (which is RBX1's). Adding GO:1990756 would give FBXW9 an informative molecular-function term in place of the uninformative bare protein binding annotations, even though its specific substrate is not yet defined. proposed_parent: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: file:human/FBXW9/FBXW9-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - reference_id: file:human/FBXW9/FBXW9-deep-research-falcon.md supporting_text: FBXW9 was identified as a SKP1-interacting prey in a high-throughput **array MAPPIT** interactome screen and validated by **co-immunoprecipitation** in **HEK293T** cells suggested_questions: - question: What are the physiological ubiquitination substrates recognized by the FBXW9 WD40 propeller, and is substrate recognition phosphodegron-dependent? Is the predicted TP53 substrate directly ubiquitinated by SCF(FBXW9)? - question: Do the p53- and CREB-driven transcriptional control of FBXW9 and the breast-cancer/glioblastoma knockdown phenotypes reflect a degradative SCF(FBXW9) substrate, or non-proteolytic/indirect mechanisms? suggested_experiments: - description: Affinity purification of tagged FBXW9 with SKP1/CUL1/RBX1 followed by mass spectrometry to identify co-purifying and ubiquitinated substrate candidates, prioritizing cell types (breast cancer, glioblastoma stem-like cells) where knockdown phenotypes were reported. - description: Reconstitute SCF(FBXW9) in vitro with SKP1, CUL1, RBX1 and an E2, and test ubiquitination of candidate substrates (e.g. TP53 predicted by UbiBrowser) comparing wild-type to F-box-deletion FBXW9.