id: Q6X9E4 gene_symbol: FBXW12 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXW12 (F-box only protein 35; FBXO12/FBXO35) is a member of the F-box/WD40 (FBXW) family, with an N-terminal F-box motif and a C-terminal beta-propeller of WD40 repeats. F-box proteins are 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 bridges to CUL1 and the RBX1-bound catalytic RING), while the WD40 propeller recognizes substrates and presents them for ubiquitination and proteasomal degradation. FBXW12 is ubiquitously expressed. It binds SKP1 and assembles into an SCF complex, and in human epithelial cells it functions as a substrate receptor that ubiquitinates the interleukin-22 receptor subunit IL22RA1: ectopic FBXW12 accelerates IL22RA1 degradation in resting and IL-22-stimulated cells, and FBXW12 reconstitutes IL22RA1 ubiquitination in a defined cell-free SCF system. Through this activity FBXW12 dampens IL-22/STAT3 signaling and acts as an epithelial cell-growth suppressor, with its knockdown enhancing proliferation, cell-cycle progression and JNK/ERK activation. existing_annotations: - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: ARBA machine-learning electronic assignment of cytoplasmic localization, a generic compartment consistent with cytosolic SCF assembly. action: KEEP_AS_NON_CORE reason: Plausible generic localization but electronically inferred and not directly demonstrated for FBXW12; subsumed by the more specific cytosol annotations. supported_by: - reference_id: file:human/FBXW12/FBXW12-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - term: id: GO:0016567 label: protein ubiquitination evidence_type: IEA original_reference_id: GO_REF:0000041 qualifier: involved_in review: summary: UniPathway-derived general protein ubiquitination process; FBXW12 facilitates ubiquitination of its substrate IL22RA1 in a defined cell-free SCF system. action: ACCEPT reason: Correct process; FBXW12 facilitates substrate ubiquitination as an SCF subunit, directly demonstrated in vitro for IL22RA1, though the more specific GO:0031146 captures the proteasomal-degradation context. additional_reference_ids: - file:human/FBXW12/FBXW12-deep-research-falcon.md supported_by: - reference_id: PMID:26171402 supporting_text: facilitates ubiquitination of IL-22R in vitro - reference_id: file:human/FBXW12/FBXW12-deep-research-falcon.md supporting_text: In a cell-free system, IL-22R ubiquitination is observed when ubiquitin machinery and SCF constituents (including FBXW12) are present - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:26171402 qualifier: part_of review: summary: Assignment of SCF complex membership; FBXW12 binds SKP1 and CUL1 and assembles with Rbx1 into a functional SCF E3 ligase (ComplexPortal CPX-7822, SCF complex FBXW12 variant). action: ACCEPT reason: Core assembly annotation, experimentally supported by demonstrated SKP1 (and CUL1) binding and reconstitution of FBXW12 into an active SCF that ubiquitinates IL-22R in vitro. additional_reference_ids: - file:human/FBXW12/FBXW12-deep-research-falcon.md supported_by: - reference_id: PMID:26171402 supporting_text: FBXW12 is a bona fide SCF E3 ligase constituent that can bind to IL-22R and other components of SCF to mediate IL-22R ubiquitination - reference_id: file:human/FBXW12/FBXW12-deep-research-falcon.md supporting_text: FBXW12 associates with SCF components including **SKP1** and **CUL1**, consistent with being an SCF substrate receptor - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:26171402 qualifier: involved_in review: summary: Assignment of involvement in SCF-dependent proteasomal degradation; FBXW12 drives proteasomal degradation of IL22RA1, shortening its half-life from ~6 h to ~2 h. action: ACCEPT reason: Core biological process, experimentally supported by accelerated IL22RA1 degradation upon FBXW12 expression and stabilization upon FBXW12 knockdown. additional_reference_ids: - file:human/FBXW12/FBXW12-deep-research-falcon.md supported_by: - reference_id: PMID:26171402 supporting_text: In the presence of overexpressed FBXW12, we observe an accelerated degradation of IL-22R with half-life closer to 2 hours - reference_id: file:human/FBXW12/FBXW12-deep-research-falcon.md supporting_text: IL-22R half-life is reported to be ~**6 hours** at baseline and is accelerated to ~**2 hours** with FBXW12 overexpression - 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 FBXW12 as an SCF subunit. action: KEEP_AS_NON_CORE reason: Plausible cytosolic localization for an SCF substrate receptor, consistent with FBXW12 assembling SCF and acting on IL22RA1 in cells, but derived from generic CRL pathway reactions rather than FBXW12-specific localization data. supported_by: - reference_id: file:human/FBXW12/FBXW12-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 FBXW12. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations. supported_by: - reference_id: file:human/FBXW12/FBXW12-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 FBXW12. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations. supported_by: - reference_id: file:human/FBXW12/FBXW12-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 FBXW12. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations. supported_by: - reference_id: file:human/FBXW12/FBXW12-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 FBXW12. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations. supported_by: - reference_id: file:human/FBXW12/FBXW12-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 FBXW12. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations. supported_by: - reference_id: file:human/FBXW12/FBXW12-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 FBXW12. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations. supported_by: - reference_id: file:human/FBXW12/FBXW12-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 FBXW12. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations. supported_by: - reference_id: file:human/FBXW12/FBXW12-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 FBXW12. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations. supported_by: - reference_id: file:human/FBXW12/FBXW12-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 FBXW12. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations. supported_by: - reference_id: file:human/FBXW12/FBXW12-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex references: - id: GO_REF:0000041 title: Gene Ontology annotation based on UniPathway vocabulary mapping findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: PMID:26171402 title: The Human IL-22 Receptor Is Regulated through the Action of the Novel E3 Ligase Subunit FBXW12, Which Functions as an Epithelial Growth Suppressor. findings: - statement: FBXW12 destabilizes human IL-22R (IL22RA1) in lung epithelia, binds SKP1, and facilitates IL22RA1 ubiquitination in a defined cell-free SCF system; FBXW12 knockdown increases IL22RA1 abundance and IL-22-induced STAT3 phosphorylation, and FBXW12 acts as an epithelial cell-growth suppressor (knockdown increases proliferation, cell-cycle progression and JNK/ERK activation). reference_section_type: RESULTS reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified; full text available. Sole functional study, providing experimental support for SCF assembly (SKP1 binding, in vitro reconstitution), IL22RA1 ubiquitination, and SCF-dependent proteasomal degradation. Basis for proposing the substrate-adaptor molecular function term. - 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/FBXW12/FBXW12-deep-research-falcon.md title: Falcon deep research report for human FBXW12 findings: - statement: FBXW12 is an SCF-family E3 ligase subunit that physically associates with SKP1 and CUL1 and with IL-22R (IL22RA1), and reconstitutes IL-22R ubiquitination in a cell-free system, confirming it as a substrate-recognition adaptor rather than an enzyme. supporting_text: FBXW12 associates with SCF components including **SKP1** and **CUL1**, consistent with being an SCF substrate receptor - statement: Ectopic FBXW12 accelerates IL-22R turnover (half-life ~6 h to ~2 h), and FBXW12 knockdown increases IL-22R abundance and IL-22-induced STAT3, ERK and JNK signaling, defining FBXW12 as a negative post-translational regulator of IL-22 signaling and an epithelial growth suppressor. supporting_text: IL-22R half-life is reported to be ~**6 hours** at baseline and is accelerated to ~**2 hours** with FBXW12 overexpression - statement: Beyond IL-22R no additional validated FBXW12 substrate, ubiquitin linkage type, or definitive subcellular localization has been established, so substrate scope remains open. supporting_text: additional validated FBXW12 protein substrates, ubiquitin linkage types, and definitive subcellular localization were not identified in the retrieved materials - statement: A circular RNA (circ-FBXW12) from the FBXW12 locus is discussed in diabetic nephropathy, but this circRNA biology is distinct from and must not be conflated with the linear FBXW12 protein's E3-adaptor function. supporting_text: This evidence concerns **circRNA biology**, and should not be conflated with the **linear FBXW12 protein**'s E3-ligase substrate receptor activity reference_review: relevance: HIGH correctness: VERIFIED review_notes: Falcon synthesis grounded chiefly in Franz et al. 2015 (J Immunol Res, doi:10.1155/2015/912713 = PMID:26171402; full text available and already the basis of this review), which provides SKP1/CUL1 association, IL22RA1 co-IP, cell-free SCF reconstitution of IL22RA1 ubiquitination, accelerated IL22RA1 turnover, and the epithelial growth-suppressor phenotype. Cross-checked against UniProt Q6X9E4 FUNCTION/SUBUNIT statements and ComplexPortal CPX-7822. The 2024 spermatogenesis review (Xuan) reports FBXW12 among high-testis-transcript F-box genes, which is a transcript-level observation that does not override the UniProt 'ubiquitously expressed' tissue-specificity statement; the circ-FBXW12 (diabetic nephropathy) literature is explicitly excluded as it concerns a distinct gene product. No annotation action changed by the falcon report. core_functions: - description: Substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) cullin-RING E3 ubiquitin ligase complex that binds SKP1 and bridges substrate to the ligase; it ubiquitinates the IL-22 receptor subunit IL22RA1, targeting it for SCF-dependent proteasomal degradation. supported_by: - reference_id: PMID:26171402 supporting_text: FBXW12 is a bona fide SCF E3 ligase constituent that can bind to IL-22R and other components of SCF to mediate IL-22R ubiquitination locations: - id: GO:0005829 label: cytosol directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process - description: By degrading IL22RA1, FBXW12 negatively regulates IL-22/STAT3 cytokine signaling and acts as an epithelial cell-growth suppressor, restraining proliferation and cell-cycle progression. supported_by: - reference_id: PMID:26171402 supporting_text: FBXW12 functions as a cell growth suppressor 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 FBXW12's annotation set. justification: FBXW12 directly bridges the substrate IL22RA1 to the SCF E3 ligase, binding SKP1 and the substrate and facilitating substrate ubiquitination in a reconstituted system. This substrate-adaptor molecular function is experimentally supported (PMID:26171402) and is more informative than the existing bare protein binding/complex-membership annotations; GO:1990756 should be added as the molecular function for FBXW12 as an SCF substrate receptor. proposed_parent: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: PMID:26171402 supporting_text: FBXW12 is a bona fide SCF E3 ligase constituent that can bind to IL-22R and other components of SCF to mediate IL-22R ubiquitination - reference_id: file:human/FBXW12/FBXW12-deep-research-falcon.md supporting_text: FBXW12 associates with SCF components including **SKP1** and **CUL1**, consistent with being an SCF substrate receptor suggested_questions: - question: What is the substrate-recognition determinant (e.g. a phosphodegron) on IL22RA1 recognized by the FBXW12 WD40 propeller, and does FBXW12 have additional epithelial substrates beyond IL22RA1? - question: Does FBXW12 loss-of-function in vivo enhance IL-22-dependent mucosal host defense or epithelial proliferation, as predicted from the cell-based growth-suppressor phenotype? suggested_experiments: - description: Map the IL22RA1 region/residues required for FBXW12 binding and ubiquitination, and test whether dephosphorylation or degron mutation abolishes recognition by the FBXW12 WD40 propeller. - description: Generate FBXW12-knockout epithelial cells and tissues and assess endogenous IL22RA1 stability, IL-22-induced STAT3 signaling, proliferation, and identify the broader SCF(FBXW12) substrate repertoire by ubiquitinome profiling.