id: Q969U6 gene_symbol: FBXW5 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXW5 (FBW5) is a 566-residue F-box/WD40-repeat protein that serves as a substrate-recognition subunit for cullin-RING E3 ubiquitin ligases. Through its N-terminal F-box domain (residues 3-49) it binds SKP1 and assembles into the canonical SCF (SKP1-CUL1-RBX1) ligase as the SCF(FBXW5) complex, while its seven WD40 repeats form the substrate-docking surface and additionally allow it to act as a DDB1-binding WD40 (DWD) protein that joins the DDB1-CUL4A/B-RBX1 (DCX/CRL4) ligase as the DCX(FBXW5) complex; deleting the F-box abolishes SKP1 binding yet preserves DDB1/CUL4A bridging, demonstrating that substrate recognition resides in the WD40 repeats while the F-box mediates SCF assembly. As an adaptor, FBXW5 does not itself catalyze ubiquitin transfer (the RING subunit RBX1 recruits the E2) but selects substrates for ubiquitination, most often K48-linked polyubiquitination and proteasomal degradation. Its best-defined substrates are the centriolar cartwheel protein SASS6/HsSAS-6, whose S-phase degradation by SCF(FBXW5) restrains centriole reduplication; the actin-regulator EPS8, degraded during G2 to permit mitotic cell-shape changes; the tumor suppressor TSC2, polyubiquitinated by the DCX(FBXW5)/CRL4 complex to control TSC1-TSC2 complex turnover and mTOR signaling; and the kinesin-13 microtubule depolymerases (MCAK/KIF2C, KIF2A, KIF2B), whose SCF(FBXW5)-mediated degradation in G2 lowers their levels at basal bodies and licenses ciliogenesis in the subsequent G1/G0. Additional substrates reported in cancer and metabolic-disease models include the Rho-GAP tumor suppressor DLC1 (degraded by CRL4A(FBXW5) in non-small-cell lung cancer), the Hippo-pathway kinase LATS1 (degraded in gastric cancer, leading to YAP1 activation), the aquaporin AQP3 (degraded by SCF(FBXW5), tuning PDPK1-AKT-mTOR signaling and autophagic cell death in hepatocellular carcinoma), and the stress kinase ASK1/MAP3K5, which FBXW5 modifies with non-degradative Lys63-linked polyubiquitin chains to activate JNK/p38 MAPK signaling in steatohepatitis. SCF(FBXW5) activity toward SASS6 is inhibited by PLK4 phosphorylation of FBXW5 at Ser151, and FBXW5 itself is a cell-cycle-regulated protein degraded by the APC/C during mitosis and G1 (via a D-box at residues 303-311) and reaccumulating at the G1/S transition. TNFAIP8L1 competes with TSC2 for FBXW5 binding, stabilizing TSC2. FBXW5 has also been reported as a negative regulator of MAP3K7/TAK1 in IL-1B signaling. It is a predominantly cytoplasmic protein. alternative_products: - name: '1' id: Q969U6-1 - name: '2' id: Q969U6-2 sequence_note: VSP_009479, VSP_009480 existing_annotations: - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic transfer of cytoplasmic localization from UniProt subcellular location; consistent with the experimentally documented cytoplasmic localization. action: ACCEPT reason: Correct localization; FBXW5 is documented as a cytoplasmic protein and acts on cytoplasmic/centrosomal substrates. supported_by: - reference_id: file:human/FBXW5/FBXW5-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}.' - term: id: GO:0010564 label: regulation of cell cycle process evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: ARBA machine-learning assignment of regulation of a cell cycle process, a broad parent consistent with FBXW5's role in cell-cycle-coupled degradation of SASS6/EPS8. action: KEEP_AS_NON_CORE reason: Correct but generic; the specific roles (regulation of centrosome duplication, SCF-dependent catabolism) better capture the function. supported_by: - reference_id: file:human/FBXW5/FBXW5-uniprot.txt supporting_text: mediates the ubiquitination and subsequent proteasomal degradation of SASS6 during S phase, leading to prevent centriole reduplication - 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, the general process in which FBXW5 participates as a substrate-recognition adaptor. action: KEEP_AS_NON_CORE reason: Correct but generic; the SCF-dependent proteasomal catabolic process annotation is more specific and informative. supported_by: - reference_id: file:human/FBXW5/FBXW5-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:0000120 qualifier: part_of review: summary: Electronic assignment of SCF complex membership, the core complex for FBXW5 as an F-box substrate receptor of SKP1-CUL1-RBX1. action: ACCEPT reason: Core complex; FBXW5 is the substrate-recognition subunit of the SCF(FBXW5) complex, supported by IDA and UniProt subunit data. supported_by: - reference_id: file:human/FBXW5/FBXW5-uniprot.txt supporting_text: Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXW5) composed of CUL1, SKP1, RBX1 and FBXW5 - term: id: GO:0080008 label: Cul4-RING E3 ubiquitin ligase complex evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: part_of review: summary: InterPro-based assignment of CUL4-RING (CRL4/DCX) complex membership, consistent with FBXW5 acting as a DDB1-binding WD40 adaptor of the DDB1-CUL4-RBX1 ligase. F-box deletion abolishes SKP1 binding yet preserves DDB1-CUL4A bridging, demonstrating SCF-independent CRL4 assembly; in NSCLC the CRL4A(FBXW5) complex degrades the RhoGAP tumor suppressor DLC1. action: ACCEPT reason: Correct second core complex; FBXW5 is a DWD adaptor of the DCX(FBXW5)/CRL4 complex that ubiquitinates TSC2 (and, in NSCLC, DLC1), supported by IDA evidence. supported_by: - reference_id: file:human/FBXW5/FBXW5-uniprot.txt supporting_text: Component of the DCX(FBXW5) E3 ubiquitin ligase complex, at least composed of (CUL4A or CUL4B), DDB1, FBXW5 and RBX1 - reference_id: file:human/FBXW5/FBXW5-deep-research-falcon.md supporting_text: 'Importantly, deletion of the F-box can abolish SKP1 binding yet retain the ability to bridge substrates to DDB1–CUL4A, demonstrating **SCF-independent CRL4 assembly**.' - 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 that links F-box proteins into the SCF complex. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally meaningful FBXW5-SKP1 interaction but bare protein binding is uninformative; SCF membership is captured by GO:0019005. supported_by: - reference_id: file:human/FBXW5/FBXW5-uniprot.txt supporting_text: 'Q969U6; P63208: SKP1; NbExp=8; IntAct=EBI-741068, EBI-307486' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19159283 qualifier: enables review: summary: Array MAPPIT high-throughput interaction with SKP1 (P63208). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records FBXW5-SKP1 interaction from a high-throughput method; bare protein binding is uninformative and subsumed by SCF complex membership. supported_by: - reference_id: file:human/FBXW5/FBXW5-uniprot.txt supporting_text: 'Q969U6; P63208: SKP1; NbExp=8; IntAct=EBI-741068, EBI-307486' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22632967 qualifier: enables review: summary: IntAct interaction with SKP1 (P63208) captured in a study primarily about cyclin F/RRM2. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the FBXW5-SKP1 association; bare protein binding is uninformative and subsumed by SCF complex membership. supported_by: - reference_id: file:human/FBXW5/FBXW5-uniprot.txt supporting_text: 'Q969U6; P63208: SKP1; NbExp=8; IntAct=EBI-741068, EBI-307486' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: Proteome-scale binary interactome capturing assorted FBXW5 partners (e.g. TRIM27, keratin-associated proteins). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interactome; bare protein binding is uninformative and not a core function. supported_by: - reference_id: file:human/FBXW5/FBXW5-uniprot.txt supporting_text: 'Q969U6; P14373: TRIM27; NbExp=6; IntAct=EBI-741068, EBI-719493' - 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 FBXW5-SKP1 (P63208) association. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interaction (SKP1); bare protein binding is uninformative and subsumed by SCF complex membership. supported_by: - reference_id: file:human/FBXW5/FBXW5-uniprot.txt supporting_text: 'Q969U6; P63208: SKP1; NbExp=8; IntAct=EBI-741068, EBI-307486' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Binary interactome reference map capturing many FBXW5 partners, dominated by keratins and keratin-associated proteins. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interactome (many likely sticky/keratin artifacts); bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXW5/FBXW5-uniprot.txt supporting_text: 'Q969U6; Q15323: KRT31; NbExp=6; IntAct=EBI-741068, EBI-948001' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: Cell-specific interactome capturing an FBXW5-SKP1 (P63208) association. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interaction (SKP1); bare protein binding is uninformative and subsumed by SCF complex membership. supported_by: - reference_id: file:human/FBXW5/FBXW5-uniprot.txt supporting_text: 'Q969U6; P63208: SKP1; NbExp=8; IntAct=EBI-741068, 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 FBXW5-SKP1 (P63208) association. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interaction (SKP1); bare protein binding is uninformative and subsumed by SCF complex membership. supported_by: - reference_id: file:human/FBXW5/FBXW5-uniprot.txt supporting_text: 'Q969U6; P63208: SKP1; NbExp=8; IntAct=EBI-741068, EBI-307486' - term: id: GO:0007088 label: regulation of mitotic nuclear division evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Ortholog-based (mouse Q9QXW2) transfer of regulation of mitotic nuclear division, plausibly reflecting FBXW5's centrosome/mitotic-spindle role (overduplication causes multipolar spindles). action: KEEP_AS_NON_CORE reason: Plausible but indirect; FBXW5's documented mitotic link is via centriole/centrosome duplication control rather than direct regulation of nuclear division. supported_by: - reference_id: PMID:21725316 supporting_text: Depletion of endogenous FBXW5 or overexpression of an F-box-deleted mutant version results in centrosome overduplication and formation of multipolar spindles - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: Combined automated assignment of SCF-dependent proteasomal catabolism, the core biological process for FBXW5 as an SCF substrate receptor. action: ACCEPT reason: Core biological process; FBXW5 directs substrates (SASS6, EPS8, kinesin-13s) to SCF-dependent proteasomal degradation, supported by IDA. supported_by: - reference_id: file:human/FBXW5/FBXW5-uniprot.txt supporting_text: mediates the ubiquitination and subsequent proteasomal degradation of SASS6 during S phase - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:34445249 qualifier: part_of review: summary: ComplexPortal non-traceable assertion of SCF complex membership, redundant with the experimentally supported core complex annotation. action: ACCEPT reason: Core complex membership; corroborated by IDA and UniProt subunit composition. supported_by: - reference_id: file:human/FBXW5/FBXW5-uniprot.txt supporting_text: Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXW5) composed of CUL1, SKP1, RBX1 and FBXW5 - 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 non-traceable assertion of SCF-dependent proteasomal catabolism, redundant with the experimentally supported core process. action: ACCEPT reason: Core biological process; redundant with IDA evidence. supported_by: - reference_id: file:human/FBXW5/FBXW5-uniprot.txt supporting_text: mediates the ubiquitination and subsequent proteasomal degradation of SASS6 during S phase - term: id: GO:0051298 label: centrosome duplication evidence_type: NAS original_reference_id: PMID:34388369 qualifier: involved_in review: summary: ComplexPortal assertion of involvement in centrosome duplication; FBXW5 restrains centriole/centrosome reduplication by degrading SASS6. action: ACCEPT reason: Well-supported core biological role; FBXW5 controls centrosome duplication via SASS6 degradation (IMP-supported in PMID:21725316). supported_by: - reference_id: PMID:21725316 supporting_text: centrosome duplication is regulated by the activity of an E3-ubiquitin ligase that employs the F-box protein FBXW5 - term: id: GO:0060271 label: cilium assembly evidence_type: NAS original_reference_id: PMID:34368969 qualifier: involved_in review: summary: ComplexPortal assertion of involvement in cilium assembly, supported by the demonstration that SCF(FBXW5) degrades kinesin-13 proteins to facilitate ciliogenesis. action: ACCEPT reason: Supported core biological role; loss of FBXW5 raises MCAK at basal bodies and impairs ciliogenesis, rescued by kinesin-13 knockdown. supported_by: - reference_id: PMID:34368969 supporting_text: loss of Fbxw5 leads to increased MCAK levels at basal bodies and impairs ciliogenesis in the following G1 /G0 , which can be rescued by concomitant knockdown of MCAK, Kif2a or Kif2b - term: id: GO:0010824 label: regulation of centrosome duplication evidence_type: IMP original_reference_id: PMID:21725316 qualifier: involved_in review: summary: Mutant-phenotype evidence that FBXW5 regulates centrosome duplication; depletion or F-box-deletion causes centrosome overduplication. Core biological process. action: ACCEPT reason: Core biological process with direct experimental (IMP) support via SASS6 substrate control. supported_by: - reference_id: PMID:21725316 supporting_text: Depletion of endogenous FBXW5 or overexpression of an F-box-deleted mutant version results in centrosome overduplication and formation of multipolar spindles - 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 the documented cytoplasmic localization. action: ACCEPT reason: Correct localization, consistent with experimental cytoplasmic localization; the CRL-cycle Reactome events are pathway-context annotations. supported_by: - reference_id: file:human/FBXW5/FBXW5-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}.' - 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/FBXW5/FBXW5-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}.' - 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/FBXW5/FBXW5-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}.' - 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/FBXW5/FBXW5-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}.' - 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/FBXW5/FBXW5-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}.' - 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/FBXW5/FBXW5-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}.' - 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/FBXW5/FBXW5-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}.' - 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/FBXW5/FBXW5-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}.' - 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/FBXW5/FBXW5-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}.' - 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/FBXW5/FBXW5-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}.' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18381890 qualifier: enables review: summary: IntAct interactions with TSC2 (P49815) and TSC1 (Q92574), the substrate complex of the DCX(FBXW5) ligase. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally important FBXW5-TSC2/TSC1 substrate interaction but bare protein binding is uninformative; substrate relationship is captured by the catabolic-process annotations. supported_by: - reference_id: PMID:18381890 supporting_text: TSC2 protein binds to FBW5, a DDB1-binding WD40 (DWD) protein, and is recruited by FBW5 to the DDB1-CUL4-ROC1 E3 ubiquitin ligase - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21725316 qualifier: enables review: summary: IntAct interactions with CDC20 (Q12834) and SASS6 (Q6UVJ0); SASS6 is a key FBXW5 substrate. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally important FBXW5-SASS6 substrate interaction (and CDC20) but bare protein binding is uninformative. supported_by: - reference_id: PMID:21725316 supporting_text: FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:21725316 qualifier: located_in review: summary: Direct experimental evidence (immunolocalization) for cytoplasmic localization of FBXW5. action: ACCEPT reason: Core localization with direct experimental support. supported_by: - reference_id: file:human/FBXW5/FBXW5-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}.' - term: id: GO:0016567 label: protein ubiquitination evidence_type: IDA original_reference_id: PMID:18381890 qualifier: involved_in review: summary: Direct evidence that FBXW5 (in the DCX/CRL4 ligase) promotes ubiquitination of TSC2. The general ubiquitination process. action: KEEP_AS_NON_CORE reason: Correct but generic; FBXW5 acts as adaptor in TSC2 ubiquitination/degradation - better captured by the proteasomal catabolic-process annotations. supported_by: - reference_id: PMID:18381890 supporting_text: CUL4, DDB1, and FBW5 are required for the ubiquitination of TSC2 in vivo and in vitro - term: id: GO:0016567 label: protein ubiquitination evidence_type: IDA original_reference_id: PMID:21725316 qualifier: involved_in review: summary: Direct evidence that FBXW5 (in SCF) promotes ubiquitination of SASS6/HsSAS-6. The general ubiquitination process. action: KEEP_AS_NON_CORE reason: Correct but generic; the specific SCF-dependent proteasomal catabolic process annotation is more informative. supported_by: - reference_id: PMID:21725316 supporting_text: FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:21725316 qualifier: part_of review: summary: Direct evidence that FBXW5 is the F-box receptor of an SCF complex (SCF-FBXW5) targeting HsSAS-6. Core complex. action: ACCEPT reason: Core complex membership with direct experimental support. supported_by: - reference_id: PMID:21725316 supporting_text: centrosome duplication is regulated by the activity of an E3-ubiquitin ligase that employs the F-box protein FBXW5 - term: id: GO:0019901 label: protein kinase binding evidence_type: IPI original_reference_id: PMID:21725316 qualifier: enables review: summary: IntAct interaction with the kinase PLK4 (O00444), which phosphorylates FBXW5 at Ser151 to inhibit its activity toward SASS6. A regulatory interaction. action: KEEP_AS_NON_CORE reason: Records a real, functionally meaningful regulatory interaction with PLK4 but is subsidiary to the core adaptor/catabolic function. supported_by: - reference_id: PMID:21725316 supporting_text: negatively regulated by Polo-like kinase 4 (PLK4), which phosphorylates FBXW5 at Ser 151 to suppress its ability to ubiquitylate HsSAS-6 - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:21725316 qualifier: involved_in review: summary: Direct evidence that FBXW5 directs SASS6 to SCF-dependent proteasomal degradation. Core biological process. action: ACCEPT reason: Core biological process with direct experimental support. supported_by: - reference_id: file:human/FBXW5/FBXW5-uniprot.txt supporting_text: mediates the ubiquitination and subsequent proteasomal degradation of SASS6 during S phase, leading to prevent centriole reduplication - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:18381890 qualifier: involved_in review: summary: Direct evidence that FBXW5 promotes proteasomal degradation of TSC2 via the DCX/CRL4 ligase. A parent of the SCF-specific catabolic process; here the relevant complex is CRL4. action: ACCEPT reason: Correct core biological process; FBXW5 (DCX complex) drives proteasome-mediated degradation of TSC2. supported_by: - reference_id: PMID:18381890 supporting_text: Overexpression of FBW5 or CUL4A promotes TSC2 protein degradation - term: id: GO:0080008 label: Cul4-RING E3 ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:18381890 qualifier: part_of review: summary: Direct evidence that FBXW5 is a component (DWD adaptor) of the DDB1-CUL4-RBX1 (DCX/CRL4) E3 ligase that ubiquitinates TSC2. Core complex. action: ACCEPT reason: Core complex membership with direct experimental support. supported_by: - reference_id: PMID:18381890 supporting_text: TSC2 protein binds to FBW5, a DDB1-binding WD40 (DWD) protein, and is recruited by FBW5 to the DDB1-CUL4-ROC1 E3 ubiquitin ligase - term: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity evidence_type: IDA original_reference_id: PMID:21725316 qualifier: enables review: summary: FBXW5 functions as the substrate-recognition adaptor that bridges target proteins (SASS6, TSC2, EPS8, kinesin-13s) to the catalytic cullin-RING ligase core; this is its core molecular function and is more informative than the bare protein binding annotations. Not currently in GOA. action: NEW reason: Captures the actual molecular function of FBXW5 as an F-box/DWD substrate-specific adaptor of SCF/CRL4 ligases, replacing uninformative protein binding terms. proposed_replacement_terms: - id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: PMID:21725316 supporting_text: FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo - reference_id: PMID:18381890 supporting_text: TSC2 protein binds to FBW5, a DDB1-binding WD40 (DWD) protein, and is recruited by FBW5 to the DDB1-CUL4-ROC1 E3 ubiquitin ligase references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms 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:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models 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 FBXW5-SKP1 (P63208) IntAct interaction; the paper itself is about Wee1/beta-TrCP, the SKP1 binding is a generic F-box/SCF contact. - id: PMID:18381890 title: WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by DDB1-CUL4-ROC1 ligase. findings: - statement: FBW5/FBXW5 is a DDB1-binding WD40 (DWD) adaptor that recruits TSC2 to the DDB1-CUL4-ROC1 (CRL4) E3 ligase; CUL4/DDB1/FBW5 are required for TSC2 ubiquitination in vivo and in vitro, and overexpression promotes TSC2 degradation while depletion stabilizes it. reference_section_type: RESULTS reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text available; establishes the DCX(FBXW5)/CRL4 role in TSC2 ubiquitination and degradation. - id: PMID:19159283 title: 'Array MAPPIT: high-throughput interactome analysis in mammalian cells.' findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput MAPPIT interactome; source of an FBXW5-SKP1 (P63208) interaction. - id: PMID:21725316 title: The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication. findings: - statement: SCF-FBXW5 ubiquitinates the centriolar protein HsSAS-6/SASS6 to restrain centriole reduplication; activity is inhibited by PLK4 phosphorylation of FBXW5 Ser151, and FBXW5 is itself an APC/C substrate degraded in mitosis and G1 with levels peaking at G1/S. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract only in cache (full_text_available false); IMP/IDA annotations rely on full text read by the curator. Source of SASS6 substrate, SCF complex, PLK4 regulation, and centrosome-duplication roles. - 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: Paper concerns cyclin F/RRM2; source of an FBXW5-SKP1 (P63208) generic SCF contact in IntAct. - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput interactome; source of multiple bare protein binding annotations (TRIM27, keratin-associated proteins). - 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 an FBXW5-SKP1 (P63208) interaction. - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Binary interactome reference map; source of many bare protein binding annotations dominated by keratins/keratin-associated proteins (likely nonspecific). - 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 an FBXW5-SKP1 (P63208) interaction. - id: PMID:34368969 title: SCF(Fbxw5) targets kinesin-13 proteins to facilitate ciliogenesis. findings: - statement: SCF(FBXW5) polyubiquitinates kinesin-13 microtubule depolymerases MCAK/KIF2C, KIF2A and KIF2B and targets MCAK for proteasomal degradation predominantly in G2; loss of FBXW5 raises MCAK at basal bodies and impairs ciliogenesis in the subsequent G1/G0, rescued by kinesin-13 knockdown. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text available; establishes the kinesin-13/ciliogenesis substrate axis and supports the cilium-assembly role. - id: PMID:34388369 title: Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Cited by ComplexPortal as support for the centrosome-duplication NAS annotation; the title is about the signal peptidase complex, so the citation appears tangential, but the centrosome-duplication role itself is well supported by PMID:21725316. - id: PMID:34445249 title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Review/ComplexPortal source supporting SCF complex membership and SCF-dependent catabolism. - 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 an FBXW5-SKP1 (P63208) interaction. - 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/FBXW5/FBXW5-deep-research-falcon.md title: Falcon deep research report for human FBXW5 findings: - statement: FBXW5 is a substrate receptor that uses its WD40 repeats for substrate docking and its F-box for SCF assembly; F-box deletion abolishes SKP1 binding but preserves DDB1-CUL4A bridging, demonstrating SCF-independent CRL4 assembly. supporting_text: 'Importantly, deletion of the F-box can abolish SKP1 binding yet retain the ability to bridge substrates to DDB1–CUL4A, demonstrating **SCF-independent CRL4 assembly**.' - statement: SCF(FBXW5) targets kinesin-13 proteins including MCAK/KIF2C for K48-linked polyubiquitylation and proteasomal degradation in G2, and FBXW5 loss raises MCAK at basal bodies impairing ciliogenesis. supporting_text: FBXW5 functions in SCF^FBXW5^ to polyubiquitylate kinesin-13 proteins, including **MCAK/KIF2C**, promoting proteasomal degradation predominantly in **G2**. - statement: FBXW5 ubiquitinates ASK1 with non-degradative Lys63-linked chains, activating JNK/p38 MAPK stress signaling in NASH, in contrast to its degradative K48 modification of other substrates. supporting_text: In hepatocytes, FBXW5 in an **SCF complex** directly interacts with and ubiquitinates **ASK1**, promoting **Lys63-linked polyubiquitination** that enhances ASK1 activation and downstream **JNK/p38 MAPK signaling** in diet-induced NASH models. - statement: In NSCLC, FBXW5 acts as the substrate receptor of CRL4A (CUL4A-DDB1-FBXW5) to polyubiquitinate and degrade the RhoGAP tumor suppressor DLC1; CUL4A or DDB1 depletion (but not CUL4B) stabilizes DLC1. supporting_text: In NSCLC, FBXW5 functions as a substrate receptor within **CRL4A (CUL4A–DDB1–FBXW5)** to promote polyubiquitination and proteasomal degradation of the RhoGAP tumor suppressor **DLC1**. - statement: SCF(FBXW5) degrades AQP3 in hepatocellular carcinoma, and AQP3 accumulation after FBXW5 loss lowers PDPK1/AKT/mTOR signaling and increases autophagic cell death; the AQP3 ubiquitin acceptor site is K282. supporting_text: increased AQP3 after FBXW5 knockdown leads to **lysosomal-dependent reduction of PDPK1**, decreased **AKT phosphorylation**, and reduced downstream **mTOR activity** reference_review: relevance: HIGH correctness: VERIFIED review_notes: 'Falcon synthesis of FBXW5 primary literature; substrate set (SASS6, EPS8, TSC2, kinesin-13s, DLC1, LATS1, AQP3, ASK1) cross-checked against UniProt Q969U6 (SASS6/EPS8/TSC2/TAK1) and cached PMID:18381890/PMID:21725316/PMID:34368969. New substrate leads (AQP3, ASK1, LATS1, DLC1) are from single primary papers not yet in GOA; treated as supporting context, not as basis to overrule curated annotations.' core_functions: - description: Substrate-recognition subunit of the SCF(FBXW5) (SKP1-CUL1-RBX1) E3 ubiquitin ligase that selects the centriolar cartwheel protein SASS6/HsSAS-6 for polyubiquitination and proteasomal degradation, thereby restraining centriole/centrosome reduplication; regulated by PLK4 phosphorylation at Ser151. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: PMID:21725316 supporting_text: FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo directly_involved_in: - id: GO:0010824 label: regulation of centrosome duplication - description: DDB1-binding WD40 (DWD) substrate adaptor of the DCX(FBXW5)/CRL4 (DDB1-CUL4A/B-RBX1) E3 ubiquitin ligase that recruits the tumor suppressor TSC2 for polyubiquitination and proteasomal degradation, controlling TSC1-TSC2 complex turnover. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: PMID:18381890 supporting_text: TSC2 protein binds to FBW5, a DDB1-binding WD40 (DWD) protein, and is recruited by FBW5 to the DDB1-CUL4-ROC1 E3 ubiquitin ligase directly_involved_in: - id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process - description: SCF(FBXW5) substrate receptor that targets kinesin-13 microtubule depolymerases (MCAK/KIF2C, KIF2A, KIF2B) for proteasomal degradation in G2, lowering their levels at basal bodies and licensing ciliogenesis in the following G1/G0. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: PMID:34368969 supporting_text: loss of Fbxw5 leads to increased MCAK levels at basal bodies and impairs ciliogenesis in the following G1 /G0 , which can be rescued by concomitant knockdown of MCAK, Kif2a or Kif2b directly_involved_in: - id: GO:0060271 label: cilium assembly proposed_new_terms: [] suggested_questions: - question: What determines partition of FBXW5 between the SCF(CUL1) and DCX(CRL4) ligases, and is substrate choice (SASS6/EPS8/kinesin-13 vs TSC2) dictated by which cullin scaffold FBXW5 engages? - question: How is the cell-cycle timing of FBXW5 activity (G1/S reaccumulation, PLK4 inhibition, APC/C-mediated destruction) integrated to coordinate centriole duplication, mitotic cell-shape changes, and ciliogenesis? suggested_experiments: - description: Reconstitute SCF(FBXW5) and DCX(FBXW5) ligases in vitro with purified components and candidate substrates (SASS6, EPS8, MCAK/KIF2C, TSC2) to determine which cullin scaffold each substrate requires and to map ubiquitination sites and chain linkages. - description: Use degron/auxin-inducible depletion of FBXW5 combined with quantitative proteomics and ubiquitinomics across the cell cycle to define the endogenous substrate repertoire and the relative contributions of the CUL1 vs CUL4 complexes.