id: Q969H0 gene_symbol: FBXW7 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXW7 (also known as hCdc4, SEL-10, FBW7, Archipelago homolog) is the F-box/WD40 substrate-recognition subunit of an SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex. Its N-terminal F-box domain binds SKP1 (and thereby connects to the CUL1-RBX1 catalytic core), while its C-terminal eight-bladed WD40 beta-propeller forms a phosphodegron-binding pocket that recognizes Cdc4 phosphodegron (CPD) motifs (a high-affinity consensus is pThr-Pro-Pro-X-pSer, with the central phosphothreonine at the P0 position), typically generated by GSK3, CDK1/2, or ERK/MAPK priming-plus-phosphorylation schemes; low-affinity and noncanonical CPDs can also be biologically decisive. By recruiting these phosphorylated substrates to the SCF complex, FBXW7 directs their polyubiquitination and subsequent proteasomal degradation. FBXW7 is a major tumor suppressor: it targets a network of oncoproteins and regulatory proteins for destruction, including cyclin E (CCNE1/CCNE2), MYC and N-MYC, the NOTCH1/NOTCH2/NOTCH4 intracellular domains, JUN, MCL1, MLST8, RICTOR, NR1D1 (REV-ERBalpha), presenilin 1, EGFR (via CPD-like motifs in its cytoplasmic tail), the Wnt effectors LEF1 and TCF7L2, and the mitophagy kinase PINK1. FBXW7 functions as a homodimer, which tunes substrate turnover and processivity. Three N-terminally distinct isoforms (alpha/nucleoplasm, beta/cytoplasm, gamma/nucleolus) localize to different subcellular compartments and access partly distinct substrate pools. Through this substrate-receptor activity FBXW7 governs cell-cycle progression (G1/S transition), Notch signaling, MYC-driven proliferation, EGFR/MAPK and Wnt/beta-catenin signaling, lipid and circadian metabolism, mitochondrial quality control, and bone homeostasis. Beyond canonical degradative K48-type ubiquitination, an ATM-phosphorylated SCF(FBXW7) pool can promote non-degradative K63-linked polyubiquitination of XRCC4 at DNA double-strand breaks to facilitate non-homologous end joining. Loss-of-function mutations, frequently clustered in the WD40 substrate-binding arginines (hotspots R465, R479, R505), are among the most common in human cancers, where they stabilize oncogenic substrates and can drive resistance to anti-EGFR and anti-Wnt therapies; germline FBXW7 variants cause an autosomal dominant neurodevelopmental disorder (DEDHIL). existing_annotations: - term: id: GO:0005634 label: nucleus evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Phylogenetic assignment of nuclear localization, consistent with the predominantly nuclear isoform 1 (FBW7alpha). action: ACCEPT reason: FBXW7 isoform 1 is nuclear/nucleoplasmic and acts on nuclear substrates (MYC, NOTCH ICD, cyclin E); supported experimentally. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 1]: Nucleus, nucleoplasm' - term: id: GO:0005737 label: cytoplasm evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Phylogenetic assignment of cytoplasmic localization, matching the cytoplasmic isoform 2 (FBW7beta). action: ACCEPT reason: Isoform 2 is documented as cytoplasmic; FBXW7 acts in the cytoplasm on substrates such as MCL1 and RICTOR. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 2]: Cytoplasm' - term: id: GO:0010992 label: ubiquitin recycling evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic assignment of ubiquitin recycling. FBXW7 is a substrate receptor that promotes substrate polyubiquitination; it is not directly involved in recycling free ubiquitin. action: MARK_AS_OVER_ANNOTATED reason: Ubiquitin recycling (deubiquitination/regeneration of free ubiquitin) is not a documented FBXW7 function; the core role is phosphodegron-directed substrate ubiquitination, not ubiquitin pool recycling. Propagated generically through the F-box phylogeny. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex - term: id: GO:0043130 label: ubiquitin binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: Phylogenetic assignment of ubiquitin binding. FBXW7 recognizes phosphodegrons on substrates rather than ubiquitin itself; the relevant binding activity is phosphothreonine/phosphodegron recognition. action: MARK_AS_OVER_ANNOTATED reason: FBXW7's characterized molecular recognition is of phospho-degron motifs (phosphothreonine residue binding), not free ubiquitin. No direct evidence FBXW7 is a ubiquitin-binding module. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: Recognizes and binds phosphorylated sites/phosphodegrons within target proteins - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic assignment of proteasome-mediated ubiquitin-dependent catabolism, the core biological process of FBXW7 as an SCF substrate receptor. action: ACCEPT reason: Core process; FBXW7 directs substrates to proteasomal degradation, directly supported by IDA/IMP evidence. supported_by: - reference_id: PMID:15103331 supporting_text: Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1 - term: id: GO:0005654 label: nucleoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic transfer of nucleoplasm localization from the UniProt subcellular location for isoform 1. action: ACCEPT reason: Correct localization for isoform 1; supported experimentally (IDA). supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 1]: Nucleus, nucleoplasm' - term: id: GO:0005694 label: chromosome evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic transfer of chromosome localization, reflecting ATM-dependent recruitment of FBXW7 to DNA double-strand breaks. action: KEEP_AS_NON_CORE reason: Real but context-specific (DNA-damage-induced) localization to chromatin/DSB sites; not the constitutive site of the core SCF substrate-receptor function. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: Localizes to site of double-strand breaks following phosphorylation by ATM - term: id: GO:0005730 label: nucleolus evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic transfer of nucleolar localization corresponding to isoform 3 (FBW7gamma). action: KEEP_AS_NON_CORE reason: Correct isoform-3 localization but a secondary compartment relative to the dominant nucleoplasmic/cytoplasmic pools. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 3]: Nucleus, nucleolus' - 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 (isoform 2). action: ACCEPT reason: Correct localization for isoform 2; supported experimentally. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 2]: Cytoplasm' - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: ARBA machine-learning assignment of the SCF-dependent proteasomal degradation process, the core biological role of FBXW7. action: ACCEPT reason: Core biological process; directly supported by multiple IDA/IMP annotations and the UniProt FUNCTION statement. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: which mediates the ubiquitination and subsequent proteasomal degradation of target proteins - term: id: GO:0042752 label: regulation of circadian rhythm evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: ARBA assignment of circadian rhythm regulation, reflecting FBXW7-mediated degradation of the clock repressor NR1D1/REV-ERBalpha. action: KEEP_AS_NON_CORE reason: A genuine downstream physiological role (via NR1D1 degradation) but a specialized output of the core substrate-receptor function rather than the core function itself. supported_by: - reference_id: PMID:27238018 supporting_text: core inhibitory component of clock transcription, is targeted for ubiquitination - term: id: GO:0048731 label: system development evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: ARBA assignment of the very general term system development. action: MARK_AS_OVER_ANNOTATED reason: Uninformatively general; FBXW7 has specific developmental roles (Notch signaling, bone, neurodevelopment) better captured by more precise terms. - term: id: GO:1901800 label: positive regulation of proteasomal protein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: ARBA assignment that FBXW7 positively regulates proteasomal protein catabolism, consistent with its role driving substrate degradation. action: KEEP_AS_NON_CORE reason: Correct but a regulatory parent of the more specific SCF-dependent catabolic process annotation that better captures the core role. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: which mediates the ubiquitination and subsequent proteasomal degradation of target proteins - term: id: GO:1903378 label: positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: ARBA assignment reflecting Fbw7beta-mediated destabilization of the pro-survival factor MCL1 in neurons under oxidative stress. action: KEEP_AS_NON_CORE reason: A specialized neuronal consequence of FBXW7 substrate targeting (MCL1); peripheral to the core function. supported_by: - reference_id: PMID:23858059 supporting_text: Parkin-dependent degradation of the F-box protein Fbw7β promotes - term: id: GO:2000060 label: positive regulation of ubiquitin-dependent protein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: ARBA assignment that FBXW7 positively regulates ubiquitin-dependent catabolism, consistent with its substrate-targeting role. action: KEEP_AS_NON_CORE reason: Correct regulatory parent; the specific SCF-dependent proteasomal catabolic process annotation better captures the core role. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: which mediates the ubiquitination and subsequent proteasomal degradation of target proteins - term: id: GO:2001205 label: negative regulation of osteoclast development evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: ARBA assignment of negative regulation of osteoclast development, reflecting SCF(FBW7)-mediated degradation of NOTCH2 that restrains osteoclast activity. action: KEEP_AS_NON_CORE reason: Genuine physiological role via NOTCH2 degradation but a specialized downstream output, not the core function. supported_by: - reference_id: PMID:29149593 supporting_text: we demonstrate that sustained osteoclast activity is largely due to accumulation - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:15070733 qualifier: enables review: summary: Interaction captured in a study of phospho-dependent ubiquitination of Wee1. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction but bare protein binding is uninformative per curation guidelines. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17157259 qualifier: enables review: summary: Interaction in a c-MYC E-box target study (SNIP1). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction but bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17314511 qualifier: enables review: summary: c-MYC-associated proteome (TAP/MudPIT) interaction. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally relevant FBXW7-MYC association, but bare protein binding is uninformative; the substrate relationship is captured elsewhere. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17909182 qualifier: enables review: summary: Interaction captured in a study of KSHV LANA stabilizing activated Notch via Sel10/FBXW7. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction relevant to Notch regulation but bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19111882 qualifier: enables review: summary: Interaction captured in an N-Myc/Aurora A stabilization study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction relevant to N-MYC turnover but bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19412162 qualifier: enables review: summary: Interaction captured in an FBXO31/cyclin D1 degradation study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction but bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20596027 qualifier: enables review: summary: Interaction captured in a cyclin F/CP110 centrosome study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction but bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20823234 qualifier: enables review: summary: Interaction in an HTLV-1 Notch/ATL study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction relevant to Notch regulation but bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21145461 qualifier: enables review: summary: Interaction captured in a quantitative proteomics map of the cullin-RING ligase network. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Documents CRL-network associations (SCF assembly) but bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21620836 qualifier: enables review: summary: Interaction captured in a study of PI3K-dependent FBXW7 phosphorylation. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction but bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22307056 qualifier: enables review: summary: Interaction in an ERK/KLF4 ES cell self-renewal study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction but bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22939624 qualifier: enables review: summary: Interaction captured in an HSP90-client interaction study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (FBXW7 as HSP90 client/HSP90AB1) but bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23022380 qualifier: enables review: summary: NOTCH1 nuclear interactome interaction. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally relevant FBXW7-NOTCH1 association but bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23108047 qualifier: enables review: summary: Interaction in an FBXW7-CCDC6 degradation/DNA-damage study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real substrate interaction (CCDC6) but bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23791182 qualifier: enables review: summary: Interaction in a study of FBXW7 regulating MYC stability in leukemia-initiating cells. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally relevant FBXW7-MYC association but bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24412244 qualifier: enables review: summary: Interaction captured in a colorectal cancer driver/susceptibility network. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput network interaction; bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25344755 qualifier: enables review: summary: Interaction captured in a cyclin C tumor suppressor study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction but bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27229929 qualifier: enables review: summary: Interactome mapping of ALL cancer gene products (Notch1/FBXW7/EXT1). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interactome; bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27880917 qualifier: enables review: summary: Interaction captured in a human phosphatase interaction profiling study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interaction; bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28007894 qualifier: enables review: summary: Interaction with the pseudophosphatase STYX, which binds the FBXW7 F-box and blocks SCF incorporation. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally important FBXW7-STYX interaction (a negative regulator of SCF(FBXW7)) but bare protein binding is uninformative. supported_by: - reference_id: PMID:28007894 supporting_text: disables its recruitment into the SCF complex. Therefore, STYX acts as a direct - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: summary: Interaction captured in the human interactome (protein communities) map. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interactome; bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: Interaction captured in a cell-specific proteome interactome map. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interactome; bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:34591642 qualifier: enables review: summary: Interaction captured in a head and neck cancer protein network map. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interactome; bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35140242 qualifier: enables review: summary: Interaction captured in a transcription-factor interaction network. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interaction; bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35512704 qualifier: enables review: summary: Interaction captured in a mutation-directed neo-PPI cancer study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interaction; bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: Interaction captured in a multimodal cell map. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interaction; bare protein binding is uninformative. - term: id: GO:0042802 label: identical protein binding evidence_type: IPI original_reference_id: PMID:21620836 qualifier: enables review: summary: FBXW7 self-interaction, consistent with the documented FBXW7 homodimerization that tunes substrate turnover. action: KEEP_AS_NON_CORE reason: Documents FBXW7 homodimerization (functionally meaningful for substrate processivity) but is subsidiary to the core substrate-receptor function. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: Homodimer; homodimerization plays a role in substrate binding and/or ubiquitination and degradation - term: id: GO:0042802 label: identical protein binding evidence_type: IPI original_reference_id: PMID:23791182 qualifier: enables review: summary: FBXW7 self-interaction captured in the leukemia MYC-stability study. action: KEEP_AS_NON_CORE reason: Documents FBXW7 homodimerization but is subsidiary to the core function. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: Homodimer; homodimerization plays a role in substrate binding and/or ubiquitination and degradation - term: id: GO:0042802 label: identical protein binding evidence_type: IPI original_reference_id: PMID:35512704 qualifier: enables review: summary: FBXW7 self-interaction captured in the neo-PPI cancer study. action: KEEP_AS_NON_CORE reason: Documents FBXW7 homodimerization but is subsidiary to the core function. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: Homodimer; homodimerization plays a role in substrate binding and/or ubiquitination and degradation - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: IGI original_reference_id: PMID:40274799 qualifier: involved_in review: summary: Genetic-interaction evidence (TTC36/c-Myc) that FBXW7 drives SCF-dependent proteasomal degradation. Core biological process. action: ACCEPT reason: Core process supported by genetic interaction in the context of c-Myc degradation. supported_by: - reference_id: PMID:40274799 supporting_text: TTC36 promotes proliferation and drug resistance in hepatocellular carcinoma cells by inhibiting c-Myc degradation - 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, a parent of the specific SCF-dependent substrate ubiquitination FBXW7 mediates. action: KEEP_AS_NON_CORE reason: Correct but generic; the specific SCF-dependent proteasomal catabolic process and adaptor-activity annotations better capture the role. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.' - term: id: GO:0005654 label: nucleoplasm evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Direct immunofluorescence (HPA) evidence for nucleoplasm localization, consistent with isoform 1. action: ACCEPT reason: IDA-supported nucleoplasm localization agrees with the documented nuclear pool. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 1]: Nucleus, nucleoplasm' - term: id: GO:0005694 label: chromosome evidence_type: EXP original_reference_id: PMID:26774286 qualifier: located_in review: summary: Experimental localization of FBXW7 to chromatin/DSB sites following ATM phosphorylation during NHEJ. action: KEEP_AS_NON_CORE reason: Directly supported but a DNA-damage-induced, context-specific localization, not the constitutive site of core SCF function. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: Localizes to site of double-strand breaks following phosphorylation by ATM - term: id: GO:0005737 label: cytoplasm evidence_type: EXP original_reference_id: PMID:17558397 qualifier: located_in review: summary: Experimental cytoplasmic localization (isoform 2/FBW7beta) from the USP28/MYC study. action: ACCEPT reason: Experimentally supported isoform-2 localization. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 2]: Cytoplasm' - term: id: GO:0005737 label: cytoplasm evidence_type: EXP original_reference_id: PMID:28007894 qualifier: located_in review: summary: Experimental cytoplasmic localization from the STYX/SCF(FBXW7) study. action: ACCEPT reason: Experimentally supported localization of a cytoplasmic FBXW7 pool. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 2]: Cytoplasm' - term: id: GO:0007346 label: regulation of mitotic cell cycle evidence_type: NAS original_reference_id: PMID:36395886 qualifier: involved_in review: summary: Author statement that SCF(FBXW7) regulates mitotic cell fate, here by degrading WDR5 to prevent mitotic slippage. action: KEEP_AS_NON_CORE reason: Genuine mitotic role (cyclin E/WDR5 turnover) but a downstream output of the core substrate-receptor function. supported_by: - reference_id: PMID:36395886 supporting_text: The SCF-FBXW7 E3 ubiquitin ligase triggers degradation of histone 3 lysine 4 methyltransferase complex component WDR5 to prevent mitotic slippage - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:34445249 qualifier: part_of review: summary: Author statement that FBXW7 is part of an SCF complex; the core complex membership for FBXW7. action: ACCEPT reason: Core localization/complex; FBXW7 is the F-box substrate receptor of SCF(FBXW7). supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: Component of the SCF(FBXW7) complex consisting of CUL1, RBX1, SKP1 and FBXW7 - 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: Author statement that SCF(FBXW7) carries out SCF-dependent proteasomal degradation. Core process. action: ACCEPT reason: Core biological process; redundant with IDA/IMP support. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: which mediates the ubiquitination and subsequent proteasomal degradation of target proteins - term: id: GO:0045742 label: positive regulation of epidermal growth factor receptor signaling pathway evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Sequence-similarity transfer (from mouse Q8VBV4) of a role in positive regulation of EGFR signaling. The directionality conflicts with direct evidence that FBXW7 degrades EGFR. action: UNDECIDED reason: Recent direct evidence (Boretto et al. 2024, summarized in the Falcon report) shows EGFR is a direct FBXW7 substrate bearing CPD-like motifs in its cytoplasmic tail, and that FBXW7 hotspot mutation stabilizes EGFR and reduces EGF dependency ~10,000-fold. That implies FBXW7 normally promotes EGFR turnover and therefore restrains (negatively regulates) EGFR signaling, which is in tension with this transferred positive regulation term. The ISS curator-judgment transfer cannot be reconciled with the degradative biology from cached sources alone, so the annotation is left UNDECIDED pending verification of the mouse source and the human substrate relationship. supported_by: - reference_id: file:human/FBXW7/FBXW7-deep-research-falcon.md supporting_text: A 2024 primary study identified **EGFR** as a **direct FBXW7 substrate** in human colon organoids, mapping **CPD-like motifs** in the EGFR cytoplasmic tail. Introducing FBXW7 hotspot mutations increased EGFR stability and caused an approximately **10,000-fold reduction in EGF dependency** for organoid growth, functionally linking FBXW7-mediated EGFR turnover to growth-factor addiction. - term: id: GO:0045746 label: negative regulation of Notch signaling pathway evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Sequence-similarity transfer of negative regulation of Notch signaling, well-established as FBXW7 degrades NOTCH1/2/4 intracellular domains. action: ACCEPT reason: Strongly supported; FBXW7/SEL-10 targets NICD for degradation, restraining Notch signaling. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: NOTCH1 released notch intracellular domain (NICD), NFE2L1, NOTCH2 - term: id: GO:0050821 label: protein stabilization evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Sequence-similarity transfer of a protein stabilization role. FBXW7 primarily destabilizes substrates; any stabilizing role is indirect/context-specific (e.g. PRR7-bound JUN). action: MARK_AS_OVER_ANNOTATED reason: The core FBXW7 activity is substrate destabilization via ubiquitination/degradation, not protein stabilization; this transferred term mischaracterizes the dominant function. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: which mediates the ubiquitination and subsequent proteasomal degradation of target proteins - term: id: GO:0070374 label: positive regulation of ERK1 and ERK2 cascade evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: acts_upstream_of review: summary: Sequence-similarity transfer of upstream positive regulation of the ERK cascade. action: UNDECIDED reason: Not directly verifiable for human FBXW7 from cached evidence; ISS curator-judgment transfer. - term: id: GO:2000060 label: positive regulation of ubiquitin-dependent protein catabolic process evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Sequence-similarity transfer of positive regulation of ubiquitin-dependent catabolism, consistent with FBXW7 substrate targeting. action: KEEP_AS_NON_CORE reason: Correct regulatory parent; subsumed by the specific SCF-dependent catabolic process annotation. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: which mediates the ubiquitination and subsequent proteasomal degradation of target proteins - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:17558397 qualifier: is_active_in review: summary: Direct evidence of nuclear FBXW7 activity (MYC degradation with USP28). Core localization for the nuclear pool. action: ACCEPT reason: Core nuclear localization where FBXW7 acts on MYC; experimentally supported. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 1]: Nucleus, nucleoplasm' - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:15103331 qualifier: involved_in review: summary: Direct evidence that FBXW7 promotes proteasome-dependent c-Myc turnover and ubiquitination. Core biological process. action: ACCEPT reason: Core process directly demonstrated for c-Myc. supported_by: - reference_id: PMID:15103331 supporting_text: Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1 - term: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity evidence_type: IDA original_reference_id: PMID:15150404 qualifier: enables review: summary: Direct evidence that FBXW7 acts as the substrate adaptor of the SCF ligase, recruiting phosphorylated c-Myc for ubiquitination. Core molecular function. action: ACCEPT reason: Core molecular function; FBXW7 is the substrate-recruiting adaptor of SCF, exactly captured by this term. supported_by: - reference_id: PMID:15150404 supporting_text: promotes proteasome-dependent c-Myc turnover in vivo and c-Myc ubiquitination in vitro - term: id: GO:1901524 label: regulation of mitophagy evidence_type: IMP original_reference_id: PMID:24912190 qualifier: involved_in review: summary: Mutant-phenotype evidence from a mitophagy RNAi screen linking FBXW7 (via SREBF1) to mitophagy regulation. A complementary mechanism is FBW7beta-mediated degradation of the mitophagy kinase PINK1. action: KEEP_AS_NON_CORE reason: A specialized, context-specific role identified in a genome-wide screen; peripheral to the core substrate-receptor function. The Falcon report adds a direct mechanistic link, with the cytoplasmic isoform FBW7beta degrading PINK1 (K48-linked, SCF/cullin-1-dependent) so that FBXW7 depletion increases PINK1 and enhances mitophagy; this reinforces a genuine but downstream role in mitochondrial quality control rather than the core substrate-receptor function. Defer to curator (IMP). supported_by: - reference_id: PMID:24912190 supporting_text: Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy - reference_id: file:human/FBXW7/FBXW7-deep-research-falcon.md supporting_text: FBW7β depletion increased PINK1 and enhanced CCCP-induced mitophagy, linking FBXW7 to mitochondrial quality control. - term: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity evidence_type: IDA original_reference_id: PMID:34741373 qualifier: enables review: summary: Direct evidence that FBXW7 acts as substrate adaptor for MLST8 ubiquitination in the SCF complex. Core molecular function. action: ACCEPT reason: Core molecular function; FBXW7 recruits phosphorylated MLST8 as the SCF substrate adaptor. supported_by: - reference_id: PMID:34741373 supporting_text: CDK1/FBXW7 facilitates degradation and ubiquitination of MLST8 to inhibit progression of renal cell carcinoma - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IMP original_reference_id: PMID:35395208 qualifier: involved_in review: summary: Mutant-phenotype evidence that germline FBXW7 variants impair ubiquitination of substrates, establishing the proteasomal catabolic role. Core biological process. action: ACCEPT reason: Core process; loss-of-function variants impair substrate ubiquitination/degradation. supported_by: - reference_id: PMID:35395208 supporting_text: Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27238018 qualifier: enables review: summary: Interaction with NR1D1/REV-ERBalpha (a substrate). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally relevant FBXW7-NR1D1 substrate interaction but bare protein binding is uninformative. supported_by: - reference_id: PMID:27238018 supporting_text: core inhibitory component of clock transcription, is targeted for ubiquitination - term: id: GO:0042752 label: regulation of circadian rhythm evidence_type: IMP original_reference_id: PMID:27238018 qualifier: involved_in review: summary: Mutant-phenotype evidence (hepatic FBXW7 disruption alters circadian gene expression) for circadian rhythm regulation via NR1D1 degradation. action: KEEP_AS_NON_CORE reason: Genuine physiological output via NR1D1 turnover but specialized relative to the core function. supported_by: - reference_id: PMID:27238018 supporting_text: targeted hepatic disruption of FBXW7 alters circadian expression of - term: id: GO:2000060 label: positive regulation of ubiquitin-dependent protein catabolic process evidence_type: IMP original_reference_id: PMID:27238018 qualifier: involved_in review: summary: Mutant-phenotype evidence that FBXW7 promotes ubiquitin-dependent degradation of NR1D1. action: KEEP_AS_NON_CORE reason: Correct regulatory parent; the specific SCF-dependent catabolic process annotation better captures the core role. supported_by: - reference_id: PMID:27238018 supporting_text: core inhibitory component of clock transcription, is targeted for ubiquitination - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27458189 qualifier: enables review: summary: Interaction with PRR7/JUN complex. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (JUN/PRR7) but bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: Found in a complex with JUN and PRR7 - term: id: GO:0010629 label: negative regulation of gene expression evidence_type: IMP original_reference_id: PMID:23823476 qualifier: involved_in review: summary: Mutant-phenotype evidence linking FBXW7 to negative regulation of gene expression in an SREBP/lipid-homeostasis miRNA loop. action: KEEP_AS_NON_CORE reason: A specialized regulatory output (via SREBP/lipid metabolism), not the core function. Defer to curator (IMP). supported_by: - reference_id: PMID:23823476 supporting_text: An SREBP-responsive microRNA operon contributes to a regulatory loop for intracellular lipid homeostasis - term: id: GO:0010629 label: negative regulation of gene expression evidence_type: IGI original_reference_id: PMID:23823476 qualifier: involved_in review: summary: Genetic-interaction evidence for FBXW7 in negative regulation of gene expression (SREBP loop). action: KEEP_AS_NON_CORE reason: Specialized regulatory output; peripheral to core function. Defer to curator (IGI). supported_by: - reference_id: PMID:23823476 supporting_text: An SREBP-responsive microRNA operon contributes to a regulatory loop for intracellular lipid homeostasis - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:28007894 qualifier: located_in isoform: Q969H0-1 review: summary: Direct nuclear localization of isoform 1 in the STYX/SCF(FBXW7) study. Core localization for the nuclear pool. action: ACCEPT reason: Core isoform-1 nuclear localization, experimentally supported. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 1]: Nucleus, nucleoplasm' - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:28007894 qualifier: part_of isoform: Q969H0-1 review: summary: Direct evidence that FBXW7 isoform 1 is part of the SCF(FBXW7) complex. Core complex. action: ACCEPT reason: Core complex membership for FBXW7 as the F-box substrate receptor. supported_by: - reference_id: PMID:28007894 supporting_text: disables its recruitment into the SCF complex. Therefore, STYX acts as a direct - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: IMP original_reference_id: PMID:28007894 qualifier: involved_in isoform: Q969H0-1 review: summary: Mutant-phenotype evidence (STYX inhibition of SCF(FBXW7)) for the SCF-dependent catabolic process. Core biological process. action: ACCEPT reason: Core process; STYX disruption of FBXW7-SKP1 inhibits SCF(FBXW7)-dependent degradation. supported_by: - reference_id: PMID:28007894 supporting_text: disables its recruitment into the SCF complex. Therefore, STYX acts as a direct - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:29149593 qualifier: enables review: summary: Interaction with NOTCH2 intracellular domain (a substrate). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally relevant FBXW7-NOTCH2 substrate interaction but bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: Interacts with NOTCH2 intracellular domain (N2ICD) - term: id: GO:2001205 label: negative regulation of osteoclast development evidence_type: IMP original_reference_id: PMID:29149593 qualifier: involved_in review: summary: Mutant-phenotype evidence (osteoclast-specific Fbw7 ablation causes osteoporosis via elevated NOTCH2) for negative regulation of osteoclast development. action: KEEP_AS_NON_CORE reason: Genuine physiological role via NOTCH2 degradation but a specialized downstream output. Defer to curator (IMP). supported_by: - reference_id: PMID:29149593 supporting_text: revealed osteoporotic phenotypes reminiscent of HCS, due to elevated Notch2 - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IMP original_reference_id: PMID:25897075 qualifier: involved_in isoform: Q969H0-1 review: summary: Mutant-phenotype evidence that FBXW7 mediates GSK3-dependent RICTOR ubiquitination and proteasomal degradation. Core biological process. action: ACCEPT reason: Core process directly demonstrated for the substrate RICTOR. supported_by: - reference_id: PMID:25897075 supporting_text: Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7-mediated Ubiquitination and Proteasomal Degradation - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27837025 qualifier: enables review: summary: Interaction with MYCN. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally relevant FBXW7-MYCN substrate interaction but bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: FBXW7 competes with AURKA for binding to unphosphorylated MYCN - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-2220967 qualifier: located_in review: summary: Reactome curation of FBXW7 nucleoplasm localization (NICD1 phosphodegron mutants). Correct localization. action: ACCEPT reason: Correct nucleoplasm localization within Notch-degradation reactions. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 1]: Nucleus, nucleoplasm' - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-NUL-2064853 qualifier: located_in review: summary: Reactome curation of FBXW7 nucleoplasm localization (binds phosphorylated NICD1). Correct localization. action: ACCEPT reason: Correct nucleoplasm localization. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 1]: Nucleus, nucleoplasm' - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-NUL-2064883 qualifier: located_in review: summary: Reactome curation of FBXW7 nucleoplasm localization (ubiquitinates phosphorylated NICD1). Correct localization. action: ACCEPT reason: Correct nucleoplasm localization. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 1]: Nucleus, nucleoplasm' - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-NUL-9604628 qualifier: located_in review: summary: Reactome curation of FBXW7 nucleoplasm localization (promotes ubiquitination of mouse p-NICD4). Correct localization. action: ACCEPT reason: Correct nucleoplasm localization. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 1]: Nucleus, nucleoplasm' - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:17434132 qualifier: part_of review: summary: Direct structural evidence that FBXW7 assembles with SKP1 (and the SCF) to recognize cyclin E. Core complex. action: ACCEPT reason: Core complex; crystal structure of the Fbw7-Skp1-cyclin E complex. supported_by: - reference_id: PMID:17434132 supporting_text: binding to the SCF(Fbw7) ubiquitin ligase complex. Structures of the Skp1-Fbw7 - term: id: GO:0030332 label: cyclin binding evidence_type: IPI original_reference_id: PMID:17434132 qualifier: enables review: summary: Direct evidence that FBXW7 binds phosphorylated cyclin E via its WD40 domain. A specific, informative substrate-binding activity. action: ACCEPT reason: Informative molecular function; FBXW7 WD40 recognizes the cyclin E phosphodegron as a key substrate. supported_by: - reference_id: PMID:17434132 supporting_text: pThr380/pSer384 cyclin E motif as an optimal, high-affinity degron - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:17434132 qualifier: involved_in review: summary: Direct evidence that SCF(Fbw7) drives cyclin E ubiquitination/degradation. Core biological process. action: ACCEPT reason: Core process; cyclin E degradation by SCF(Fbw7). supported_by: - reference_id: PMID:17434132 supporting_text: Cyclin E degradation is triggered by multisite phosphorylation, which induces - term: id: GO:0050816 label: phosphothreonine residue binding evidence_type: IDA original_reference_id: PMID:17434132 qualifier: enables review: summary: Direct structural evidence that the FBXW7 WD40 pocket binds phosphothreonine-containing degrons (pThr380 cyclin E). The defining substrate-recognition activity. action: ACCEPT reason: Core molecular function; phosphodegron (phosphothreonine) recognition is the basis of FBXW7 substrate selection. supported_by: - reference_id: PMID:17434132 supporting_text: pThr380/pSer384 cyclin E motif as an optimal, high-affinity degron - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24344117 qualifier: enables review: summary: Interaction with FAM83D (which promotes FBXW7 degradation). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (a negative regulator of FBXW7) but bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: Interacts with FAM83D; promotes FBXW7 degradation - term: id: GO:1903749 label: positive regulation of protein localization to mitochondrion evidence_type: IMP original_reference_id: PMID:24912190 qualifier: involved_in review: summary: Mutant-phenotype evidence from the mitophagy screen linking FBXW7 to mitochondrial protein localization (Parkin/mitophagy context). action: KEEP_AS_NON_CORE reason: Specialized, context-specific role from a genome-wide screen; peripheral to the core function. Defer to curator (IMP). supported_by: - reference_id: PMID:24912190 supporting_text: as a regulator of mitophagy - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24000165 qualifier: enables review: summary: Interaction with the E2 enzyme UBE2QL1. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (UBE2QL1) but bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: Interacts with UBE2QL1 - term: id: GO:0031625 label: ubiquitin protein ligase binding evidence_type: IPI original_reference_id: PMID:12628165 qualifier: enables review: summary: Evidence that hSel-10/FBXW7 associates with the parkin ubiquitin ligase in an SCF-like complex. Captures binding to an E3 ligase partner. action: KEEP_AS_NON_CORE reason: Documents FBXW7 association with parkin within an SCF-like ligase complex; informative for complex assembly but ancillary to the core substrate-receptor function. supported_by: - reference_id: PMID:12628165 supporting_text: functions in a multiprotein ubiquitin ligase complex that includes the F-box/WD - term: id: GO:1903378 label: positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway evidence_type: IDA original_reference_id: PMID:23858059 qualifier: involved_in review: summary: Direct evidence that Fbw7beta promotes neuronal oxidative-stress apoptosis by destabilizing the pro-survival factor MCL1. action: KEEP_AS_NON_CORE reason: Genuine neuronal apoptotic role via MCL1 turnover but a specialized downstream output of substrate targeting. supported_by: - reference_id: PMID:23858059 supporting_text: Parkin-dependent degradation of the F-box protein Fbw7β promotes - term: id: GO:1990452 label: Parkin-FBXW7-Cul1 ubiquitin ligase complex evidence_type: IPI original_reference_id: PMID:12628165 qualifier: part_of review: summary: Evidence that FBXW7/hSel-10 forms an SCF-like complex with parkin and Cullin-1. A specific complex membership. action: ACCEPT reason: Directly supported complex membership; FBXW7 serves as the substrate receptor targeting the parkin/CUL1 complex to cyclin E. supported_by: - reference_id: PMID:12628165 supporting_text: functions in a multiprotein ubiquitin ligase complex that includes the F-box/WD - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:12628165 qualifier: part_of review: summary: Evidence that FBXW7/hSel-10 is part of an SCF-like complex (with CUL1). Core complex. action: ACCEPT reason: Core complex membership for FBXW7. supported_by: - reference_id: PMID:12628165 supporting_text: functions in a multiprotein ubiquitin ligase complex that includes the F-box/WD - term: id: GO:0030332 label: cyclin binding evidence_type: IDA original_reference_id: PMID:12628165 qualifier: enables review: summary: Evidence that hSel-10/FBXW7 binds cyclin E as a substrate. Specific, informative substrate-binding activity. action: ACCEPT reason: Informative molecular function; FBXW7 recognizes cyclin E. supported_by: - reference_id: PMID:12628165 supporting_text: ubiquitin ligase activity to cyclin E, an hSel-10-interacting protein previously - term: id: GO:0030674 label: protein-macromolecule adaptor activity evidence_type: IDA original_reference_id: PMID:12628165 qualifier: enables review: summary: Evidence that FBXW7/hSel-10 acts as an adaptor targeting the ligase to its substrate (cyclin E). Captures the substrate-adaptor role. action: MODIFY reason: The generic adaptor term is better expressed by the specific GO:1990756 ubiquitin-like ligase-substrate adaptor activity, which precisely describes FBXW7's F-box/WD40 substrate-receptor function. proposed_replacement_terms: - id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: PMID:12628165 supporting_text: ubiquitin ligase activity to cyclin E, an hSel-10-interacting protein previously - term: id: GO:0031398 label: positive regulation of protein ubiquitination evidence_type: IDA original_reference_id: PMID:12628165 qualifier: involved_in review: summary: Evidence that FBXW7 promotes ubiquitination of substrates (cyclin E) by the ligase complex. action: KEEP_AS_NON_CORE reason: Correct but a regulatory framing; the core function is captured by the substrate-adaptor activity and SCF-dependent catabolic process terms. supported_by: - reference_id: PMID:12628165 supporting_text: ubiquitin ligase activity to cyclin E, an hSel-10-interacting protein previously - term: id: GO:0097027 label: ubiquitin-protein transferase activator activity evidence_type: IDA original_reference_id: PMID:12628165 qualifier: enables review: summary: Evidence framing FBXW7 as activating the ubiquitin-transferase activity of the complex toward cyclin E. FBXW7 is the substrate receptor, not the catalytic transferase. action: MODIFY reason: FBXW7 does not itself possess or directly activate transferase chemistry (that is RBX1/E2); it recruits substrate. The substrate-adaptor activity term (GO:1990756) more accurately captures its role. proposed_replacement_terms: - id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex - term: id: GO:1902806 label: regulation of cell cycle G1/S phase transition evidence_type: TAS original_reference_id: PMID:12628165 qualifier: involved_in review: summary: Author statement linking FBXW7-mediated cyclin E degradation to G1/S regulation. A core cell-cycle output of cyclin E turnover. action: ACCEPT reason: Well-supported; FBXW7 controls G1/S progression via cyclin E degradation. supported_by: - reference_id: PMID:12628165 supporting_text: ubiquitin ligase activity to cyclin E, an hSel-10-interacting protein previously - term: id: GO:1901800 label: positive regulation of proteasomal protein catabolic process evidence_type: IDA original_reference_id: PMID:23858059 qualifier: involved_in review: summary: Evidence that Fbw7beta promotes proteasomal degradation of MCL1. action: KEEP_AS_NON_CORE reason: Correct regulatory parent; the specific SCF-dependent catabolic process annotation better captures the core role. supported_by: - reference_id: PMID:23858059 supporting_text: parkin targets the SCF substrate adapter Fbw7β for proteasomal - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:23858059 qualifier: located_in review: summary: Direct cytoplasmic localization of Fbw7beta in the neuronal oxidative-stress study. action: ACCEPT reason: Experimentally supported localization of the cytoplasmic isoform. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 2]: Cytoplasm' - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-2220978 qualifier: located_in review: summary: Reactome curation of FBXW7 nucleoplasm localization (WD mutants do not bind NICD1). Correct localization. action: ACCEPT reason: Correct nucleoplasm localization. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 1]: Nucleus, nucleoplasm' - 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 CRL1 neddylation reactions. Consistent with the cytoplasmic FBXW7 pool/SCF assembly. action: KEEP_AS_NON_CORE reason: Cytosol is correct for the cytoplasmic isoform/SCF assembly context but redundant with the cytoplasm annotations. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 2]: Cytoplasm' - 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 (NEDD8:UBE2M binds CRL1). Consistent with cytoplasmic SCF assembly. action: KEEP_AS_NON_CORE reason: Correct but redundant with the cytoplasm annotations. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 2]: Cytoplasm' - 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 binds cytosolic CRLs). Consistent with cytoplasmic SCF assembly. action: KEEP_AS_NON_CORE reason: Correct but redundant with the cytoplasm annotations. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 2]: Cytoplasm' - 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 (COMMDs displace CAND1). Consistent with cytoplasmic SCF assembly. action: KEEP_AS_NON_CORE reason: Correct but redundant with the cytoplasm annotations. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 2]: Cytoplasm' - 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 deneddylates CRLs). Consistent with cytoplasmic SCF assembly. action: KEEP_AS_NON_CORE reason: Correct but redundant with the cytoplasm annotations. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 2]: Cytoplasm' - 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 binds CRL1). Consistent with cytoplasmic SCF assembly. action: KEEP_AS_NON_CORE reason: Correct but redundant with the cytoplasm annotations. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 2]: Cytoplasm' - 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 (transfer of Ub from E2 to substrate). Consistent with cytoplasmic SCF function. action: KEEP_AS_NON_CORE reason: Correct but redundant with the cytoplasm annotations. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 2]: Cytoplasm' - 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 (release of E3 from polyubiquitinated substrate). Consistent with cytoplasmic SCF function. action: KEEP_AS_NON_CORE reason: Correct but redundant with the cytoplasm annotations. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 2]: Cytoplasm' - 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 cytoplasmic SCF function. action: KEEP_AS_NON_CORE reason: Correct but redundant with the cytoplasm annotations. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 2]: Cytoplasm' - 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 (interaction of E3 with substrate and E2-Ub). Consistent with cytoplasmic SCF function. action: KEEP_AS_NON_CORE reason: Correct but redundant with the cytoplasm annotations. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 2]: Cytoplasm' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17873522 qualifier: enables isoform: Q969H0-1 review: summary: Interaction with MYC and USP28 in the DNA-damage MYC stability study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records functionally relevant MYC/USP28 interactions but bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: Interacts with USP28, counteracting ubiquitination of MYC - term: id: GO:0006974 label: DNA damage response evidence_type: IDA original_reference_id: PMID:17873522 qualifier: involved_in isoform: Q969H0-1 review: summary: Direct evidence that FBXW7/USP28 regulate MYC stability in response to DNA damage. action: KEEP_AS_NON_CORE reason: A genuine DNA-damage-context role (MYC turnover) but a specialized output; the core function is substrate-receptor activity. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: Interacts with USP28, counteracting ubiquitination of MYC - term: id: GO:0032991 label: protein-containing complex evidence_type: IDA original_reference_id: PMID:17873522 qualifier: part_of isoform: Q969H0-1 review: summary: Generic complex membership (FBXW7-MYC-USP28). Less informative than the specific SCF complex annotation. action: KEEP_AS_NON_CORE reason: Generic; subsumed by the specific SCF ubiquitin ligase complex annotation. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: Interacts with USP28, counteracting ubiquitination of MYC - term: id: GO:0034644 label: cellular response to UV evidence_type: IDA original_reference_id: PMID:17873522 qualifier: involved_in isoform: Q969H0-1 review: summary: Direct evidence of FBXW7 involvement in cellular response to UV (DNA-damage MYC regulation). action: KEEP_AS_NON_CORE reason: Specialized DNA-damage-context role; peripheral to the core function. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: Interacts with USP28, counteracting ubiquitination of MYC - term: id: GO:2000639 label: negative regulation of SREBP signaling pathway evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Sequence-similarity transfer of negative regulation of SREBP signaling, consistent with FBXW7-mediated SREBP turnover and lipid metabolism roles. action: KEEP_AS_NON_CORE reason: A genuine metabolic regulatory output (FBXW7 degrades SREBP family members) but specialized relative to the core function. supported_by: - reference_id: PMID:23823476 supporting_text: An SREBP-responsive microRNA operon contributes to a regulatory loop for intracellular lipid homeostasis - term: id: GO:0001944 label: vasculature development evidence_type: TAS original_reference_id: PMID:21123947 qualifier: involved_in review: summary: Author statement linking Fbxw7 to vasculature development (mouse liver metabolism/cell fate study). action: KEEP_AS_NON_CORE reason: A developmental output; peripheral to the core function and supported by TAS in a mouse study. - term: id: GO:0010868 label: negative regulation of triglyceride biosynthetic process evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Sequence-similarity transfer of negative regulation of triglyceride biosynthesis (lipid metabolism role). action: KEEP_AS_NON_CORE reason: Specialized metabolic output via SREBP regulation; peripheral to core function. - term: id: GO:0010883 label: regulation of lipid storage evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Sequence-similarity transfer of regulation of lipid storage. action: KEEP_AS_NON_CORE reason: Specialized metabolic output; peripheral to core function. - term: id: GO:0032880 label: regulation of protein localization evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Sequence-similarity transfer of a generic regulation of protein localization role. action: MARK_AS_OVER_ANNOTATED reason: Uninformatively general and not a characterized core FBXW7 activity; FBXW7 regulates substrate abundance, not localization per se. - term: id: GO:0055088 label: lipid homeostasis evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Sequence-similarity transfer of a lipid homeostasis role, consistent with FBXW7 regulation of lipid metabolism in liver. action: KEEP_AS_NON_CORE reason: Genuine metabolic role but a specialized physiological output of substrate targeting. supported_by: - reference_id: PMID:23823476 supporting_text: a regulatory loop for intracellular lipid homeostasis - term: id: GO:2000346 label: negative regulation of hepatocyte proliferation evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Sequence-similarity transfer of negative regulation of hepatocyte proliferation, consistent with FBXW7 tumor-suppressor function in liver. action: KEEP_AS_NON_CORE reason: A tissue-specific anti-proliferative output of substrate (MYC/cyclin E) turnover; peripheral to the core function. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:15103331 qualifier: enables review: summary: Interaction with c-Myc (substrate). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally relevant FBXW7-MYC substrate interaction but bare protein binding is uninformative. supported_by: - reference_id: PMID:15103331 supporting_text: Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17558397 qualifier: enables isoform: Q969H0-1 review: summary: Interaction with MYC/USP28. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records functionally relevant MYC/USP28 interactions but bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: Interacts with USP28, counteracting ubiquitination of MYC - term: id: GO:0005654 label: nucleoplasm evidence_type: IDA original_reference_id: PMID:17558397 qualifier: located_in isoform: Q969H0-1 review: summary: Direct nucleoplasm localization of isoform 1 in the USP28/MYC study. Core localization for the nuclear pool. action: ACCEPT reason: Core isoform-1 nucleoplasm localization, experimentally supported. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: '[Isoform 1]: Nucleus, nucleoplasm' - term: id: GO:0016567 label: protein ubiquitination evidence_type: IDA original_reference_id: PMID:15103331 qualifier: involved_in review: summary: Direct evidence of FBXW7-mediated c-Myc ubiquitination. Captures the ubiquitination process. action: KEEP_AS_NON_CORE reason: Correct but generic; the specific SCF-dependent catabolic process and substrate-adaptor activity better capture the role. supported_by: - reference_id: PMID:15103331 supporting_text: Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1 - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:15103331 qualifier: part_of review: summary: Direct evidence that FBXW7 is a component of the SCF(Fbw7) complex. Core complex. action: ACCEPT reason: Core complex membership. supported_by: - reference_id: PMID:15103331 supporting_text: Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7 - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:15103331 qualifier: involved_in review: summary: Direct evidence that SCF(Fbw7) drives proteasome-dependent c-Myc degradation. Core biological process. action: ACCEPT reason: Core process directly demonstrated for c-Myc. supported_by: - reference_id: PMID:15103331 supporting_text: Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1 - term: id: GO:0007062 label: sister chromatid cohesion evidence_type: IMP original_reference_id: PMID:15917200 qualifier: involved_in review: summary: Mutant-phenotype evidence relating FBXW7/SCF function to chromosomal/cohesion biology in a Cornelia de Lange syndrome context. action: UNDECIDED reason: The cached entry concerns chromosomal function/DNA repair broadly; direct FBXW7 involvement in sister chromatid cohesion is not verifiable from cached text. Defer (cannot verify supporting evidence). - term: id: GO:0016567 label: protein ubiquitination evidence_type: IDA original_reference_id: PMID:12354302 qualifier: acts_upstream_of_or_within review: summary: Direct evidence that SEL-10/FBXW7 facilitates ubiquitination of presenilin 1. Captures the ubiquitination process. action: KEEP_AS_NON_CORE reason: Correct but generic; the specific SCF-dependent catabolic process and adaptor activity better capture the role. PSEN1 is a probable substrate. supported_by: - reference_id: file:human/FBXW7/FBXW7-uniprot.txt supporting_text: and probably PSEN1 references: - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000041 title: Gene Ontology annotation based on UniPathway vocabulary mapping findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: PMID:12354302 title: SEL-10 interacts with presenilin 1, facilitates its ubiquitination, and alters A-beta peptide production. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Establishes PSEN1 as a probable FBXW7/SEL-10 substrate; source of the isoform-3 cloning and a protein-ubiquitination annotation. - id: PMID:12628165 title: Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity. findings: - statement: hSel-10/FBXW7 forms an SCF-like complex with parkin and Cullin-1 and targets the ligase activity to cyclin E. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Source of the Parkin-FBXW7-Cul1 complex, SCF complex, cyclin binding, and adaptor-activity annotations. - 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: Primarily about SCF(beta-TrCP)/Wee1; source of a bare protein binding annotation. - id: PMID:15103331 title: Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. findings: - statement: Fbw7 interacts with and destabilizes c-Myc in a phosphorylation (MB1)-dependent manner via the SCF(Fbw7) complex, promoting proteasomal turnover. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text available; establishes c-Myc as a key FBXW7 substrate and the SCF complex/catabolic process annotations. - id: PMID:15150404 title: The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. findings: - statement: Fbw7 promotes proteasome-dependent c-Myc turnover and in vitro ubiquitination; GSK3 phosphorylation of c-Myc T58 regulates Fbw7 binding. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text available; source of the IDA ubiquitin-like ligase-substrate adaptor activity annotation. - id: PMID:15917200 title: Cornelia de Lange Syndrome and the link between chromosomal function, DNA repair and developmental gene regulation. findings: [] reference_review: relevance: LOW correctness: UNVERIFIED review_notes: Review on chromosomal function/DNA repair; direct FBXW7 role in sister chromatid cohesion not verifiable from cached text. - id: PMID:17157259 title: SNIP1 is a candidate modifier of the transcriptional activity of c-Myc on E box-dependent target genes. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: c-MYC target-gene study; source of a bare protein binding annotation. - id: PMID:17314511 title: Large-scale identification of c-MYC-associated proteins using a combined TAP/MudPIT approach. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: c-MYC interactome; source of a bare protein binding annotation. - id: PMID:17434132 title: 'Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases.' findings: - statement: Crystal structures of Skp1-Fbw7 bound to cyclin E phosphopeptides define the WD40 phosphodegron-binding pocket and a high-affinity pThr380/pSer384 degron; Fbw7 dimerizes. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Structural basis of phosphothreonine residue binding and cyclin binding; key support for substrate-recognition function. - id: PMID:17558397 title: The ubiquitin-specific protease USP28 is required for MYC stability. findings: - statement: FBXW7 (with USP28) controls MYC stability; isoform 1 is nucleoplasmic. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Source of nucleoplasm/nucleus localization and MYC-related annotations. - id: PMID:17873522 title: Fbw7 and Usp28 regulate myc protein stability in response to DNA damage. findings: - statement: FBXW7/USP28 regulate MYC protein stability in response to DNA damage. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Source of DNA damage response, cellular response to UV, and complex annotations (isoform 1). - id: PMID:17909182 title: Kaposi's sarcoma herpesvirus-encoded latency-associated nuclear antigen stabilizes intracellular activated Notch by targeting the Sel10 protein. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Viral antagonism of SEL10/FBXW7-mediated Notch degradation; source of a bare protein binding annotation. - id: PMID:19111882 title: Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: AURKA stabilizes N-Myc against FBXW7; source of a bare protein binding annotation. - id: PMID:19412162 title: F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Primarily about FBXO31/cyclin D1; source of a bare protein binding annotation. - id: PMID:20596027 title: SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Primarily about SCF(Cyclin F); source of a bare protein binding annotation. - id: PMID:20823234 title: Notch signaling contributes to proliferation and tumor formation of human T-cell leukemia virus type 1-associated adult T-cell leukemia. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Notch/ATL study; source of a bare protein binding annotation. - id: PMID:21123947 title: Fbxw7 regulates lipid metabolism and cell fate decisions in the mouse liver. findings: - statement: Hepatic Fbxw7 regulates lipid metabolism and cell-fate decisions. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Mouse liver study; basis for lipid/metabolism and vasculature-development annotations. - id: PMID:21145461 title: Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: CRL-network proteomics; source of a bare protein binding annotation. - id: PMID:21620836 title: PI3K-dependent phosphorylation of Fbw7 modulates substrate degradation and activity. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: FBXW7 regulation by PI3K; source of protein binding and identical protein binding annotations. - id: PMID:22307056 title: ERK1 and ERK2 regulate embryonic stem cell self-renewal through phosphorylation of Klf4. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: ERK/KLF4 study; source of a bare protein binding annotation. - id: PMID:22939624 title: Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: HSP90-client study (FBXW7 as client); source of a bare protein binding annotation. - id: PMID:23022380 title: NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: NOTCH1 interactome; source of a bare protein binding annotation. - id: PMID:23108047 title: FBXW7-mediated degradation of CCDC6 is impaired by ATM during DNA damage response in lung cancer cells. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: CCDC6 as FBXW7 substrate; source of a bare protein binding annotation. - id: PMID:23791182 title: The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: FBXW7/MYC in leukemia; source of protein binding and self-interaction annotations. - id: PMID:23823476 title: An SREBP-responsive microRNA operon contributes to a regulatory loop for intracellular lipid homeostasis. findings: - statement: An SREBP-responsive microRNA operon (with FBXW7) contributes to a regulatory loop for intracellular lipid homeostasis. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Source of negative regulation of gene expression and SREBP/lipid metabolism annotations. - id: PMID:23858059 title: Parkin-dependent degradation of the F-box protein Fbw7beta promotes neuronal survival in response to oxidative stress by stabilizing Mcl-1. findings: - statement: Parkin targets the SCF substrate adapter Fbw7beta for proteasomal degradation; Fbw7beta destabilizes the pro-survival factor Mcl-1. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Source of MCL1/oxidative-stress apoptosis and cytoplasmic localization annotations for Fbw7beta. - id: PMID:24000165 title: UBE2QL1 is disrupted by a constitutional translocation associated with renal tumor predisposition and is a novel candidate renal tumor suppressor gene. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Source of the FBXW7-UBE2QL1 interaction (bare protein binding). - id: PMID:24344117 title: FAM83D promotes cell proliferation and motility by downregulating tumor suppressor gene FBXW7. findings: - statement: FAM83D promotes FBXW7 degradation, downregulating the tumor suppressor. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Source of the FBXW7-FAM83D interaction (bare protein binding). - id: PMID:24412244 title: Charting the molecular links between driver and susceptibility genes in colorectal cancer. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Colorectal cancer network; source of a bare protein binding annotation. - id: PMID:24912190 title: Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy. findings: - statement: Genome-wide RNAi screen implicates SREBF1 (and FBXW7) in mitophagy regulation. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Source of regulation of mitophagy and positive regulation of protein localization to mitochondrion annotations. - id: PMID:25344755 title: Cyclin C is a haploinsufficient tumour suppressor. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Cyclin C study; source of a bare protein binding annotation. - id: PMID:25897075 title: Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7-mediated Ubiquitination and Proteasomal Degradation. findings: - statement: RICTOR undergoes GSK3-dependent, FBXW7-mediated ubiquitination and proteasomal degradation. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Source of the RICTOR proteasomal catabolic process annotation (isoform 1). - id: PMID:26774286 title: FBXW7 Facilitates Nonhomologous End-Joining via K63-Linked Polyubiquitylation of XRCC4. findings: - statement: ATM phosphorylates FBXW7 at Ser26 to recruit it to DSBs; SCF(FBXW7) then promotes K63-linked polyubiquitylation of XRCC4, facilitating NHEJ. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text available; establishes the non-canonical K63 ubiquitination/NHEJ role and chromosome localization. - id: PMID:27229929 title: Systematic interactome mapping of acute lymphoblastic leukemia cancer gene products reveals EXT-1 tumor suppressor as a Notch1 and FBWX7 common interactor. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: ALL interactome; source of a bare protein binding annotation. - id: PMID:27238018 title: Circadian Amplitude Regulation via FBXW7-Targeted REV-ERBalpha Degradation. findings: - statement: FBXW7 targets phosphorylated REV-ERBalpha (NR1D1) for ubiquitination and degradation, regulating circadian amplitude and hepatic clock/metabolic gene expression. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Source of circadian rhythm, NR1D1 interaction, and ubiquitin-dependent catabolism annotations. - id: PMID:27458189 title: Synaptonuclear messenger PRR7 inhibits c-Jun ubiquitination and regulates NMDA-mediated excitotoxicity. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PRR7/JUN complex with FBXW7; source of a bare protein binding annotation. - id: PMID:27837025 title: Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: AURKA/N-Myc structure; source of the FBXW7-MYCN interaction (bare protein binding). - id: PMID:27880917 title: Phenotypic and Interaction Profiling of the Human Phosphatases Identifies Diverse Mitotic Regulators. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Phosphatase interaction profiling; source of a bare protein binding annotation. - id: PMID:28007894 title: The pseudophosphatase STYX targets the F-box of FBXW7 and inhibits SCFFBXW7 function. findings: - statement: STYX binds the F-box of FBXW7 and disables its recruitment into the SCF complex, inhibiting SCF(FBXW7) function; FBXW7 isoform 1 is nuclear and part of the SCF complex. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text available; establishes FBXW7 as the substrate-recruiting SCF subunit and the STYX-mediated inhibition; source of nucleus/SCF/catabolic annotations (isoform 1). - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Human interactome; source of a bare protein binding annotation. - id: PMID:29149593 title: NOTCH2 Hajdu-Cheney Mutations Escape SCF(FBW7)-Dependent Proteolysis to Promote Osteoporosis. findings: - statement: NOTCH2 truncations escape FBW7-mediated ubiquitination/degradation; osteoclast-specific Fbw7 ablation causes osteoporosis via elevated Notch2 signaling. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text available; establishes NOTCH2 substrate and the negative regulation of osteoclast development role. - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Cell-specific interactome; source of a bare protein binding annotation. - id: PMID:34445249 title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: ComplexPortal-associated review; source of NAS SCF complex and SCF-dependent catabolic process annotations. - id: PMID:34591642 title: A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Head/neck cancer network; source of a bare protein binding annotation. - id: PMID:34741373 title: CDK1/FBXW7 facilitates degradation and ubiquitination of MLST8 to inhibit progression of renal cell carcinoma. findings: - statement: CDK1/FBXW7 facilitates ubiquitination and degradation of MLST8 in renal cell carcinoma. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Source of the IDA ubiquitin-like ligase-substrate adaptor activity and SCF identification annotations. - id: PMID:35140242 title: Human transcription factor protein interaction networks. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Transcription-factor interactome; source of a bare protein binding annotation. - id: PMID:35395208 title: Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome. findings: - statement: Germline FBXW7 variants impair substrate ubiquitination and cause an autosomal dominant neurodevelopmental syndrome (DEDHIL). reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text available; establishes the catabolic/ubiquitination function via loss-of-function variants and disease relevance. - id: PMID:35512704 title: Systematic discovery of mutation-directed neo-protein-protein interactions in cancer. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Neo-PPI cancer study; source of protein binding and self-interaction annotations. - id: PMID:36395886 title: The SCF-FBXW7 E3 ubiquitin ligase triggers degradation of histone 3 lysine 4 methyltransferase complex component WDR5 to prevent mitotic slippage. findings: - statement: SCF-FBXW7 triggers degradation of WDR5 to promote mitotic cell death and prevent mitotic slippage. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Source of the NAS regulation of mitotic cell cycle annotation (WDR5 substrate). - 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; source of a bare protein binding annotation. - id: PMID:40274799 title: TTC36 promotes proliferation and drug resistance in hepatocellular carcinoma cells by inhibiting c-Myc degradation. findings: - statement: TTC36 inhibits c-Myc degradation (FBXW7-dependent), promoting HCC proliferation and drug resistance. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Source of the IGI SCF-dependent catabolic process annotation in the c-Myc context. - id: Reactome:R-HSA-2220967 title: p-NICD1 PEST domain mutants do not bind FBXW7 findings: [] - id: Reactome:R-HSA-2220978 title: FBXW7 WD mutants do not bind NICD1 findings: [] - 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: Reactome:R-NUL-2064853 title: FBXW7 binds phosphorylated NICD1 findings: [] - id: Reactome:R-NUL-2064883 title: FBXW7 mediates ubiquitination of phosphorylated NICD1 findings: [] - id: Reactome:R-NUL-9604628 title: FBXW7 promotes ubiquitination of mouse p-NICD4 findings: [] - id: file:human/FBXW7/FBXW7-deep-research-falcon.md title: Falcon deep research report for human FBXW7 findings: - statement: FBXW7 is the substrate-recognition subunit of an SCF (SKP1-CUL1-RBX1) Cullin-RING E3 ubiquitin ligase that recognizes phosphorylated Cdc4 phosphodegrons (CPD) via its WD40 beta-propeller, a high-affinity consensus being pThr-Pro-Pro-X-pSer; WD40 hotspot arginines R465/R479/R505 are required for phosphodegron recognition and are recurrently mutated in cancer. supporting_text: FBXW7 recognizes phosphorylated Cdc4 phosphodegrons (CPDs) using its WD40 domain; a high-affinity consensus described in recent review is pThr-Pro-Pro-X-pSer, though lower-affinity/noncanonical CPDs also exist. Substrate phosphorylation is often created or reinforced by GSK3, and can involve kinase cascades including CDK1/2 and ERK/MAPK; hotspot arginines such as R465/R479/R505 are critical for phosphodegron recognition and are recurrently mutated in cancer - statement: EGFR is a direct FBXW7 substrate; CPD-like motifs in the EGFR cytoplasmic tail are recognized, and FBXW7 hotspot mutation stabilizes EGFR and dramatically reduces EGF dependency, implying that FBXW7 normally restrains (rather than activates) EGFR signaling by promoting EGFR turnover. supporting_text: A 2024 primary study identified **EGFR** as a **direct FBXW7 substrate** in human colon organoids, mapping **CPD-like motifs** in the EGFR cytoplasmic tail. Introducing FBXW7 hotspot mutations increased EGFR stability and caused an approximately **10,000-fold reduction in EGF dependency** for organoid growth, functionally linking FBXW7-mediated EGFR turnover to growth-factor addiction. - statement: The Wnt effectors LEF1 and TCF7L2 are FBXW7-interacting substrates whose binding depends on the WD40 substrate-binding surface, linking FBXW7 loss to altered Wnt transcriptional output. supporting_text: A 2023 mechanistic endometrial cancer study validated **LEF1** and **TCF7L2** as novel FBXW7-interacting substrates. Co-immunoprecipitation showed interaction that was disrupted by an FBXW7 WD40 "hotspot" substrate-binding mutant - statement: The cytoplasmic isoform FBW7beta binds endogenous PINK1 in the cytosol and promotes its K48-linked polyubiquitination and proteasomal degradation in an SCF/cullin-1-dependent manner, linking FBXW7 to mitochondrial quality control. supporting_text: A 2024 JBC study reports that the cytoplasmic isoform **FBW7β** binds endogenous **PINK1** (interaction detected by co-IP and proximity ligation), primarily in the **cytosol**, and promotes **K48-linked polyubiquitination** and **proteasome-dependent degradation** of PINK1. - statement: FBXW7 substrate selection is not governed solely by perfect CPD matches; low-affinity and noncanonical degrons can be biologically decisive, and hotspot WD40 mutations differentially disrupt subsets of substrates, helping explain variant-specific cancer phenotypes. supporting_text: substrate selection is not governed solely by "perfect" CPD matches; **low-affinity substrates and alternative binding modes** can be decisive, and **hotspot WD40 mutations** may differentially disrupt subsets of substrates—helping explain cancer-specific phenotypes and inconsistent clinical associations. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Falcon (Edison Scientific) synthesis cross-checked against the UniProt FUNCTION statement and cached primary literature (PMID:17434132 phosphodegron structure; PMID:15103331/15150404 MYC; PMID:29149593 NOTCH2). Author-year/DOI citations (Boretto 2024 PNAS, Brown 2023 EMBO Mol Med, Jeon 2024 JBC, de la Cova 2023 Cells) are leads, not yet PMID-verified here; EGFR/LEF1/TCF7L2/PINK1 substrate claims are treated as proposed and not added as new GO annotations. core_functions: - description: >- Substrate-recognition (F-box/WD40) subunit of the SCF(FBXW7) E3 ubiquitin ligase that recruits phosphodegron-bearing substrates to the CUL1-RBX1 catalytic core for polyubiquitination and proteasomal degradation. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005654 label: nucleoplasm - id: GO:0005737 label: cytoplasm supported_by: - reference_id: PMID:15150404 supporting_text: promotes proteasome-dependent c-Myc turnover in vivo and c-Myc ubiquitination in vitro directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process - description: >- Phosphodegron recognition by the WD40 beta-propeller (phosphothreonine residue binding), which provides the substrate selectivity underlying FBXW7-directed degradation of cyclin E, MYC, NOTCH ICD and other targets. molecular_function: id: GO:0050816 label: phosphothreonine residue binding locations: - id: GO:0005654 label: nucleoplasm supported_by: - reference_id: PMID:17434132 supporting_text: pThr380/pSer384 cyclin E motif as an optimal, high-affinity degron directly_involved_in: - id: GO:1902806 label: regulation of cell cycle G1/S phase transition proposed_new_terms: [] suggested_questions: - question: How is FBXW7 substrate choice partitioned among its three isoforms (nucleoplasmic alpha, cytoplasmic beta, nucleolar gamma), and to what extent does isoform-specific localization rather than intrinsic specificity determine which substrates are degraded? - question: What governs the switch between canonical K48-linked degradative ubiquitination and the ATM-dependent K63-linked non-degradative ubiquitination of XRCC4 at DNA double-strand breaks? - question: Do individual WD40 hotspot mutations (e.g., R465C vs R465H vs R479 vs R505) differentially disrupt distinct subsets of substrates (e.g., cyclin E, MYC, EGFR, NOTCH, LEF1/TCF7L2), and does this substrate-selective loss explain the variant-specific clinical outcomes observed in cancer? - question: Given that FBXW7 directly degrades EGFR via CPD-like motifs in its cytoplasmic tail, does FBXW7 act as a bona fide negative regulator of EGFR/MAPK signaling in normal tissues, and how should the inherited positive-regulation-of-EGFR annotation be reconciled with this degradative role? suggested_experiments: - description: Reconstitute SCF(FBXW7) ubiquitination in vitro with purified CUL1-RBX1, SKP1, FBXW7 (monomer vs forced dimer) and a panel of phosphorylated substrates to quantify how dimerization and degron multiplicity affect chain processivity and linkage type. - description: Generate isoform-specific FBXW7 knock-in/knockout cells and perform quantitative ubiquitinome and proteome profiling to map the endogenous substrate repertoire of each isoform under basal, DNA-damage, and metabolic-stress conditions. - description: Compare panels of cancer-derived WD40 hotspot point mutants (R465C/H, R479, R505) side by side for binding and degradation of a defined substrate set (cyclin E, MYC, NOTCH ICD, EGFR, LEF1/TCF7L2, MCL1) to test whether low-affinity/noncanonical degrons are selectively spared and to map mutation-to-substrate vulnerability for therapy stratification.