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).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of nuclear localization, consistent with the predominantly nuclear isoform 1 (FBW7alpha). Reason: FBXW7 isoform 1 is nuclear/nucleoplasmic and acts on nuclear substrates (MYC, NOTCH ICD, cyclin E); supported experimentally. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 1]: Nucleus, nucleoplasm |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of cytoplasmic localization, matching the cytoplasmic isoform 2 (FBW7beta). Reason: Isoform 2 is documented as cytoplasmic; FBXW7 acts in the cytoplasm on substrates such as MCL1 and RICTOR. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 2]: Cytoplasm |
| GO:0010992 ubiquitin recycling | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Phylogenetic assignment of ubiquitin recycling. FBXW7 is a substrate receptor that promotes substrate polyubiquitination; it is not directly involved in recycling free ubiquitin. 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. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex |
| GO:0043130 ubiquitin binding | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Phylogenetic assignment of ubiquitin binding. FBXW7 recognizes phosphodegrons on substrates rather than ubiquitin itself; the relevant binding activity is phosphothreonine/phosphodegron recognition. 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. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt Recognizes and binds phosphorylated sites/phosphodegrons within target proteins |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of proteasome-mediated ubiquitin-dependent catabolism, the core biological process of FBXW7 as an SCF substrate receptor. Reason: Core process; FBXW7 directs substrates to proteasomal degradation, directly supported by IDA/IMP evidence. Supporting Evidence: PMID:15103331 Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1 |
| GO:0005654 nucleoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of nucleoplasm localization from the UniProt subcellular location for isoform 1. Reason: Correct localization for isoform 1; supported experimentally (IDA). Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 1]: Nucleus, nucleoplasm |
| GO:0005694 chromosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic transfer of chromosome localization, reflecting ATM-dependent recruitment of FBXW7 to DNA double-strand breaks. Reason: Real but context-specific (DNA-damage-induced) localization to chromatin/DSB sites; not the constitutive site of the core SCF substrate-receptor function. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt Localizes to site of double-strand breaks following phosphorylation by ATM |
| GO:0005730 nucleolus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic transfer of nucleolar localization corresponding to isoform 3 (FBW7gamma). Reason: Correct isoform-3 localization but a secondary compartment relative to the dominant nucleoplasmic/cytoplasmic pools. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 3]: Nucleus, nucleolus |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of cytoplasmic localization (isoform 2). Reason: Correct localization for isoform 2; supported experimentally. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 2]: Cytoplasm |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning assignment of the SCF-dependent proteasomal degradation process, the core biological role of FBXW7. Reason: Core biological process; directly supported by multiple IDA/IMP annotations and the UniProt FUNCTION statement. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt which mediates the ubiquitination and subsequent proteasomal degradation of target proteins |
| GO:0042752 regulation of circadian rhythm | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA assignment of circadian rhythm regulation, reflecting FBXW7-mediated degradation of the clock repressor NR1D1/REV-ERBalpha. 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. Supporting Evidence: PMID:27238018 core inhibitory component of clock transcription, is targeted for ubiquitination |
| GO:0048731 system development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA assignment of the very general term system development. Reason: Uninformatively general; FBXW7 has specific developmental roles (Notch signaling, bone, neurodevelopment) better captured by more precise terms. |
| GO:1901800 positive regulation of proteasomal protein catabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA assignment that FBXW7 positively regulates proteasomal protein catabolism, consistent with its role driving substrate degradation. Reason: Correct but a regulatory parent of the more specific SCF-dependent catabolic process annotation that better captures the core role. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt which mediates the ubiquitination and subsequent proteasomal degradation of target proteins |
| GO:1903378 positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA assignment reflecting Fbw7beta-mediated destabilization of the pro-survival factor MCL1 in neurons under oxidative stress. Reason: A specialized neuronal consequence of FBXW7 substrate targeting (MCL1); peripheral to the core function. Supporting Evidence: PMID:23858059 Parkin-dependent degradation of the F-box protein Fbw7Ξ² promotes |
| GO:2000060 positive regulation of ubiquitin-dependent protein catabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA assignment that FBXW7 positively regulates ubiquitin-dependent catabolism, consistent with its substrate-targeting role. Reason: Correct regulatory parent; the specific SCF-dependent proteasomal catabolic process annotation better captures the core role. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt which mediates the ubiquitination and subsequent proteasomal degradation of target proteins |
| GO:2001205 negative regulation of osteoclast development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA assignment of negative regulation of osteoclast development, reflecting SCF(FBW7)-mediated degradation of NOTCH2 that restrains osteoclast activity. Reason: Genuine physiological role via NOTCH2 degradation but a specialized downstream output, not the core function. Supporting Evidence: PMID:29149593 we demonstrate that sustained osteoclast activity is largely due to accumulation |
| GO:0005515 protein binding | IPI PMID:15070733 M-phase kinases induce phospho-dependent ubiquitination of s... | KEEP AS NON CORE | Summary: Interaction captured in a study of phospho-dependent ubiquitination of Wee1. Bare protein binding is uninformative. Reason: Records a real interaction but bare protein binding is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:17157259 SNIP1 is a candidate modifier of the transcriptional activit... | KEEP AS NON CORE | Summary: Interaction in a c-MYC E-box target study (SNIP1). Bare protein binding is uninformative. Reason: Records a real interaction but bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:17314511 Large-scale identification of c-MYC-associated proteins usin... | KEEP AS NON CORE | Summary: c-MYC-associated proteome (TAP/MudPIT) interaction. Bare protein binding is uninformative. Reason: Records the functionally relevant FBXW7-MYC association, but bare protein binding is uninformative; the substrate relationship is captured elsewhere. |
| GO:0005515 protein binding | IPI PMID:17909182 Kaposi's sarcoma herpesvirus-encoded latency-associated nucl... | KEEP AS NON CORE | Summary: Interaction captured in a study of KSHV LANA stabilizing activated Notch via Sel10/FBXW7. Bare protein binding is uninformative. Reason: Records a real interaction relevant to Notch regulation but bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:19111882 Stabilization of N-Myc is a critical function of Aurora A in... | KEEP AS NON CORE | Summary: Interaction captured in an N-Myc/Aurora A stabilization study. Bare protein binding is uninformative. Reason: Records a real interaction relevant to N-MYC turnover but bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:19412162 F-box protein FBXO31 mediates cyclin D1 degradation to induc... | KEEP AS NON CORE | Summary: Interaction captured in an FBXO31/cyclin D1 degradation study. Bare protein binding is uninformative. Reason: Records a real interaction but bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:20596027 SCF(Cyclin F) controls centrosome homeostasis and mitotic fi... | KEEP AS NON CORE | Summary: Interaction captured in a cyclin F/CP110 centrosome study. Bare protein binding is uninformative. Reason: Records a real interaction but bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:20823234 Notch signaling contributes to proliferation and tumor forma... | KEEP AS NON CORE | Summary: Interaction in an HTLV-1 Notch/ATL study. Bare protein binding is uninformative. Reason: Records a real interaction relevant to Notch regulation but bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:21145461 Dynamics of cullin-RING ubiquitin ligase network revealed by... | KEEP AS NON CORE | Summary: Interaction captured in a quantitative proteomics map of the cullin-RING ligase network. Bare protein binding is uninformative. Reason: Documents CRL-network associations (SCF assembly) but bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:21620836 PI3K-dependent phosphorylation of Fbw7 modulates substrate d... | KEEP AS NON CORE | Summary: Interaction captured in a study of PI3K-dependent FBXW7 phosphorylation. Bare protein binding is uninformative. Reason: Records a real interaction but bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:22307056 ERK1 and ERK2 regulate embryonic stem cell self-renewal thro... | KEEP AS NON CORE | Summary: Interaction in an ERK/KLF4 ES cell self-renewal study. Bare protein binding is uninformative. Reason: Records a real interaction but bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:22939624 Quantitative analysis of HSP90-client interactions reveals p... | KEEP AS NON CORE | Summary: Interaction captured in an HSP90-client interaction study. Bare protein binding is uninformative. Reason: Records a real interaction (FBXW7 as HSP90 client/HSP90AB1) but bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:23022380 NOTCH1 nuclear interactome reveals key regulators of its tra... | KEEP AS NON CORE | Summary: NOTCH1 nuclear interactome interaction. Bare protein binding is uninformative. Reason: Records the functionally relevant FBXW7-NOTCH1 association but bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:23108047 FBXW7-mediated degradation of CCDC6 is impaired by ATM durin... | KEEP AS NON CORE | Summary: Interaction in an FBXW7-CCDC6 degradation/DNA-damage study. Bare protein binding is uninformative. Reason: Records a real substrate interaction (CCDC6) but bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:23791182 The ubiquitin ligase FBXW7 modulates leukemia-initiating cel... | KEEP AS NON CORE | Summary: Interaction in a study of FBXW7 regulating MYC stability in leukemia-initiating cells. Bare protein binding is uninformative. Reason: Records the functionally relevant FBXW7-MYC association but bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:24412244 Charting the molecular links between driver and susceptibili... | KEEP AS NON CORE | Summary: Interaction captured in a colorectal cancer driver/susceptibility network. Bare protein binding is uninformative. Reason: High-throughput network interaction; bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:25344755 Cyclin C is a haploinsufficient tumour suppressor. | KEEP AS NON CORE | Summary: Interaction captured in a cyclin C tumor suppressor study. Bare protein binding is uninformative. Reason: Records a real interaction but bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:27229929 Systematic interactome mapping of acute lymphoblastic leukem... | KEEP AS NON CORE | Summary: Interactome mapping of ALL cancer gene products (Notch1/FBXW7/EXT1). Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:27880917 Phenotypic and Interaction Profiling of the Human Phosphatas... | KEEP AS NON CORE | Summary: Interaction captured in a human phosphatase interaction profiling study. Bare protein binding is uninformative. Reason: High-throughput interaction; bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:28007894 The pseudophosphatase STYX targets the F-box of FBXW7 and in... | KEEP AS NON CORE | Summary: Interaction with the pseudophosphatase STYX, which binds the FBXW7 F-box and blocks SCF incorporation. Bare protein binding is uninformative. Reason: Records the functionally important FBXW7-STYX interaction (a negative regulator of SCF(FBXW7)) but bare protein binding is uninformative. Supporting Evidence: PMID:28007894 disables its recruitment into the SCF complex. Therefore, STYX acts as a direct |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: Interaction captured in the human interactome (protein communities) map. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Interaction captured in a cell-specific proteome interactome map. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:34591642 A protein network map of head and neck cancer reveals PIK3CA... | KEEP AS NON CORE | Summary: Interaction captured in a head and neck cancer protein network map. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:35140242 Human transcription factor protein interaction networks. | KEEP AS NON CORE | Summary: Interaction captured in a transcription-factor interaction network. Bare protein binding is uninformative. Reason: High-throughput interaction; bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | KEEP AS NON CORE | Summary: Interaction captured in a mutation-directed neo-PPI cancer study. Bare protein binding is uninformative. Reason: High-throughput interaction; bare protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: Interaction captured in a multimodal cell map. Bare protein binding is uninformative. Reason: High-throughput interaction; bare protein binding is uninformative. |
| GO:0042802 identical protein binding | IPI PMID:21620836 PI3K-dependent phosphorylation of Fbw7 modulates substrate d... | KEEP AS NON CORE | Summary: FBXW7 self-interaction, consistent with the documented FBXW7 homodimerization that tunes substrate turnover. Reason: Documents FBXW7 homodimerization (functionally meaningful for substrate processivity) but is subsidiary to the core substrate-receptor function. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt Homodimer; homodimerization plays a role in substrate binding and/or ubiquitination and degradation |
| GO:0042802 identical protein binding | IPI PMID:23791182 The ubiquitin ligase FBXW7 modulates leukemia-initiating cel... | KEEP AS NON CORE | Summary: FBXW7 self-interaction captured in the leukemia MYC-stability study. Reason: Documents FBXW7 homodimerization but is subsidiary to the core function. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt Homodimer; homodimerization plays a role in substrate binding and/or ubiquitination and degradation |
| GO:0042802 identical protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | KEEP AS NON CORE | Summary: FBXW7 self-interaction captured in the neo-PPI cancer study. Reason: Documents FBXW7 homodimerization but is subsidiary to the core function. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt Homodimer; homodimerization plays a role in substrate binding and/or ubiquitination and degradation |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IGI PMID:40274799 TTC36 promotes proliferation and drug resistance in hepatoce... | ACCEPT | Summary: Genetic-interaction evidence (TTC36/c-Myc) that FBXW7 drives SCF-dependent proteasomal degradation. Core biological process. Reason: Core process supported by genetic interaction in the context of c-Myc degradation. Supporting Evidence: PMID:40274799 TTC36 promotes proliferation and drug resistance in hepatocellular carcinoma cells by inhibiting c-Myc degradation |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: UniPathway-derived general protein ubiquitination process, a parent of the specific SCF-dependent substrate ubiquitination FBXW7 mediates. Reason: Correct but generic; the specific SCF-dependent proteasomal catabolic process and adaptor-activity annotations better capture the role. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt PATHWAY: Protein modification; protein ubiquitination. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) evidence for nucleoplasm localization, consistent with isoform 1. Reason: IDA-supported nucleoplasm localization agrees with the documented nuclear pool. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 1]: Nucleus, nucleoplasm |
| GO:0005694 chromosome | EXP PMID:26774286 FBXW7 Facilitates Nonhomologous End-Joining via K63-Linked P... | KEEP AS NON CORE | Summary: Experimental localization of FBXW7 to chromatin/DSB sites following ATM phosphorylation during NHEJ. Reason: Directly supported but a DNA-damage-induced, context-specific localization, not the constitutive site of core SCF function. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt Localizes to site of double-strand breaks following phosphorylation by ATM |
| GO:0005737 cytoplasm | EXP PMID:17558397 The ubiquitin-specific protease USP28 is required for MYC st... | ACCEPT | Summary: Experimental cytoplasmic localization (isoform 2/FBW7beta) from the USP28/MYC study. Reason: Experimentally supported isoform-2 localization. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 2]: Cytoplasm |
| GO:0005737 cytoplasm | EXP PMID:28007894 The pseudophosphatase STYX targets the F-box of FBXW7 and in... | ACCEPT | Summary: Experimental cytoplasmic localization from the STYX/SCF(FBXW7) study. Reason: Experimentally supported localization of a cytoplasmic FBXW7 pool. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 2]: Cytoplasm |
| GO:0007346 regulation of mitotic cell cycle | NAS PMID:36395886 The SCF-FBXW7 E3 ubiquitin ligase triggers degradation of hi... | KEEP AS NON CORE | Summary: Author statement that SCF(FBXW7) regulates mitotic cell fate, here by degrading WDR5 to prevent mitotic slippage. Reason: Genuine mitotic role (cyclin E/WDR5 turnover) but a downstream output of the core substrate-receptor function. Supporting Evidence: PMID:36395886 The SCF-FBXW7 E3 ubiquitin ligase triggers degradation of histone 3 lysine 4 methyltransferase complex component WDR5 to prevent mitotic slippage |
| GO:0019005 SCF ubiquitin ligase complex | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | Summary: Author statement that FBXW7 is part of an SCF complex; the core complex membership for FBXW7. Reason: Core localization/complex; FBXW7 is the F-box substrate receptor of SCF(FBXW7). Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt Component of the SCF(FBXW7) complex consisting of CUL1, RBX1, SKP1 and FBXW7 |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | Summary: Author statement that SCF(FBXW7) carries out SCF-dependent proteasomal degradation. Core process. Reason: Core biological process; redundant with IDA/IMP support. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt which mediates the ubiquitination and subsequent proteasomal degradation of target proteins |
| GO:0045742 positive regulation of epidermal growth factor receptor signaling pathway | ISS GO_REF:0000024 | UNDECIDED | 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. 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. Supporting Evidence: file:human/FBXW7/FBXW7-deep-research-falcon.md 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. |
| GO:0045746 negative regulation of Notch signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of negative regulation of Notch signaling, well-established as FBXW7 degrades NOTCH1/2/4 intracellular domains. Reason: Strongly supported; FBXW7/SEL-10 targets NICD for degradation, restraining Notch signaling. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt NOTCH1 released notch intracellular domain (NICD), NFE2L1, NOTCH2 |
| GO:0050821 protein stabilization | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | 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). Reason: The core FBXW7 activity is substrate destabilization via ubiquitination/degradation, not protein stabilization; this transferred term mischaracterizes the dominant function. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt which mediates the ubiquitination and subsequent proteasomal degradation of target proteins |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | ISS GO_REF:0000024 | UNDECIDED | Summary: Sequence-similarity transfer of upstream positive regulation of the ERK cascade. Reason: Not directly verifiable for human FBXW7 from cached evidence; ISS curator-judgment transfer. |
| GO:2000060 positive regulation of ubiquitin-dependent protein catabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer of positive regulation of ubiquitin-dependent catabolism, consistent with FBXW7 substrate targeting. Reason: Correct regulatory parent; subsumed by the specific SCF-dependent catabolic process annotation. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt which mediates the ubiquitination and subsequent proteasomal degradation of target proteins |
| GO:0005634 nucleus | IDA PMID:17558397 The ubiquitin-specific protease USP28 is required for MYC st... | ACCEPT | Summary: Direct evidence of nuclear FBXW7 activity (MYC degradation with USP28). Core localization for the nuclear pool. Reason: Core nuclear localization where FBXW7 acts on MYC; experimentally supported. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 1]: Nucleus, nucleoplasm |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:15103331 Phosphorylation-dependent degradation of c-Myc is mediated b... | ACCEPT | Summary: Direct evidence that FBXW7 promotes proteasome-dependent c-Myc turnover and ubiquitination. Core biological process. Reason: Core process directly demonstrated for c-Myc. Supporting Evidence: PMID:15103331 Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1 |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:15150404 The Fbw7 tumor suppressor regulates glycogen synthase kinase... | ACCEPT | Summary: Direct evidence that FBXW7 acts as the substrate adaptor of the SCF ligase, recruiting phosphorylated c-Myc for ubiquitination. Core molecular function. Reason: Core molecular function; FBXW7 is the substrate-recruiting adaptor of SCF, exactly captured by this term. Supporting Evidence: PMID:15150404 promotes proteasome-dependent c-Myc turnover in vivo and c-Myc ubiquitination in vitro |
| GO:1901524 regulation of mitophagy | IMP PMID:24912190 Genome-wide RNAi screen identifies the Parkinson disease GWA... | KEEP AS NON CORE | 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. 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). Supporting Evidence: PMID:24912190 Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy file:human/FBXW7/FBXW7-deep-research-falcon.md FBW7Ξ² depletion increased PINK1 and enhanced CCCP-induced mitophagy, linking FBXW7 to mitochondrial quality control. |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:34741373 CDK1/FBXW7 facilitates degradation and ubiquitination of MLS... | ACCEPT | Summary: Direct evidence that FBXW7 acts as substrate adaptor for MLST8 ubiquitination in the SCF complex. Core molecular function. Reason: Core molecular function; FBXW7 recruits phosphorylated MLST8 as the SCF substrate adaptor. Supporting Evidence: PMID:34741373 CDK1/FBXW7 facilitates degradation and ubiquitination of MLST8 to inhibit progression of renal cell carcinoma |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IMP PMID:35395208 Germline variants in tumor suppressor FBXW7 lead to impaired... | ACCEPT | Summary: Mutant-phenotype evidence that germline FBXW7 variants impair ubiquitination of substrates, establishing the proteasomal catabolic role. Core biological process. Reason: Core process; loss-of-function variants impair substrate ubiquitination/degradation. Supporting Evidence: PMID:35395208 Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome |
| GO:0005515 protein binding | IPI PMID:27238018 Circadian Amplitude Regulation via FBXW7-Targeted REV-ERBalp... | KEEP AS NON CORE | Summary: Interaction with NR1D1/REV-ERBalpha (a substrate). Bare protein binding is uninformative. Reason: Records the functionally relevant FBXW7-NR1D1 substrate interaction but bare protein binding is uninformative. Supporting Evidence: PMID:27238018 core inhibitory component of clock transcription, is targeted for ubiquitination |
| GO:0042752 regulation of circadian rhythm | IMP PMID:27238018 Circadian Amplitude Regulation via FBXW7-Targeted REV-ERBalp... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence (hepatic FBXW7 disruption alters circadian gene expression) for circadian rhythm regulation via NR1D1 degradation. Reason: Genuine physiological output via NR1D1 turnover but specialized relative to the core function. Supporting Evidence: PMID:27238018 targeted hepatic disruption of FBXW7 alters circadian expression of |
| GO:2000060 positive regulation of ubiquitin-dependent protein catabolic process | IMP PMID:27238018 Circadian Amplitude Regulation via FBXW7-Targeted REV-ERBalp... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence that FBXW7 promotes ubiquitin-dependent degradation of NR1D1. Reason: Correct regulatory parent; the specific SCF-dependent catabolic process annotation better captures the core role. Supporting Evidence: PMID:27238018 core inhibitory component of clock transcription, is targeted for ubiquitination |
| GO:0005515 protein binding | IPI PMID:27458189 Synaptonuclear messenger PRR7 inhibits c-Jun ubiquitination ... | KEEP AS NON CORE | Summary: Interaction with PRR7/JUN complex. Bare protein binding is uninformative. Reason: Records a real interaction (JUN/PRR7) but bare protein binding is uninformative. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt Found in a complex with JUN and PRR7 |
| GO:0010629 negative regulation of gene expression | IMP PMID:23823476 An SREBP-responsive microRNA operon contributes to a regulat... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence linking FBXW7 to negative regulation of gene expression in an SREBP/lipid-homeostasis miRNA loop. Reason: A specialized regulatory output (via SREBP/lipid metabolism), not the core function. Defer to curator (IMP). Supporting Evidence: PMID:23823476 An SREBP-responsive microRNA operon contributes to a regulatory loop for intracellular lipid homeostasis |
| GO:0010629 negative regulation of gene expression | IGI PMID:23823476 An SREBP-responsive microRNA operon contributes to a regulat... | KEEP AS NON CORE | Summary: Genetic-interaction evidence for FBXW7 in negative regulation of gene expression (SREBP loop). Reason: Specialized regulatory output; peripheral to core function. Defer to curator (IGI). Supporting Evidence: PMID:23823476 An SREBP-responsive microRNA operon contributes to a regulatory loop for intracellular lipid homeostasis |
| GO:0005634 nucleus | IDA Q969H0-1 PMID:28007894 The pseudophosphatase STYX targets the F-box of FBXW7 and in... | ACCEPT | Summary: Direct nuclear localization of isoform 1 in the STYX/SCF(FBXW7) study. Core localization for the nuclear pool. Reason: Core isoform-1 nuclear localization, experimentally supported. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 1]: Nucleus, nucleoplasm |
| GO:0019005 SCF ubiquitin ligase complex | IDA Q969H0-1 PMID:28007894 The pseudophosphatase STYX targets the F-box of FBXW7 and in... | ACCEPT | Summary: Direct evidence that FBXW7 isoform 1 is part of the SCF(FBXW7) complex. Core complex. Reason: Core complex membership for FBXW7 as the F-box substrate receptor. Supporting Evidence: PMID:28007894 disables its recruitment into the SCF complex. Therefore, STYX acts as a direct |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IMP Q969H0-1 PMID:28007894 The pseudophosphatase STYX targets the F-box of FBXW7 and in... | ACCEPT | Summary: Mutant-phenotype evidence (STYX inhibition of SCF(FBXW7)) for the SCF-dependent catabolic process. Core biological process. Reason: Core process; STYX disruption of FBXW7-SKP1 inhibits SCF(FBXW7)-dependent degradation. Supporting Evidence: PMID:28007894 disables its recruitment into the SCF complex. Therefore, STYX acts as a direct |
| GO:0005515 protein binding | IPI PMID:29149593 NOTCH2 Hajdu-Cheney Mutations Escape SCF(FBW7)-Dependent Pro... | KEEP AS NON CORE | Summary: Interaction with NOTCH2 intracellular domain (a substrate). Bare protein binding is uninformative. Reason: Records the functionally relevant FBXW7-NOTCH2 substrate interaction but bare protein binding is uninformative. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt Interacts with NOTCH2 intracellular domain (N2ICD) |
| GO:2001205 negative regulation of osteoclast development | IMP PMID:29149593 NOTCH2 Hajdu-Cheney Mutations Escape SCF(FBW7)-Dependent Pro... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence (osteoclast-specific Fbw7 ablation causes osteoporosis via elevated NOTCH2) for negative regulation of osteoclast development. Reason: Genuine physiological role via NOTCH2 degradation but a specialized downstream output. Defer to curator (IMP). Supporting Evidence: PMID:29149593 revealed osteoporotic phenotypes reminiscent of HCS, due to elevated Notch2 |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IMP Q969H0-1 PMID:25897075 Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent... | ACCEPT | Summary: Mutant-phenotype evidence that FBXW7 mediates GSK3-dependent RICTOR ubiquitination and proteasomal degradation. Core biological process. Reason: Core process directly demonstrated for the substrate RICTOR. Supporting Evidence: PMID:25897075 Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7-mediated Ubiquitination and Proteasomal Degradation |
| GO:0005515 protein binding | IPI PMID:27837025 Structural basis of N-Myc binding by Aurora-A and its destab... | KEEP AS NON CORE | Summary: Interaction with MYCN. Bare protein binding is uninformative. Reason: Records the functionally relevant FBXW7-MYCN substrate interaction but bare protein binding is uninformative. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt FBXW7 competes with AURKA for binding to unphosphorylated MYCN |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2220967 | ACCEPT | Summary: Reactome curation of FBXW7 nucleoplasm localization (NICD1 phosphodegron mutants). Correct localization. Reason: Correct nucleoplasm localization within Notch-degradation reactions. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 1]: Nucleus, nucleoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-NUL-2064853 | ACCEPT | Summary: Reactome curation of FBXW7 nucleoplasm localization (binds phosphorylated NICD1). Correct localization. Reason: Correct nucleoplasm localization. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 1]: Nucleus, nucleoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-NUL-2064883 | ACCEPT | Summary: Reactome curation of FBXW7 nucleoplasm localization (ubiquitinates phosphorylated NICD1). Correct localization. Reason: Correct nucleoplasm localization. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 1]: Nucleus, nucleoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-NUL-9604628 | ACCEPT | Summary: Reactome curation of FBXW7 nucleoplasm localization (promotes ubiquitination of mouse p-NICD4). Correct localization. Reason: Correct nucleoplasm localization. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 1]: Nucleus, nucleoplasm |
| GO:0019005 SCF ubiquitin ligase complex | IDA PMID:17434132 Structure of a Fbw7-Skp1-cyclin E complex: multisite-phospho... | ACCEPT | Summary: Direct structural evidence that FBXW7 assembles with SKP1 (and the SCF) to recognize cyclin E. Core complex. Reason: Core complex; crystal structure of the Fbw7-Skp1-cyclin E complex. Supporting Evidence: PMID:17434132 binding to the SCF(Fbw7) ubiquitin ligase complex. Structures of the Skp1-Fbw7 |
| GO:0030332 cyclin binding | IPI PMID:17434132 Structure of a Fbw7-Skp1-cyclin E complex: multisite-phospho... | ACCEPT | Summary: Direct evidence that FBXW7 binds phosphorylated cyclin E via its WD40 domain. A specific, informative substrate-binding activity. Reason: Informative molecular function; FBXW7 WD40 recognizes the cyclin E phosphodegron as a key substrate. Supporting Evidence: PMID:17434132 pThr380/pSer384 cyclin E motif as an optimal, high-affinity degron |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IDA PMID:17434132 Structure of a Fbw7-Skp1-cyclin E complex: multisite-phospho... | ACCEPT | Summary: Direct evidence that SCF(Fbw7) drives cyclin E ubiquitination/degradation. Core biological process. Reason: Core process; cyclin E degradation by SCF(Fbw7). Supporting Evidence: PMID:17434132 Cyclin E degradation is triggered by multisite phosphorylation, which induces |
| GO:0050816 phosphothreonine residue binding | IDA PMID:17434132 Structure of a Fbw7-Skp1-cyclin E complex: multisite-phospho... | ACCEPT | Summary: Direct structural evidence that the FBXW7 WD40 pocket binds phosphothreonine-containing degrons (pThr380 cyclin E). The defining substrate-recognition activity. Reason: Core molecular function; phosphodegron (phosphothreonine) recognition is the basis of FBXW7 substrate selection. Supporting Evidence: PMID:17434132 pThr380/pSer384 cyclin E motif as an optimal, high-affinity degron |
| GO:0005515 protein binding | IPI PMID:24344117 FAM83D promotes cell proliferation and motility by downregul... | KEEP AS NON CORE | Summary: Interaction with FAM83D (which promotes FBXW7 degradation). Bare protein binding is uninformative. Reason: Records a real interaction (a negative regulator of FBXW7) but bare protein binding is uninformative. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt Interacts with FAM83D; promotes FBXW7 degradation |
| GO:1903749 positive regulation of protein localization to mitochondrion | IMP PMID:24912190 Genome-wide RNAi screen identifies the Parkinson disease GWA... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence from the mitophagy screen linking FBXW7 to mitochondrial protein localization (Parkin/mitophagy context). Reason: Specialized, context-specific role from a genome-wide screen; peripheral to the core function. Defer to curator (IMP). Supporting Evidence: PMID:24912190 as a regulator of mitophagy |
| GO:0005515 protein binding | IPI PMID:24000165 UBE2QL1 is disrupted by a constitutional translocation assoc... | KEEP AS NON CORE | Summary: Interaction with the E2 enzyme UBE2QL1. Bare protein binding is uninformative. Reason: Records a real interaction (UBE2QL1) but bare protein binding is uninformative. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt Interacts with UBE2QL1 |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:12628165 Parkin is a component of an SCF-like ubiquitin ligase comple... | KEEP AS NON CORE | Summary: Evidence that hSel-10/FBXW7 associates with the parkin ubiquitin ligase in an SCF-like complex. Captures binding to an E3 ligase partner. Reason: Documents FBXW7 association with parkin within an SCF-like ligase complex; informative for complex assembly but ancillary to the core substrate-receptor function. Supporting Evidence: PMID:12628165 functions in a multiprotein ubiquitin ligase complex that includes the F-box/WD |
| GO:1903378 positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway | IDA PMID:23858059 Parkin-dependent degradation of the F-box protein Fbw7beta p... | KEEP AS NON CORE | Summary: Direct evidence that Fbw7beta promotes neuronal oxidative-stress apoptosis by destabilizing the pro-survival factor MCL1. Reason: Genuine neuronal apoptotic role via MCL1 turnover but a specialized downstream output of substrate targeting. Supporting Evidence: PMID:23858059 Parkin-dependent degradation of the F-box protein Fbw7Ξ² promotes |
| GO:1990452 Parkin-FBXW7-Cul1 ubiquitin ligase complex | IPI PMID:12628165 Parkin is a component of an SCF-like ubiquitin ligase comple... | ACCEPT | Summary: Evidence that FBXW7/hSel-10 forms an SCF-like complex with parkin and Cullin-1. A specific complex membership. Reason: Directly supported complex membership; FBXW7 serves as the substrate receptor targeting the parkin/CUL1 complex to cyclin E. Supporting Evidence: PMID:12628165 functions in a multiprotein ubiquitin ligase complex that includes the F-box/WD |
| GO:0019005 SCF ubiquitin ligase complex | IDA PMID:12628165 Parkin is a component of an SCF-like ubiquitin ligase comple... | ACCEPT | Summary: Evidence that FBXW7/hSel-10 is part of an SCF-like complex (with CUL1). Core complex. Reason: Core complex membership for FBXW7. Supporting Evidence: PMID:12628165 functions in a multiprotein ubiquitin ligase complex that includes the F-box/WD |
| GO:0030332 cyclin binding | IDA PMID:12628165 Parkin is a component of an SCF-like ubiquitin ligase comple... | ACCEPT | Summary: Evidence that hSel-10/FBXW7 binds cyclin E as a substrate. Specific, informative substrate-binding activity. Reason: Informative molecular function; FBXW7 recognizes cyclin E. Supporting Evidence: PMID:12628165 ubiquitin ligase activity to cyclin E, an hSel-10-interacting protein previously |
| GO:0030674 protein-macromolecule adaptor activity | IDA PMID:12628165 Parkin is a component of an SCF-like ubiquitin ligase comple... | MODIFY | Summary: Evidence that FBXW7/hSel-10 acts as an adaptor targeting the ligase to its substrate (cyclin E). Captures the substrate-adaptor role. 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 replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:12628165 ubiquitin ligase activity to cyclin E, an hSel-10-interacting protein previously |
| GO:0031398 positive regulation of protein ubiquitination | IDA PMID:12628165 Parkin is a component of an SCF-like ubiquitin ligase comple... | KEEP AS NON CORE | Summary: Evidence that FBXW7 promotes ubiquitination of substrates (cyclin E) by the ligase complex. Reason: Correct but a regulatory framing; the core function is captured by the substrate-adaptor activity and SCF-dependent catabolic process terms. Supporting Evidence: PMID:12628165 ubiquitin ligase activity to cyclin E, an hSel-10-interacting protein previously |
| GO:0097027 ubiquitin-protein transferase activator activity | IDA PMID:12628165 Parkin is a component of an SCF-like ubiquitin ligase comple... | MODIFY | 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. 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 replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex |
| GO:1902806 regulation of cell cycle G1/S phase transition | TAS PMID:12628165 Parkin is a component of an SCF-like ubiquitin ligase comple... | ACCEPT | Summary: Author statement linking FBXW7-mediated cyclin E degradation to G1/S regulation. A core cell-cycle output of cyclin E turnover. Reason: Well-supported; FBXW7 controls G1/S progression via cyclin E degradation. Supporting Evidence: PMID:12628165 ubiquitin ligase activity to cyclin E, an hSel-10-interacting protein previously |
| GO:1901800 positive regulation of proteasomal protein catabolic process | IDA PMID:23858059 Parkin-dependent degradation of the F-box protein Fbw7beta p... | KEEP AS NON CORE | Summary: Evidence that Fbw7beta promotes proteasomal degradation of MCL1. Reason: Correct regulatory parent; the specific SCF-dependent catabolic process annotation better captures the core role. Supporting Evidence: PMID:23858059 parkin targets the SCF substrate adapter Fbw7Ξ² for proteasomal |
| GO:0005737 cytoplasm | IDA PMID:23858059 Parkin-dependent degradation of the F-box protein Fbw7beta p... | ACCEPT | Summary: Direct cytoplasmic localization of Fbw7beta in the neuronal oxidative-stress study. Reason: Experimentally supported localization of the cytoplasmic isoform. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 2]: Cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2220978 | ACCEPT | Summary: Reactome curation of FBXW7 nucleoplasm localization (WD mutants do not bind NICD1). Correct localization. Reason: Correct nucleoplasm localization. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 1]: Nucleus, nucleoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952618 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization within CRL1 neddylation reactions. Consistent with the cytoplasmic FBXW7 pool/SCF assembly. Reason: Cytosol is correct for the cytoplasmic isoform/SCF assembly context but redundant with the cytoplasm annotations. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 2]: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952620 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization (NEDD8:UBE2M binds CRL1). Consistent with cytoplasmic SCF assembly. Reason: Correct but redundant with the cytoplasm annotations. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 2]: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955241 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization (CAND1 binds cytosolic CRLs). Consistent with cytoplasmic SCF assembly. Reason: Correct but redundant with the cytoplasm annotations. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 2]: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955289 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization (COMMDs displace CAND1). Consistent with cytoplasmic SCF assembly. Reason: Correct but redundant with the cytoplasm annotations. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 2]: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956040 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization (COP9 signalosome deneddylates CRLs). Consistent with cytoplasmic SCF assembly. Reason: Correct but redundant with the cytoplasm annotations. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 2]: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956200 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization (DCUN1D3 binds CRL1). Consistent with cytoplasmic SCF assembly. Reason: Correct but redundant with the cytoplasm annotations. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 2]: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983140 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization (transfer of Ub from E2 to substrate). Consistent with cytoplasmic SCF function. Reason: Correct but redundant with the cytoplasm annotations. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 2]: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983147 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization (release of E3 from polyubiquitinated substrate). Consistent with cytoplasmic SCF function. Reason: Correct but redundant with the cytoplasm annotations. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 2]: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983156 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization (polyubiquitination of substrate). Consistent with cytoplasmic SCF function. Reason: Correct but redundant with the cytoplasm annotations. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 2]: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983157 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization (interaction of E3 with substrate and E2-Ub). Consistent with cytoplasmic SCF function. Reason: Correct but redundant with the cytoplasm annotations. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 2]: Cytoplasm |
| GO:0005515 protein binding | IPI Q969H0-1 PMID:17873522 Fbw7 and Usp28 regulate myc protein stability in response to... | KEEP AS NON CORE | Summary: Interaction with MYC and USP28 in the DNA-damage MYC stability study. Bare protein binding is uninformative. Reason: Records functionally relevant MYC/USP28 interactions but bare protein binding is uninformative. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt Interacts with USP28, counteracting ubiquitination of MYC |
| GO:0006974 DNA damage response | IDA Q969H0-1 PMID:17873522 Fbw7 and Usp28 regulate myc protein stability in response to... | KEEP AS NON CORE | Summary: Direct evidence that FBXW7/USP28 regulate MYC stability in response to DNA damage. Reason: A genuine DNA-damage-context role (MYC turnover) but a specialized output; the core function is substrate-receptor activity. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt Interacts with USP28, counteracting ubiquitination of MYC |
| GO:0032991 protein-containing complex | IDA Q969H0-1 PMID:17873522 Fbw7 and Usp28 regulate myc protein stability in response to... | KEEP AS NON CORE | Summary: Generic complex membership (FBXW7-MYC-USP28). Less informative than the specific SCF complex annotation. Reason: Generic; subsumed by the specific SCF ubiquitin ligase complex annotation. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt Interacts with USP28, counteracting ubiquitination of MYC |
| GO:0034644 cellular response to UV | IDA Q969H0-1 PMID:17873522 Fbw7 and Usp28 regulate myc protein stability in response to... | KEEP AS NON CORE | Summary: Direct evidence of FBXW7 involvement in cellular response to UV (DNA-damage MYC regulation). Reason: Specialized DNA-damage-context role; peripheral to the core function. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt Interacts with USP28, counteracting ubiquitination of MYC |
| GO:2000639 negative regulation of SREBP signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer of negative regulation of SREBP signaling, consistent with FBXW7-mediated SREBP turnover and lipid metabolism roles. Reason: A genuine metabolic regulatory output (FBXW7 degrades SREBP family members) but specialized relative to the core function. Supporting Evidence: PMID:23823476 An SREBP-responsive microRNA operon contributes to a regulatory loop for intracellular lipid homeostasis |
| GO:0001944 vasculature development | TAS PMID:21123947 Fbxw7 regulates lipid metabolism and cell fate decisions in ... | KEEP AS NON CORE | Summary: Author statement linking Fbxw7 to vasculature development (mouse liver metabolism/cell fate study). Reason: A developmental output; peripheral to the core function and supported by TAS in a mouse study. |
| GO:0010868 negative regulation of triglyceride biosynthetic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer of negative regulation of triglyceride biosynthesis (lipid metabolism role). Reason: Specialized metabolic output via SREBP regulation; peripheral to core function. |
| GO:0010883 regulation of lipid storage | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer of regulation of lipid storage. Reason: Specialized metabolic output; peripheral to core function. |
| GO:0032880 regulation of protein localization | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Sequence-similarity transfer of a generic regulation of protein localization role. Reason: Uninformatively general and not a characterized core FBXW7 activity; FBXW7 regulates substrate abundance, not localization per se. |
| GO:0055088 lipid homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer of a lipid homeostasis role, consistent with FBXW7 regulation of lipid metabolism in liver. Reason: Genuine metabolic role but a specialized physiological output of substrate targeting. Supporting Evidence: PMID:23823476 a regulatory loop for intracellular lipid homeostasis |
| GO:2000346 negative regulation of hepatocyte proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer of negative regulation of hepatocyte proliferation, consistent with FBXW7 tumor-suppressor function in liver. Reason: A tissue-specific anti-proliferative output of substrate (MYC/cyclin E) turnover; peripheral to the core function. |
| GO:0005515 protein binding | IPI PMID:15103331 Phosphorylation-dependent degradation of c-Myc is mediated b... | KEEP AS NON CORE | Summary: Interaction with c-Myc (substrate). Bare protein binding is uninformative. Reason: Records the functionally relevant FBXW7-MYC substrate interaction but bare protein binding is uninformative. Supporting Evidence: PMID:15103331 Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1 |
| GO:0005515 protein binding | IPI Q969H0-1 PMID:17558397 The ubiquitin-specific protease USP28 is required for MYC st... | KEEP AS NON CORE | Summary: Interaction with MYC/USP28. Bare protein binding is uninformative. Reason: Records functionally relevant MYC/USP28 interactions but bare protein binding is uninformative. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt Interacts with USP28, counteracting ubiquitination of MYC |
| GO:0005654 nucleoplasm | IDA Q969H0-1 PMID:17558397 The ubiquitin-specific protease USP28 is required for MYC st... | ACCEPT | Summary: Direct nucleoplasm localization of isoform 1 in the USP28/MYC study. Core localization for the nuclear pool. Reason: Core isoform-1 nucleoplasm localization, experimentally supported. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt [Isoform 1]: Nucleus, nucleoplasm |
| GO:0016567 protein ubiquitination | IDA PMID:15103331 Phosphorylation-dependent degradation of c-Myc is mediated b... | KEEP AS NON CORE | Summary: Direct evidence of FBXW7-mediated c-Myc ubiquitination. Captures the ubiquitination process. Reason: Correct but generic; the specific SCF-dependent catabolic process and substrate-adaptor activity better capture the role. Supporting Evidence: PMID:15103331 Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1 |
| GO:0019005 SCF ubiquitin ligase complex | IDA PMID:15103331 Phosphorylation-dependent degradation of c-Myc is mediated b... | ACCEPT | Summary: Direct evidence that FBXW7 is a component of the SCF(Fbw7) complex. Core complex. Reason: Core complex membership. Supporting Evidence: PMID:15103331 Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7 |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IDA PMID:15103331 Phosphorylation-dependent degradation of c-Myc is mediated b... | ACCEPT | Summary: Direct evidence that SCF(Fbw7) drives proteasome-dependent c-Myc degradation. Core biological process. Reason: Core process directly demonstrated for c-Myc. Supporting Evidence: PMID:15103331 Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1 |
| GO:0007062 sister chromatid cohesion | IMP PMID:15917200 Cornelia de Lange Syndrome and the link between chromosomal ... | UNDECIDED | Summary: Mutant-phenotype evidence relating FBXW7/SCF function to chromosomal/cohesion biology in a Cornelia de Lange syndrome context. 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). |
| GO:0016567 protein ubiquitination | IDA PMID:12354302 SEL-10 interacts with presenilin 1, facilitates its ubiquiti... | KEEP AS NON CORE | Summary: Direct evidence that SEL-10/FBXW7 facilitates ubiquitination of presenilin 1. Captures the ubiquitination process. Reason: Correct but generic; the specific SCF-dependent catabolic process and adaptor activity better capture the role. PSEN1 is a probable substrate. Supporting Evidence: file:human/FBXW7/FBXW7-uniprot.txt and probably PSEN1 |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: 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?
Q: 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?
Q: 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?
Q: 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?
Experiment: 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.
Experiment: 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.
Experiment: 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.
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)