FBXW7

UniProt ID: Q969H0
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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 Review

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.
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.
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

Core Functions

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:
ubiquitin-like ligase-substrate adaptor activity
Directly Involved In:
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
Cellular Locations:
nucleoplasm cytoplasm
Supporting Evidence:
  • PMID:15150404
    promotes proteasome-dependent c-Myc turnover in vivo and c-Myc ubiquitination in vitro

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:
phosphothreonine residue binding
Directly Involved In:
regulation of cell cycle G1/S phase transition
Cellular Locations:
nucleoplasm
Supporting Evidence:
  • PMID:17434132
    pThr380/pSer384 cyclin E motif as an optimal, high-affinity degron

References

GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000041
Gene Ontology annotation based on UniPathway vocabulary mapping
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
PMID:12354302
SEL-10 interacts with presenilin 1, facilitates its ubiquitination, and alters A-beta peptide production.
PMID:12628165
Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity.
  • hSel-10/FBXW7 forms an SCF-like complex with parkin and Cullin-1 and targets the ligase activity to cyclin E.
PMID:15070733
M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP.
PMID:15103331
Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7.
  • Fbw7 interacts with and destabilizes c-Myc in a phosphorylation (MB1)-dependent manner via the SCF(Fbw7) complex, promoting proteasomal turnover.
PMID:15150404
The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation.
  • Fbw7 promotes proteasome-dependent c-Myc turnover and in vitro ubiquitination; GSK3 phosphorylation of c-Myc T58 regulates Fbw7 binding.
PMID:15917200
Cornelia de Lange Syndrome and the link between chromosomal function, DNA repair and developmental gene regulation.
PMID:17157259
SNIP1 is a candidate modifier of the transcriptional activity of c-Myc on E box-dependent target genes.
PMID:17314511
Large-scale identification of c-MYC-associated proteins using a combined TAP/MudPIT approach.
PMID:17434132
Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases.
  • 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.
PMID:17558397
The ubiquitin-specific protease USP28 is required for MYC stability.
  • FBXW7 (with USP28) controls MYC stability; isoform 1 is nucleoplasmic.
PMID:17873522
Fbw7 and Usp28 regulate myc protein stability in response to DNA damage.
  • FBXW7/USP28 regulate MYC protein stability in response to DNA damage.
PMID:17909182
Kaposi's sarcoma herpesvirus-encoded latency-associated nuclear antigen stabilizes intracellular activated Notch by targeting the Sel10 protein.
PMID:19111882
Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma.
PMID:19412162
F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage.
PMID:20596027
SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation.
PMID:20823234
Notch signaling contributes to proliferation and tumor formation of human T-cell leukemia virus type 1-associated adult T-cell leukemia.
PMID:21123947
Fbxw7 regulates lipid metabolism and cell fate decisions in the mouse liver.
  • Hepatic Fbxw7 regulates lipid metabolism and cell-fate decisions.
PMID:21145461
Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.
PMID:21620836
PI3K-dependent phosphorylation of Fbw7 modulates substrate degradation and activity.
PMID:22307056
ERK1 and ERK2 regulate embryonic stem cell self-renewal through phosphorylation of Klf4.
PMID:22939624
Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition.
PMID:23022380
NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function.
PMID:23108047
FBXW7-mediated degradation of CCDC6 is impaired by ATM during DNA damage response in lung cancer cells.
PMID:23791182
The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability.
PMID:23823476
An SREBP-responsive microRNA operon contributes to a regulatory loop for intracellular lipid homeostasis.
  • An SREBP-responsive microRNA operon (with FBXW7) contributes to a regulatory loop for intracellular lipid homeostasis.
PMID:23858059
Parkin-dependent degradation of the F-box protein Fbw7beta promotes neuronal survival in response to oxidative stress by stabilizing Mcl-1.
  • Parkin targets the SCF substrate adapter Fbw7beta for proteasomal degradation; Fbw7beta destabilizes the pro-survival factor Mcl-1.
PMID:24000165
UBE2QL1 is disrupted by a constitutional translocation associated with renal tumor predisposition and is a novel candidate renal tumor suppressor gene.
PMID:24344117
FAM83D promotes cell proliferation and motility by downregulating tumor suppressor gene FBXW7.
  • FAM83D promotes FBXW7 degradation, downregulating the tumor suppressor.
PMID:24412244
Charting the molecular links between driver and susceptibility genes in colorectal cancer.
PMID:24912190
Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy.
  • Genome-wide RNAi screen implicates SREBF1 (and FBXW7) in mitophagy regulation.
PMID:25344755
Cyclin C is a haploinsufficient tumour suppressor.
PMID:25897075
Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7-mediated Ubiquitination and Proteasomal Degradation.
  • RICTOR undergoes GSK3-dependent, FBXW7-mediated ubiquitination and proteasomal degradation.
PMID:26774286
FBXW7 Facilitates Nonhomologous End-Joining via K63-Linked Polyubiquitylation of XRCC4.
  • ATM phosphorylates FBXW7 at Ser26 to recruit it to DSBs; SCF(FBXW7) then promotes K63-linked polyubiquitylation of XRCC4, facilitating NHEJ.
PMID:27229929
Systematic interactome mapping of acute lymphoblastic leukemia cancer gene products reveals EXT-1 tumor suppressor as a Notch1 and FBWX7 common interactor.
PMID:27238018
Circadian Amplitude Regulation via FBXW7-Targeted REV-ERBalpha Degradation.
  • FBXW7 targets phosphorylated REV-ERBalpha (NR1D1) for ubiquitination and degradation, regulating circadian amplitude and hepatic clock/metabolic gene expression.
PMID:27458189
Synaptonuclear messenger PRR7 inhibits c-Jun ubiquitination and regulates NMDA-mediated excitotoxicity.
PMID:27837025
Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors.
PMID:27880917
Phenotypic and Interaction Profiling of the Human Phosphatases Identifies Diverse Mitotic Regulators.
PMID:28007894
The pseudophosphatase STYX targets the F-box of FBXW7 and inhibits SCFFBXW7 function.
  • 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.
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
PMID:29149593
NOTCH2 Hajdu-Cheney Mutations Escape SCF(FBW7)-Dependent Proteolysis to Promote Osteoporosis.
  • NOTCH2 truncations escape FBW7-mediated ubiquitination/degradation; osteoclast-specific Fbw7 ablation causes osteoporosis via elevated Notch2 signaling.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:34445249
The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
PMID:34591642
A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity.
PMID:34741373
CDK1/FBXW7 facilitates degradation and ubiquitination of MLST8 to inhibit progression of renal cell carcinoma.
  • CDK1/FBXW7 facilitates ubiquitination and degradation of MLST8 in renal cell carcinoma.
PMID:35140242
Human transcription factor protein interaction networks.
PMID:35395208
Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome.
  • Germline FBXW7 variants impair substrate ubiquitination and cause an autosomal dominant neurodevelopmental syndrome (DEDHIL).
PMID:35512704
Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.
PMID:36395886
The SCF-FBXW7 E3 ubiquitin ligase triggers degradation of histone 3 lysine 4 methyltransferase complex component WDR5 to prevent mitotic slippage.
  • SCF-FBXW7 triggers degradation of WDR5 to promote mitotic cell death and prevent mitotic slippage.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.
PMID:40274799
TTC36 promotes proliferation and drug resistance in hepatocellular carcinoma cells by inhibiting c-Myc degradation.
  • TTC36 inhibits c-Myc degradation (FBXW7-dependent), promoting HCC proliferation and drug resistance.
Reactome:R-HSA-2220967
p-NICD1 PEST domain mutants do not bind FBXW7
Reactome:R-HSA-2220978
FBXW7 WD mutants do not bind NICD1
Reactome:R-HSA-8952618
AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex
Reactome:R-HSA-8952620
NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex
Reactome:R-HSA-8955241
CAND1 binds cytosolic CRL E3 ubiquitin ligases
Reactome:R-HSA-8955289
COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes
Reactome:R-HSA-8956040
COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes
Reactome:R-HSA-8956200
MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex
Reactome:R-HSA-983140
Transfer of Ub from E2 to substrate and release of E2
Reactome:R-HSA-983147
Release of E3 from polyubiquitinated substrate
Reactome:R-HSA-983156
Polyubiquitination of substrate
Reactome:R-HSA-983157
Interaction of E3 with substrate and E2-Ub complex
Reactome:R-NUL-2064853
FBXW7 binds phosphorylated NICD1
Reactome:R-NUL-2064883
FBXW7 mediates ubiquitination of phosphorylated NICD1
Reactome:R-NUL-9604628
FBXW7 promotes ubiquitination of mouse p-NICD4
file:human/FBXW7/FBXW7-deep-research-falcon.md
Falcon deep research report for human FBXW7
  • 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.
    "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"
  • 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.
    "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."
  • 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.
    "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"
  • 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.
    "A 2024 JBC study reports that the cytoplasmic isoform **FBW7Ξ²** 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."
  • 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.
    "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 substratesβ€”helping explain cancer-specific phenotypes and inconsistent clinical associations."

Suggested Questions for Experts

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?

Suggested Experiments

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.

Deep Research

Falcon

(FBXW7-deep-research-falcon.md)
Research Report: Human **FBXW7** (UniProt **Q969H0**) β€” Functional Annotation and Translational Relevance (2023–2024 emphasis) Falcon Edison Scientific Literature 42 citations 1 artifacts 2026-06-13T07:07:53.623180
Edison artifact artifact-00 (text/markdown)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Human FBXW7 (UniProt Q969H0) β€” Functional Annotation and Translational Relevance (2023–2024 emphasis)

Executive summary

FBXW7 (also known as FBW7, hCDC4, SEL10, AGO/archipelago) is a substrate-recognition adaptor of the SCF (SKP1–CUL1–RBX1) Cullin-RING E3 ubiquitin ligase, best known for suppressing oncogenic signaling by promoting polyubiquitination and proteasomal degradation of phosphorylated client proteins. Its defining biochemical role is phosphodegron-dependent recognition (classically the Cdc4 phosphodegron, CPD) via a WD40 Ξ²-propeller, enabling selective ubiquitin transfer to substrates. Recent 2023–2024 work expands FBXW7’s validated substrate repertoire (e.g., EGFR, LEF1/TCF7L2, PINK1) and clarifies therapy-relevant consequences (anti-EGFR and anti-Wnt resistance mechanisms and vulnerabilities). (cova2023thehighsand pages 1-2, chen2023fbxw7inbreast pages 1-2, boretto2024epidermalgrowthfactor pages 1-2, zhong2024recurrentmutationsin pages 1-2, jeon2024thescffbw7Ξ²e3 pages 2-3)

1. Target identity verification (critical disambiguation)

The target described by UniProt accession Q969H0 corresponds to human FBXW7, an F-box/WD40 repeat protein historically named hCDC4, SEL-10, and AGO/archipelago in different model organisms and early literature. Multiple peer-reviewed sources explicitly connect these aliases and define the same SCF substrate-receptor function, matching the UniProt domain architecture (F-box + WD40 repeats) and human context. (zhang2020functionandregulation pages 2-3, cova2023thehighsand pages 1-2, fiore2023theroleof pages 1-2)

2. Key concepts and definitions (current understanding)

2.1 What FBXW7 is (molecular function)

FBXW7 is the substrate receptor of an SCF-type E3 ubiquitin ligase. In SCF complexes, the scaffold CUL1 and RING protein RBX1 recruit the E2 enzyme, SKP1 links the variable F-box adaptor, and FBXW7 confers substrate specificity by binding substrates and positioning them for ubiquitination and subsequent proteasomal degradation. (cova2023thehighsand pages 1-2)

2.2 Domain architecture

FBXW7 proteins share: (i) an N-terminal dimerization domain, (ii) an F-box (SKP1 binding), and (iii) a C-terminal WD40-repeat Ξ²-propeller substrate-binding region. This structure directly supports its role as an SCF substrate receptor. (cova2023thehighsand pages 1-2, wang2023fbxw7andhuman pages 1-2)

2.3 Isoforms and subcellular localization

Human FBXW7 encodes three major N-terminal isoforms with distinct localization:
- FBXW7Ξ±: predominantly nuclear/nucleoplasmic (broadly expressed) (zhang2020functionandregulation pages 2-3, cova2023thehighsand pages 1-2)
- FBXW7Ξ²: predominantly cytoplasmic (cova2023thehighsand pages 1-2)
- FBXW7Ξ³: predominantly nucleolar (zhang2020functionandregulation pages 2-3, cova2023thehighsand pages 1-2)

This compartmentalization is functionally important because it constrains which substrates can be engaged in vivo. (cova2023thehighsand pages 1-2, jeon2024thescffbw7Ξ²e3 pages 2-3)

2.4 Degrons and phosphodegrons: the CPD concept

A degron is a sequence feature that confers regulated instability; FBXW7 typically recognizes a phosphorylated degron (the Cdc4 phosphodegron, CPD) in substrates. A high-affinity CPD described in a 2023 review is pThr–Pro–Pro–X–pSer, with the central phosphorylated threonine at the P0 position. The field increasingly recognizes that low-affinity and noncanonical CPDs can still be biologically decisive. (cova2023thehighsand pages 1-2, cova2023thehighsand pages 8-10)

Kinase signaling creates CPDs; sources explicitly discuss roles for GSK3 (often as a key CPD-generating kinase) and additional kinases such as CDK1/2 and ERK/MAPK in multi-kinase β€œpriming + phosphorylation” schemes that tune substrate engagement. (cova2023thehighsand pages 8-10, zhang2020functionandregulation pages 4-6, chen2023fbxw7inbreast pages 1-2)

3. Core biology: pathways, substrates, and mechanistic evidence

3.1 Primary biochemical role in cells

FBXW7’s primary function is to reduce abundance of specific regulatory proteins by targeting them for polyubiquitination and 26S proteasome degradation, thereby constraining oncogenic transcriptional programs, cell-cycle progression, and survival pathways. (cova2023thehighsand pages 1-2, wang2023fbxw7andhuman pages 1-2)

3.2 Canonical substrates (high-confidence)

Across multiple 2023 reviews and earlier mechanistic literature, repeatedly supported substrates include:
- Cyclin E (cell-cycle control) (wang2023fbxw7andhuman pages 1-2, fiore2023theroleof pages 1-2)
- c-MYC and c-JUN (oncogenic transcription factors) (zhang2020functionandregulation pages 4-6, wang2023fbxw7andhuman pages 1-2)
- NOTCH1/NOTCH4 signaling components (zhang2020functionandregulation pages 4-6)
- MCL1 (anti-apoptotic factor; phosphorylation-linked turnover) (zhang2020functionandregulation pages 4-6, wang2023fbxw7andhuman pages 1-2)
- mTOR pathway components (accumulation noted upon FBXW7 loss) (zhang2020functionandregulation pages 4-6, chen2023fbxw7inbreast pages 1-2)
- BRAF (noted in 2023 review; and mutation-specific functional impairment discussed in CRC cohort analysis) (cova2023thehighsand pages 1-2, liu2023comprehensivecharacterizationof pages 7-8)

Mechanistic specificity often depends on substrate phosphorylation: for example, c-MYC regulation can depend on phosphorylation at Thr58, and MCL1 turnover can be triggered by GSK3-dependent phosphorylation that initiates ubiquitination and degradation. (zhang2020functionandregulation pages 4-6)

3.3 2023–2024 mechanistic expansions and β€œlatest research” highlights

(A) EGFR as an FBXW7 substrate (PNAS 2024)

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. The study also reports reduced sensitivity to EGFR–MAPK inhibitors in FBXW7-mutant organoids and relates this to clinical anti-EGFR response in metastatic CRC. (boretto2024epidermalgrowthfactor pages 1-2)

(B) Anti-Wnt therapy resistance and lineage plasticity (Science Advances 2024)

In RNF43-mutant/RSPO-fusion cancers, FBXW7 mutations were shown to cause intrinsic resistance to anti-Wnt therapies. Mechanistically, FBXW7 inactivation stabilizes multiple oncoproteins (including Cyclin E and MYC) and leads tumors to lose dependence on Ξ²-catenin signaling, accompanied by dedifferentiation and loss of lineage specificity. Importantly, these Wnt-independent FBXW7-mutant states were reported to remain susceptible to multi–cyclin-dependent kinase inhibition, suggesting an actionable alternative vulnerability. (zhong2024recurrentmutationsin pages 1-2)

(C) New Wnt-effector substrates LEF1 and TCF7L2 (EMBO Mol Med 2023)

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 β€œhotspot” substrate-binding mutant, with densitometry ratios decreasing from 1.0 β†’ 0.44 (LEF1) and 1.0 β†’ 0.17 (TCF7L2). This provides direct substrate-binding evidence and supports a mechanistic connection between FBXW7 loss and altered Wnt transcriptional outputs. (brown2023functionalanalysisreveals pages 10-12)

(D) PINK1 degradation by cytosolic SCF–FBW7Ξ² (JBC 2024)

A 2024 JBC study reports that the cytoplasmic isoform FBW7Ξ² 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. Mechanistic SCF dependency was supported by cullin-1 perturbation and inhibition of cullin neddylation (MLN4924), which increased PINK1 levels. Functionally, FBW7Ξ² depletion increased PINK1 and enhanced CCCP-induced mitophagy, linking FBXW7 to mitochondrial quality control. (jeon2024thescffbw7Ξ²e3 pages 1-2, jeon2024thescffbw7Ξ²e3 pages 3-6, jeon2024thescffbw7Ξ²e3 pages 2-3)

4. Quantitative statistics and data points (recent studies)

4.1 Colorectal cancer: frequency and survival statistics

A 2023 colorectal cancer clinicogenomic analysis reported that FBXW7 mutations occur in approximately 18% of CRC patients in their dataset, and that FBXW7-mutant CRC cases were associated with higher MSI and TMB and lower chromosomal instability. In that analysis, FBXW7 mutation status overall was associated with better overall survival (HR 0.67, 95% CI 0.55–0.80; P < 0.001). However, the hotspot R465C variant was associated with worse outcomes than other FBXW7 mutations, including R465C vs R465H (HR 3.08, 95% CI 1.28–7.39; P = 0.0082). (liu2023comprehensivecharacterizationof pages 7-8)

These findings support a key expert-level interpretation: variant identity mattersβ€”not all FBXW7 alterations are equivalent biologically or clinically. (cova2023thehighsand pages 8-10, liu2023comprehensivecharacterizationof pages 7-8)

4.2 Functional effect sizes in primary models

  • FBXW7 hotspot mutation in colon organoids caused ~10,000-fold reduced EGF dependence (a very large phenotypic shift in growth-factor addiction). (boretto2024epidermalgrowthfactor pages 1-2)
  • WD40 hotspot mutation reduced FBXW7 binding to LEF1 and TCF7L2 to ~44% and 17% of control co-IP signals, respectively. (brown2023functionalanalysisreveals pages 10-12)

5. Current applications and real-world implementations

5.1 Precision oncology biomarker contexts

Anti-EGFR therapy (metastatic CRC): The 2024 PNAS organoid and patient-linked study supports the concept that FBXW7 loss can stabilize EGFR via CPD disruption and thereby negatively modulate response to anti-EGFR–based regimens and EGFR–MAPK pathway inhibition. This supports practical use of FBXW7 status as a candidate biomarker for resistance or faster progression under EGFR-directed therapy, especially in organoid-guided precision approaches. (boretto2024epidermalgrowthfactor pages 1-2)

Anti-Wnt therapy selection: For RNF43-mutant/RSPO-fusion cancers treated with Wnt-ligand biogenesis inhibitors (e.g., PORCN inhibitors), FBXW7 mutation was proposed as a biomarker of primary resistance, motivating alternative strategies (e.g., CDK inhibition). (zhong2024recurrentmutationsin pages 1-2)

5.2 Mechanism-informed therapeutic hypotheses (expert synthesis)

Contemporary reviews emphasize that FBXW7’s tumor-suppressor role derives from multi-substrate turnover; thus, rather than β€œinhibiting FBXW7,” translational work often aims to:
- target stabilized downstream proteins (e.g., MCL1 when FBXW7 is impaired), and/or
- target pathway consequences of substrate accumulation (EGFR/MAPK; Wnt addiction bypass), and/or
- exploit synthetic vulnerabilities emerging from rewired cell-cycle control.

This strategic framing is consistent with mechanistic evidence for substrate stabilization (Cyclin E/MYC, EGFR) in 2024 primary studies and 2023–2024 reviews emphasizing resistance mechanisms. (wang2023fbxw7andhuman pages 1-2, boretto2024epidermalgrowthfactor pages 1-2, zhong2024recurrentmutationsin pages 1-2)

6. Expert opinions and authoritative analysis (from reviews)

A 2023 mechanistic review highlights an emerging conceptual refinement: substrate selection is not governed solely by β€œperfect” CPD matches; low-affinity substrates and alternative binding modes can be decisive, and hotspot WD40 mutations may differentially disrupt subsets of substratesβ€”helping explain cancer-specific phenotypes and inconsistent clinical associations. (cova2023thehighsand pages 8-10)

Cancer-focused reviews in 2023 emphasize FBXW7 as a central SCF adaptor whose loss contributes to malignant progression and therapy resistance through stabilization of multiple proto-oncoproteins and survival factors, reinforcing its role as a multi-pathway node rather than a single-pathway regulator. (chen2023fbxw7inbreast pages 1-2, wang2023fbxw7andhuman pages 1-2, fiore2023theroleof pages 1-2)

7. Subcellular site of action

FBXW7 operates primarily in intracellular compartments consistent with its isoform localization:
- nuclear substrates (FBXW7Ξ±) (cova2023thehighsand pages 1-2)
- cytosolic substrates (FBXW7Ξ²) including demonstrated cytosolic PINK1 interaction/degradation (jeon2024thescffbw7Ξ²e3 pages 1-2, jeon2024thescffbw7Ξ²e3 pages 2-3)
- nucleolar substrates (FBXW7Ξ³) (cova2023thehighsand pages 1-2)

The 2024 PINK1 study provides direct evidence for cytosolic interaction between endogenous PINK1 and FBW7Ξ², establishing a concrete locale for one FBXW7-dependent pathway in mitochondrial quality control signaling. (jeon2024thescffbw7Ξ²e3 pages 1-2)

8. Consolidated evidence map (artifact)

The following table provides a compact map of identity, mechanism, substrates, recent studies, and translational implications with publication dates and URLs.

Aspect Key points Best recent sources (2023-2024 prioritized) with publication date and URL
Identity/complex FBXW7 in this report matches human UniProt Q969H0 and the historical aliases hCDC4, SEL-10, and AGO/archipelago homolog. It is the substrate-recognition subunit of the SCF (SKP1-CUL1-RBX1-FBXW7) Cullin-RING E3 ubiquitin ligase complex that promotes ubiquitination and proteasomal degradation of phosphorylated substrates, especially growth- and cell-cycle regulators (zhang2020functionandregulation pages 2-3, cova2023thehighsand pages 1-2, fiore2023theroleof pages 1-2). de la Cova, Cells (2023-08), https://doi.org/10.3390/cells12172141; Di Fiore et al., Cells (2023-05), https://doi.org/10.3390/cells12101415; Zhang et al., Oncology Letters (2020-06), https://doi.org/10.3892/ol.2020.11728
Domains/isoforms/localization FBXW7 contains an N-terminal dimerization region, an F-box that binds SKP1, and a C-terminal WD40 Ξ²-propeller substrate-binding domain. Human isoforms are N-terminally distinct: FBXW7Ξ± is mainly nuclear/nucleoplasmic, FBXW7Ξ² is cytoplasmic, and FBXW7Ξ³ is nucleolar; this matches the UniProt F-box/WD40 annotation and explains compartment-specific substrate control (zhang2020functionandregulation pages 2-3, singh2022mapkdependentregulation pages 21-25, cova2023thehighsand pages 1-2, singh2022mapkdependentregulation pages 29-33). de la Cova, Cells (2023-08), https://doi.org/10.3390/cells12172141; Zhang et al., Oncology Letters (2020-06), https://doi.org/10.3892/ol.2020.11728
Degron recognition/kinases 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 (cova2023thehighsand pages 1-2, cova2023thehighsand pages 8-10, zhang2020functionandregulation pages 4-6, chen2023fbxw7inbreast pages 1-2, singh2022mapkdependentregulation pages 29-33). de la Cova, Cells (2023-08), https://doi.org/10.3390/cells12172141; Chen et al., J Exp Clin Cancer Res (2023-09), https://doi.org/10.1186/s13046-023-02767-1
Key substrates Canonical and strongly supported substrates include Cyclin E, c-MYC, c-JUN, NOTCH1/NOTCH4, MCL1, KLF5, mTOR, and BRAF. Recent primary studies extend the substrate list to EGFR (direct target in colorectal organoids/patients), LEF1 and TCF7L2 (endometrial cancer models), and PINK1 via SCF-FBW7Ξ² in the cytosol; recent systematic/functional work also highlights context-dependent effects on CRY2, ZEB2, and others (zhang2020functionandregulation pages 4-6, wang2023fbxw7andhuman pages 1-2, boretto2024epidermalgrowthfactor pages 1-2, brown2023functionalanalysisreveals pages 10-12, jeon2024thescffbw7Ξ²e3 pages 1-2, jeon2024thescffbw7Ξ²e3 pages 3-6). Boretto et al., PNAS (2024-03), https://doi.org/10.1073/pnas.2309902121; Brown et al., EMBO Mol Med (2023-08), https://doi.org/10.15252/emmm.202217094; Jeon & Chung, J Biol Chem (2024-04), https://doi.org/10.1016/j.jbc.2024.107198
2023-2024 primary study highlights 2024 PNAS: EGFR was identified as a direct FBXW7 substrate; FBXW7 hotspot-mutant colon organoids showed markedly increased EGFR stability and ~10,000-fold reduced EGF dependence, with poorer response to EGFR-MAPK blockade and faster progression in FBXW7-mutant metastatic CRC on anti-EGFR therapy (boretto2024epidermalgrowthfactor pages 1-2). 2024 Science Advances: FBXW7 mutations in RNF43-mutant/RSPO-fusion cancers caused intrinsic resistance to anti-Wnt therapies, with loss of Ξ²-catenin dependence but retained sensitivity to multi-CDK inhibition (zhong2024recurrentmutationsin pages 1-2). 2024 JBC: SCF-FBW7Ξ² promoted K48-linked polyubiquitination and proteasomal degradation of PINK1, with endogenous interaction primarily in the cytosol (jeon2024thescffbw7Ξ²e3 pages 1-2, jeon2024thescffbw7Ξ²e3 pages 3-6, jeon2024thescffbw7Ξ²e3 pages 2-3). 2023 EMBO Mol Med: LEF1 and TCF7L2 were validated as novel FBXW7-interacting substrates, and WD40 hotspot mutation weakened binding (LEF1 co-IP ratio ~1.0β†’0.44; TCF7L2 ~1.0β†’0.17) (brown2023functionalanalysisreveals pages 10-12). Boretto et al., PNAS (2024-03), https://doi.org/10.1073/pnas.2309902121; Zhong & Virshup, Science Advances (2024-04), https://doi.org/10.1126/sciadv.adk1031; Jeon & Chung, J Biol Chem (2024-04), https://doi.org/10.1016/j.jbc.2024.107198; Brown et al., EMBO Mol Med (2023-08), https://doi.org/10.15252/emmm.202217094
Clinical/genomic statistics FBXW7 is among the most recurrently altered F-box genes in cancer. In CRC, recent summaries place mutation prevalence around 6-10% overall, with cohort-specific estimates near 14.8-18.75% in several Asian series and ~18% in one 2023 clinicogenomic analysis (arrivi2025fbxw7genemutation pages 1-2, liu2023comprehensivecharacterizationof pages 7-8, arrivi2025fbxw7genemutation pages 14-16). In the 2023 Frontiers in Oncology CRC study, patients with FBXW7 mutations had better overall survival overall (HR 0.67, 95% CI 0.55-0.80, P<0.001), but the specific R465C variant had worse survival than other FBXW7 variants (HR 1.6, 95% CI 1.13-3.1, P=0.015) and versus R465H (HR 3.08, 95% CI 1.28-7.39, P=0.0082) (liu2023comprehensivecharacterizationof pages 7-8). RNF43 mutations occur in ~5-10% of pancreatic cancers and RSPO2/3 fusions in ~2-10% of CRC; within that molecular subgroup, FBXW7 mutation marks likely anti-Wnt resistance (zhong2024recurrentmutationsin pages 1-2). Liu et al., Frontiers in Oncology (2023-03), https://doi.org/10.3389/fonc.2023.1154432; Afolabi et al., Heliyon (2024-06), https://doi.org/10.1016/j.heliyon.2024.e31471; Zhong & Virshup, Science Advances (2024-04), https://doi.org/10.1126/sciadv.adk1031
Therapeutic/application implications Current translational interest centers on biomarker use and pathway-guided therapy rather than direct FBXW7-targeted drugs. FBXW7 status may help predict resistance to anti-EGFR therapy in metastatic CRC, primary resistance to anti-Wnt/PORCN-pathway inhibition in RNF43/RSPO tumors, and altered sensitivity to apoptosis-targeted approaches when MCL1 accumulates. Mechanistically informed alternatives proposed in recent work include multi-CDK inhibition for FBXW7-mutant Wnt-independent tumors, MCL1-directed strategies, and exploiting synthetic vulnerabilities created by FBXW7 loss; reviews also emphasize potential immunotherapy relevance and the need for hotspot-specific interpretation rather than treating all FBXW7 variants as equivalent (arrivi2025fbxw7genemutation pages 19-20, boretto2024epidermalgrowthfactor pages 1-2, arrivi2025fbxw7genemutation pages 20-22, zhong2024recurrentmutationsin pages 1-2). Wang et al., Frontiers in Pharmacology (2024-12), https://doi.org/10.3389/fphar.2024.1505027; Wang et al., Frontiers in Pharmacology (2023-11), https://doi.org/10.3389/fphar.2023.1278056; Chen et al., Frontiers in Oncology (2023-03), https://doi.org/10.3389/fonc.2023.1147239; Boretto et al., PNAS (2024-03), https://doi.org/10.1073/pnas.2309902121

Table: This table summarizes verified identity, molecular function, localization, substrates, recent 2023-2024 discoveries, and translational implications for human FBXW7 (UniProt Q969H0). It is useful as a compact evidence map for narrative functional annotation and recent literature synthesis.

Limitations of this synthesis

  • The evidence base retrieved here did not include clinical trial registry records directly; thus, no FBXW7-specific interventional trial IDs are cited. Most β€œreal-world” implementation evidence is observational/biomarker-driven or based on patient-derived organoid studies rather than FBXW7-targeted drugs. (boretto2024epidermalgrowthfactor pages 1-2, zhong2024recurrentmutationsin pages 1-2)

Key recent references (URLs + publication months)

  • de la Cova. The Highs and Lows of FBXW7… Cells (Aug 2023). https://doi.org/10.3390/cells12172141 (cova2023thehighsand pages 1-2)
  • Chen et al. FBXW7 in breast cancer… J Exp Clin Cancer Res (Sep 2023). https://doi.org/10.1186/s13046-023-02767-1 (chen2023fbxw7inbreast pages 1-2)
  • Brown et al. Functional analysis reveals driver cooperativity… EMBO Mol Med (Aug 2023). https://doi.org/10.15252/emmm.202217094 (brown2023functionalanalysisreveals pages 10-12)
  • Liu et al. Comprehensive characterization of FBXW7… CRC Frontiers in Oncology (Mar 2023). https://doi.org/10.3389/fonc.2023.1154432 (liu2023comprehensivecharacterizationof pages 7-8)
  • Boretto et al. EGFR is a target of… FBXW7 PNAS (Mar 2024). https://doi.org/10.1073/pnas.2309902121 (boretto2024epidermalgrowthfactor pages 1-2)
  • Zhong & Virshup. FBXW7 mutations bypass Wnt/Ξ²-catenin addiction… Science Advances (Apr 2024). https://doi.org/10.1126/sciadv.adk1031 (zhong2024recurrentmutationsin pages 1-2)
  • Jeon & Chung. SCF-FBW7Ξ² mediates ubiquitination and degradation of PINK1 J Biol Chem (Apr 2024). https://doi.org/10.1016/j.jbc.2024.107198 (jeon2024thescffbw7Ξ²e3 pages 1-2)

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Artifacts

Citations

  1. cova2023thehighsand pages 1-2
  2. zhang2020functionandregulation pages 4-6
  3. boretto2024epidermalgrowthfactor pages 1-2
  4. zhong2024recurrentmutationsin pages 1-2
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πŸ“š Additional Documentation

Pn Notes

(FBXW7-pn-notes.md)

FBXW7 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q969H0
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-13
  • Batch change status: added

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Deep Research Files

AIGR Review Snapshot

  • 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/core annotation action counts: ACCEPT: 39; KEEP_AS_NON_CORE: 81; MARK_AS_OVER_ANNOTATED: 5; MODIFY: 2; UNDECIDED: 3

PN Consistency Summary

  • Consistency: Rows 1–2 consistent. FBXW7 is the textbook tumor-suppressor SCF receptor; review has GO:1990756 (IDA x2, ACCEPT) β€” matching Row2 "already_in_goa_exact" β€” plus GO:0050816 phosphothreonine binding, GO:0030332 cyclin binding, and a large substrate set (cyclin E, MYC, NOTCH ICD, MCL1, RICTOR, MLST8, NR1D1, EGFR). Row1 mTORC1/SHOC2 role corresponds to KEEP_AS_NON_CORE downstream outputs. Row3 INCONSISTENT: PN projects GO:0061630 ubiquitin protein ligase activity from PMID:21070969 (Pashkova 2010, DOI), a paper (per PubMed) about WD40 propellers as ubiquitin-binding domains regulating F-box turnover β€” with Cdc4 (the FBXW7 ortholog) shown to use Ub-binding to promote its own auto-ubiquitination, not substrate ligation. The review independently flags exactly this: GO:0043130 ubiquitin binding (IBA) is MARK_AS_OVER_ANNOTATED ("FBXW7 recognizes phosphodegrons, not free ubiquitin"). So the YAML directly contradicts the PN Row3 catalytic projection.
  • PN story / NEW pressure: Row2 GO:1990756 already in GOA (IDA) and accepted β€” no new pressure. Row3 GO:0061630 over-reaches (wrong activity class for a non-catalytic receptor; and the source paper is about Ub binding/auto-turnover). Both GO:0061630 and GO:0043130 verified real via OLS. No defensible NEW catalytic term.
  • Evidence alignment: Strong overlap on the receptor story; Row2 PN PMID:15340381 (family review) vs review's gene-specific PMID:17434132 (cyclin E structure), PMID:15103331/15150404 (MYC), PMID:28007894 (STYX), PMID:35395208 (DEDHIL). Row3 PMID:21070969 is NOT cited in the FBXW7 review (only its IBA-derived ubiquitin-binding term is, via GO_REF:0000033) and is mischaracterized by the GO:0061630 mapping.
  • Verdict: Rows 1–2 CONSISTENT; Row3 PN node OVER-REACHES (contradicts the review's own over-annotation call). Recommended edits: [MAP] change Row3 Ubiquitin and UBL binding|E3 ligase projection for FBXW7 from GO:0061630 ubiquitin protein ligase activity to GO:0043130 ubiquitin binding or no_mapping β€” PMID:21070969 = WD40 ubiquitin BINDING controlling F-box auto-turnover, not catalytic ligase; the FBXW7 review already marks ubiquitin binding as over-annotated.

Full Consistency Review

  • UniProt: Q969H0 Β· batch: proteostasis-batch-2026-06-13 Β· review status: COMPLETE (very comprehensive, ~2220 lines)
  • PN placement (3 rows): Row1 ALP Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, direct|Modulator of mTORC1 activity (SHOC2-Raptor); Row2 UPS|...|Cul1 substrate receptor|F-box|WD40; Row3 UPS|Ubiquitin and UBL binding|E3 ligase|CUL1 receptor|idiosyncratic Ub binding / WD40 (PMID:21070969). PN-node mapping: Row2 group=mapped GO:1990756 (already_in_goa_exact); Row3 group=mapped GO:0061630 (new_to_goa); Row1 ALP no_mapping (GO:0010506 reg. of autophagy held too_broad).
  • Consistency: Rows 1–2 consistent. FBXW7 is the textbook tumor-suppressor SCF receptor; review has GO:1990756 (IDA x2, ACCEPT) β€” matching Row2 "already_in_goa_exact" β€” plus GO:0050816 phosphothreonine binding, GO:0030332 cyclin binding, and a large substrate set (cyclin E, MYC, NOTCH ICD, MCL1, RICTOR, MLST8, NR1D1, EGFR). Row1 mTORC1/SHOC2 role corresponds to KEEP_AS_NON_CORE downstream outputs. Row3 INCONSISTENT: PN projects GO:0061630 ubiquitin protein ligase activity from PMID:21070969 (Pashkova 2010, DOI), a paper (per PubMed) about WD40 propellers as ubiquitin-binding domains regulating F-box turnover β€” with Cdc4 (the FBXW7 ortholog) shown to use Ub-binding to promote its own auto-ubiquitination, not substrate ligation. The review independently flags exactly this: GO:0043130 ubiquitin binding (IBA) is MARK_AS_OVER_ANNOTATED ("FBXW7 recognizes phosphodegrons, not free ubiquitin"). So the YAML directly contradicts the PN Row3 catalytic projection.
  • PN story / NEW pressure: Row2 GO:1990756 already in GOA (IDA) and accepted β€” no new pressure. Row3 GO:0061630 over-reaches (wrong activity class for a non-catalytic receptor; and the source paper is about Ub binding/auto-turnover). Both GO:0061630 and GO:0043130 verified real via OLS. No defensible NEW catalytic term.
  • Mapping strategy: Row2 correct (GO:1990756 matches review core MF; already_in_goa_exact). Row1 ALP no_mapping correct. Row3 mapping wrong: GO:0061630 should be GO:0043130 ubiquitin binding (and even that the review judges over-annotated for FBXW7 since recognition is phosphodegron-based) or no_mapping. Not broader/narrower issue β€” it is a wrong-activity issue.
  • Evidence alignment: Strong overlap on the receptor story; Row2 PN PMID:15340381 (family review) vs review's gene-specific PMID:17434132 (cyclin E structure), PMID:15103331/15150404 (MYC), PMID:28007894 (STYX), PMID:35395208 (DEDHIL). Row3 PMID:21070969 is NOT cited in the FBXW7 review (only its IBA-derived ubiquitin-binding term is, via GO_REF:0000033) and is mischaracterized by the GO:0061630 mapping.
  • Verdict: Rows 1–2 CONSISTENT; Row3 PN node OVER-REACHES (contradicts the review's own over-annotation call). Recommended edits: [MAP] change Row3 Ubiquitin and UBL binding|E3 ligase projection for FBXW7 from GO:0061630 ubiquitin protein ligase activity to GO:0043130 ubiquitin binding or no_mapping β€” PMID:21070969 = WD40 ubiquitin BINDING controlling F-box auto-turnover, not catalytic ligase; the FBXW7 review already marks ubiquitin binding as over-annotated.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-13
  • review_yaml: genes/human/FBXW7/FBXW7-ai-review.yaml
  • PN workbook rows: 3

PN row 1: Autophagy-Lysosome Pathway | Pre-initiation autophagy signaling | mTORC1 pathway, direct | Modulator of mTORC1 activity

  • UniProt: Q969H0
  • In branches: ALP, UPS
  • Notes: F-box protein, member of SCF E3 ubiquitin ligase. Mediates ubiquitination and thereby degradation of SHOC2, which binds and activates RPTOR to inhibit mTORC1, thereby activating mTORC1 and suppressing autophagy.
  • PN references (titles):
    • A Destiny for Degradation: Interplay between Cullin-RING E3 Ligases and Autophagy - ScienceDirect
    • The FBXW7-SHOC2-Raptor Axis Controls the Cross-Talks between the RAS-ERK and mTORC1 Signaling Pathways - ScienceDirect
  • PN-node mapping records (path + ancestors):
    • [type] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, direct|Modulator of mTORC1 activity
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
    • [group] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, direct
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
    • [class] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling
      status=context_only scope=too_broad_to_propagate GO=[GO:0010506 regulation of autophagy]
      rationale: This class organizes upstream signaling inputs to autophagy initiation. Because the subtree contains generic insulin, AMPK, mTORC1, nutrient-sensing, and miscellaneous signaling components, class-level propagation to regulation of autophagy would over-annotate many genes.
    • [branch] Autophagy-Lysosome Pathway
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | WD40

  • UniProt: Q969H0
  • In branches: ALP, UPS
  • Signature domains: IPR001810
  • Auxiliary domains: IPR001680
  • PN references (titles):
    • 15340381 / rev
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|WD40
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
    • [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
    • [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor
      status=mapped scope=ok_for_propagation_to_go GO=[GO:1990756 ubiquitin-like ligase-substrate adaptor activity]
      rationale: This PN group captures substrate receptors/adaptors for cullin/UBL ligase systems. The shared GO molecular-function target is ubiquitin-like ligase-substrate adaptor activity.
    • [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
      status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

PN row 3: Ubiquitin Proteasome System | Ubiquitin and UBL binding | E3 ligase | CUL1 receptor | idiosyncratic Ub binding / WD40

  • UniProt: Q969H0
  • In branches: ALP, UPS
  • Signature domains: PMID: 21070969 (IPR001680)
  • Auxiliary domains: IPR001810
  • PN references (titles):
    • 21070969
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase|CUL1 receptor|idiosyncratic Ub binding / WD40
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower enzyme-family, domain, or architecture subdivision already covered by a curated parent enzyme mapping. No additional direct GO mapping is needed at this node.
    • [type] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase|CUL1 receptor
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower enzyme-family, domain, or architecture subdivision already covered by a curated parent enzyme mapping. No additional direct GO mapping is needed at this node.
    • [group] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This PN group captures ubiquitin/UBL-binding factors that are E3 ligases. The shared molecular-function target is ubiquitin protein ligase activity.
    • [class] Ubiquitin Proteasome System|Ubiquitin and UBL binding
      status=context_only scope=too_broad_to_propagate GO=[GO:0140036 ubiquitin-modified protein reader activity]
      rationale: This class records ubiquitin/UBL-reader context, but the subtree mixes ubiquitin, SUMO, UBL-domain, domain-architecture, catalytic, signaling, trafficking, and nucleic-acid process buckets. It is useful context, not a safe direct propagation.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (2)

  • GO:1990756 ubiquitin-like ligase-substrate adaptor activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor
  • GO:0061630 ubiquitin protein ligase activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

πŸ“„ View Raw YAML

 
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 Fbw7Ξ² 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: FBW7Ξ² 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 Fbw7Ξ² 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 Fbw7Ξ² 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 **FBW7Ξ²** 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 substratesβ€”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.