{"gene":"FBXW7","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2001,"finding":"Mammalian SEL-10/mSel-10 (FBXW7) physically interacts with the Notch1 intracellular domain (IC) in the cell nucleus, ubiquitinates Notch1 IC in a manner requiring the PEST domain at the C-terminal region, and reduces Notch1 IC-mediated activation of the HES1 promoter. Ubiquitinated Notch1 IC accumulates in the presence of proteasome inhibitor MG132 but is a less potent transactivator, indicating that ubiquitination itself reduces Notch activity independent of degradation.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, reporter gene assay (HES1 promoter), proteasome inhibitor treatment, nuclear localization by subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction data, in vivo ubiquitination, functional reporter assay; independently replicated in two contemporaneous papers (PMID:11425854, PMID:11585921)","pmids":["11461910"],"is_preprint":false},{"year":2001,"finding":"Human SEL-10 specifically interacts with nuclear (active transcriptional factor) forms of Notch1, not with inactive membrane-anchored forms, and this interaction requires a phosphorylation event. A dominant-negative SEL-10 (F-box deleted) stabilizes intracellular Notch1 and enhances its transcriptional activity. Notch1 IC undergoes polyubiquitination in vitro and is stabilized by proteasome inhibitors in vivo.","method":"Dominant-negative expression, co-immunoprecipitation, in vitro ubiquitination assay, proteasome inhibitor treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (dominant-negative, Co-IP, in vitro ubiquitination), replicated across labs","pmids":["11425854"],"is_preprint":false},{"year":2001,"finding":"SEL-10 negatively regulates Notch1 and Notch4 receptor activity by targeting their intracellular domains for ubiquitin-mediated proteasomal degradation via its WD40 repeats. SEL-10 binds preferentially to a phosphorylated form of Notch4 IC; binding requires the C-terminal region of Notch4 downstream of the ankyrin repeats. In vitro ubiquitination of Notch1 and Notch4 IC is dependent on SEL-10.","method":"Dominant-negative expression, co-immunoprecipitation, in vitro ubiquitination assay, Notch signaling reporter assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro ubiquitination, domain mapping, multiple substrates tested; replicated across labs","pmids":["11585921"],"is_preprint":false},{"year":2003,"finding":"Mouse Fbxw7 is required for vascular development; Fbxw7-null embryos die at E10.5-11.5 with impaired vascular remodeling. In Fbxw7-/- embryos, Notch4 (but not Notch1, -2, or -3 or cyclin E) specifically accumulates, resulting in increased expression of Hey1, a downstream Notch transcriptional repressor implicated in vascular development.","method":"Genetic knockout (Fbxw7-/- mice), immunoblotting for substrates, in vitro para-aortic explant culture, gene expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with defined cellular phenotype and substrate-specific mechanistic readout","pmids":["14672936"],"is_preprint":false},{"year":2002,"finding":"Human SEL-10 (FBXW7) interacts with presenilin 1 (PS1) and enhances PS1 ubiquitination, altering cellular levels of unprocessed PS1 and its N- and C-terminal fragments. Co-transfection of sel-10 and APP in HEK293 cells alters APP metabolism and increases amyloid beta-peptide production.","method":"Co-immunoprecipitation, ubiquitination assay, co-transfection in HEK293 cells, western blot","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and ubiquitination assay in a single study, no independent replication cited","pmids":["12354302"],"is_preprint":false},{"year":2007,"finding":"Fbw7 mediates proteasomal degradation of the Myc oncoprotein in response to DNA damage (UV irradiation). The ubiquitin-specific protease Usp28 binds to the nucleoplasmic isoform Fbw7alpha and counteracts Fbw7-mediated Myc degradation; UV irradiation causes Usp28 to dissociate from Fbw7alpha, thereby enhancing Fbw7-mediated Myc degradation.","method":"Proteasome inhibitor assays, co-immunoprecipitation, western blot following UV irradiation, overexpression/knockdown","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional consequence, mechanistic model supported by multiple experiments in single lab","pmids":["17873522"],"is_preprint":false},{"year":2008,"finding":"The Fbxw7 locus encodes three isoforms (alpha, beta, gamma) with distinct subcellular localizations. The nucleoplasmic Fbw7alpha isoform accounts for almost all Fbw7 activity toward cyclin E, c-Myc, and SREBP1. Cyclin E sensitivity to Fbw7 varies during the cell cycle, correlating with changes in cyclin E-CDK2-specific activity, cyclin E autophosphorylation, and CDK2 inhibitory phosphorylation.","method":"Isoform-specific gene targeting (AAV-mediated) in human cells, substrate turnover assays, cell-cycle synchronization","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — isoform-specific gene targeting with substrate readouts, multiple substrates and cell-cycle-dependent analysis in single rigorous study","pmids":["18559665"],"is_preprint":false},{"year":2009,"finding":"Adenovirus E1A oncoprotein inhibits SCF(Fbw7) ubiquitin ligase activity by directly binding to Roc1/Rbx1 and CUL1 subunits of the SCF complex. E1A inhibits the ubiquitin ligase activity of the Roc1/Rbx1-CUL1 complex in vitro (but not that of Mdm2), and decelerates degradation of SCF(Fbw7) substrates in vivo.","method":"In vitro ubiquitin ligase assay with purified SCF components, co-immunoprecipitation, in vivo substrate stability assay, viral infection","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted ubiquitin ligase assay with purified components plus functional in vivo confirmation","pmids":["19679664"],"is_preprint":false},{"year":2010,"finding":"Fbxw7 controls neural stem and progenitor cell (NSC/NPC) viability and differentiation in the mouse brain. Fbxw7 deficiency causes accumulation of active Notch1 and N-terminally phosphorylated c-Jun. Genetic and pharmacological rescue experiments established that c-Jun is the key Fbxw7 substrate controlling progenitor cell viability, while Notch signaling inhibition alleviates the block in stem cell differentiation.","method":"Conditional neural-specific Fbxw7 knockout mice, genetic epistasis (Notch inhibitor, c-Jun deletion), substrate immunoblotting","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with genetic epistasis to dissect specific substrates, multiple orthogonal approaches","pmids":["20935640"],"is_preprint":false},{"year":2010,"finding":"Hepatic ablation of Fbxw7 results in hepatomegaly and steatohepatitis with massive triglyceride deposition, and skews liver stem cell differentiation toward the cholangiocyte lineage rather than hepatocyte lineage. Additional loss of Notch cofactor RBP-J corrects the biliary proliferation bias, establishing Notch accumulation as the causal mechanism.","method":"Liver-specific conditional knockout (Mx1-Cre and Alb-Cre), substrate immunoblotting, differentiation assays in vitro, genetic epistasis with RBP-J","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two independent Cre systems, genetic epistasis identifying Notch as the relevant substrate","pmids":["21123947"],"is_preprint":false},{"year":2011,"finding":"Intestine-specific deletion of Fbxw7 in mice elevates Notch, c-Jun, and DEK protooncogene expression. DEK accumulation promotes cell division and alters splicing of tropomyosin (TPM) RNA. In the context of APC deficiency, Fbxw7 loss accelerates tumorigenesis and promotes β-catenin accumulation at late time points.","method":"Conditional gut-specific knockout (Villin-Cre), compound genetic models (Apc-Min/+), immunoblotting, RNA splicing analysis, genetic epistasis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple substrates identified, genetic epistasis in compound mutant mouse model","pmids":["21282377"],"is_preprint":false},{"year":2011,"finding":"Fbxw7 is required for cerebellar development; conditional deletion in the cerebellar anlage reduces Purkinje cell number and causes axonal arborization defects. Protein levels of Notch1 and N-terminally phosphorylated c-Jun are elevated. Concomitant deletion of c-Jun (or junAA knock-in abrogating c-Jun N-terminal phosphorylation) rescues Purkinje cell numbers and arborization, identifying N-terminally phosphorylated c-Jun as an important Fbxw7 substrate during neurogenesis.","method":"Conditional cerebellar Fbxw7 knockout, genetic rescue (c-Jun deletion, junAA knock-in), substrate immunoblotting","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with genetic epistasis using both c-Jun deletion and phospho-specific knock-in","pmids":["21827743"],"is_preprint":false},{"year":2012,"finding":"In C. elegans, SEL-10 (Fbxw7 ortholog) regulates degradation of LIN-45/Braf through a Cdc4 phosphodegron (CPD). MPK-1/ERK activity is required for LIN-45 protein degradation in a negative feedback loop: where ERK is highly active, LIN-45 is degraded by SEL-10. Mutation of the CPD in LIN-45 or loss of sel-10 results in increased LIN-45 activity and protein stability in vivo.","method":"C. elegans genetics, CPD mutant analysis, epistasis with sel-10 and mpk-1, in vivo protein stability assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic epistasis in vivo with CPD mutagenesis identifying substrate degron","pmids":["23154983"],"is_preprint":false},{"year":2013,"finding":"FBW7 targets KLF2 for ubiquitination and proteasomal degradation in endothelial cells. GSK3-mediated phosphorylation of KLF2 at two conserved phosphodegron motifs is required for FBW7 binding; mutation of these phosphodegrons abolishes FBW7-mediated KLF2 ubiquitination and degradation. FBW7-mediated KLF2 degradation regulates angiogenesis, leukocyte adhesion, and endothelial barrier integrity in vitro and in vivo (zebrafish).","method":"Co-immunoprecipitation, in vivo ubiquitination assay, phosphodegron mutagenesis, siRNA knockdown, angiogenesis assays in vitro and in zebrafish","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — phosphodegron mutagenesis, ubiquitination assay, and functional in vivo rescue in zebrafish","pmids":["23507969"],"is_preprint":false},{"year":2015,"finding":"ERK directly interacts with FBW7 and phosphorylates FBW7 at Thr205, which promotes FBW7 ubiquitination and proteasomal degradation. A phospho-deficient T205A FBW7 mutant is resistant to ERK-mediated degradation. This mechanism explains how oncogenic KRAS mutations impair FBW7 tumor suppressor function in pancreatic cancer.","method":"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (T205A), proteasome inhibitor assays, xenograft tumor models","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay with mutagenesis and in vivo functional validation","pmids":["25753158"],"is_preprint":false},{"year":2015,"finding":"FBW7 mediates cell cycle-dependent ubiquitylation and degradation of NDE1, a negative regulator of ciliary length. CDK5, active in G1/G0, primes NDE1 for FBW7-mediated recognition. Cells depleted of FBW7 or CDK5 show elevated NDE1 levels and reduced ciliary length; this phenotype is corrected by co-depletion of NDE1, placing NDE1 downstream of CDK5-FBW7 in the ciliary length regulatory pathway.","method":"Co-immunoprecipitation, ubiquitination assay, genetic epistasis (FBW7/CDK5/NDE1 siRNA co-depletion), ciliary length measurement, cell cycle synchronization","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with three-way knockdown, ubiquitination assay, and functional ciliary length readout","pmids":["26206584"],"is_preprint":false},{"year":2015,"finding":"FBW7 targets ENO1 for ubiquitin-mediated degradation. FBXW7 physically binds ENO1 and its depletion increases ENO1 protein levels; overexpression of FBXW7 suppresses ENO1-induced lactate production, cell proliferation, and migration.","method":"2D gel/mass spectrometry to identify substrate, co-immunoprecipitation, in vivo ubiquitination assay, functional proliferation and migration assays","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and ubiquitination assay with functional consequence in a single lab study","pmids":["26097998"],"is_preprint":false},{"year":2015,"finding":"Usp28 deubiquitinates Fbw7 substrates (NICD1, c-Jun, c-Myc) independently of Fbw7, recognizing their unphosphorylated phosphodegron motif (while Fbw7 binds the phosphorylated form). Genetic deletion of Usp28 rescues lethality of Fbw7-deficient fibroblasts and corrects substrate accumulation in intestinal cells, indicating direct antagonism between Fbw7 and Usp28 on the same substrates.","method":"Genetic deletion of Usp28 in Fbw7-deficient backgrounds, conditional intestine-specific knockouts, substrate immunoblotting, compound mutant mice","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in vivo with mechanistic explanation for reciprocal phosphodegron binding","pmids":["25716680"],"is_preprint":false},{"year":2014,"finding":"Usp28 preferentially antagonizes autocatalytic (self-)ubiquitination of Fbw7, thereby stabilizing Fbw7 protein. Monoallelic Usp28 deletion maintains stable Fbw7 and drives substrate degradation; complete Usp28 knockout triggers Fbw7 degradation and substrate accumulation. Overexpression of Usp28 stabilizes both Fbw7 and its substrates. Both loss and overexpression of Usp28 promote Ras-driven oncogenic transformation.","method":"Usp28 conditional and complete knockout mice, substrate immunoblotting, oncogenic transformation assays, MEF studies","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple mouse models (heterozygous, homozygous, OE) with mechanistic substrate readouts","pmids":["25437563"],"is_preprint":false},{"year":2016,"finding":"SOX9 is a direct substrate of FBW7. FBW7 recognizes a conserved degron surrounding Thr236 in SOX9 phosphorylated by GSK3 kinase; SCFFBW7alpha mediates subsequent SOX9 proteasomal degradation. Failure to degrade SOX9 promotes migration, metastasis, and treatment resistance in medulloblastoma. Pharmacological PI3K/AKT/mTOR inhibition destabilizes SOX9 in a GSK3/FBW7-dependent manner.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, degron mutagenesis, conditional knockout, xenograft/migration/metastasis assays, pharmacological rescue","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — degron mutagenesis, ubiquitination assay, and pharmacological epistasis with in vivo validation","pmids":["27625374"],"is_preprint":false},{"year":2016,"finding":"CDK1-mediated phosphorylation of REV-ERBα is required for FBXW7 recognition. FBXW7 ubiquitinates REV-ERBα and targets it for degradation, relieving REV-ERBα-dependent repression and enhancing circadian clock gene transcription amplitude. Hepatic disruption of FBXW7 alters circadian expression of core clock genes and perturbs whole-body lipid and glucose levels.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, kinase assay, liver-specific FBXW7 knockout, circadian gene expression profiling, metabolic phenotyping","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay, ubiquitination assay, conditional KO with defined molecular and metabolic phenotypes","pmids":["27238018"],"is_preprint":false},{"year":2017,"finding":"Multisite phosphorylation of c-Jun is required for high-affinity interaction with the WD40 domain of Fbw7. Pin1 (prolyl isomerase) interacts with the multiply phosphorylated disordered region of c-Jun and isomerizes a pSer-Pro peptide bond at the c-Jun N-terminus, which modulates c-Jun binding to Fbw7 and thereby regulates ubiquitin-mediated c-Jun degradation.","method":"NMR spectroscopy, fluorescence binding assays, c-Jun phosphorylation mapping, Pin1 domain interaction studies","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR with fluorescence validation and mechanistic mutagenesis in a single rigorous structural study","pmids":["29225075"],"is_preprint":false},{"year":2018,"finding":"SCFFBW7 targets Brg1/SMARCA4 (ATPase subunit of SWI/SNF) for ubiquitination and proteasomal degradation. CK1δ phosphorylates Brg1 at Ser31/Ser35 to facilitate FBW7 binding; phospho-deficient mutations abolish FBW7-mediated Brg1 degradation. Brg1 stabilization in gastric cancer cells suppresses E-cadherin expression, promoting metastasis.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, CK1δ kinase assay, phosphodegron mutagenesis, E-cadherin expression analysis, clinical sample correlation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — kinase assay, ubiquitination assay, phosphodegron mutagenesis, with functional metastasis readout","pmids":["30177679"],"is_preprint":false},{"year":2018,"finding":"The deubiquitinase USP9X interacts with FBW7, antagonizes FBW7 ubiquitylation, and stabilizes FBW7 protein. Deletion of Usp9x causes Fbw7 destabilization, increased c-Myc levels, reduced secretory cell differentiation, and increased intestinal tumor burden. c-Myc heterozygosity abrogates the increased proliferation and tumor burden in Usp9x-deficient mice, placing USP9X upstream of FBW7 and c-Myc.","method":"Proteomics/MS to identify USP9X, co-immunoprecipitation, conditional gut-specific Usp9x knockout, genetic epistasis with c-Myc heterozygosity, tumor burden analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — proteomics-identified interaction, conditional KO with genetic epistasis in vivo","pmids":["29346117"],"is_preprint":false},{"year":2019,"finding":"FBXW7 degrades EZH2 in macrophages, suppressing H3K27me3 modification and thereby promoting Ccl2 and Ccl7 expression. In CX3CR1hi resident macrophages, FBXW7 deficiency results in decreased CCL2/CCL7 production and reduced accumulation of pro-inflammatory macrophages in colitis.","method":"Co-immunoprecipitation, ubiquitination assay, myeloid-specific conditional knockout, colitis models (DSS and TNBS), AAV-shFbxw7 in vivo, chromatin analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional myeloid-specific KO with mechanistic substrate (EZH2) and downstream histone mark analysis","pmids":["31246581"],"is_preprint":false},{"year":2019,"finding":"FBXO45-MYCBP2 E3 ubiquitin ligase targets FBXW7 for ubiquitylation and proteasomal degradation during prolonged mitotic arrest. FBXO45 binds a conserved acidic N-terminal motif of FBXW7 specifically under conditions of extended mitotic delay, reducing FBXW7 levels and thereby promoting mitotic slippage over cell death.","method":"Co-immunoprecipitation, ubiquitination assay, FBXW7 domain mapping, overexpression/knockdown, mitotic slippage assay","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, ubiquitination assay, functional mitotic outcome assay","pmids":["31285543"],"is_preprint":false},{"year":2019,"finding":"SCFFBXW7/GSK3β targets GFI1 transcription factor for degradation. GSK3β-mediated GFI1 phosphorylation at S94/S98 triggers interaction with FBXW7 and subsequent SCFFBW7-mediated ubiquitination and degradation. A non-degradable GFI1 S94A/S98A mutant more potently drives gastric cancer cell proliferation than wild-type GFI1.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, phosphodegron mutagenesis (S94A/S98A), kinase assay, proliferation/tumorigenesis assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — kinase assay, phosphodegron mutagenesis, ubiquitination assay, and functional in vivo readout","pmids":["31289136"],"is_preprint":false},{"year":2019,"finding":"LSD1 (KDM1A) directly binds FBXW7 and acts as a pseudosubstrate, promoting FBXW7 self-ubiquitylation by preventing FBXW7 dimerization. LSD1-FBXW7 binding does not trigger LSD1 ubiquitylation but destabilizes FBXW7 in a manner independent of LSD1 demethylase activity. Self-ubiquitylated FBXW7 is degraded by both proteasome and lysosome/autophagy (p62/SQSTM1-dependent).","method":"Co-immunoprecipitation, ubiquitination assay, dimerization assays, LSD1 catalytic mutant, proteasome and lysosome inhibitors, autophagy pathway analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — catalytic mutant, multiple degradation pathway inhibitors, dimerization assay; mechanistically rigorous","pmids":["31152129"],"is_preprint":false},{"year":2020,"finding":"FBXW7 binds to telomere protection protein 1 (TPP1) and facilitates TPP1 multisite polyubiquitination and degradation, triggering telomere uncapping and DNA damage response. This mechanism underlies stress-induced cell senescence and pulmonary fibrosis. Overexpressing TPP1 or inhibiting FBW7 reduces telomere uncapping and shortening.","method":"Co-immunoprecipitation, ubiquitination assay, FBW7 genetic ablation, telomere dysfunction assays, mouse pulmonary fibrosis models","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP with ubiquitination assay, genetic rescue, and in vivo fibrosis model with mechanistic substrate identification","pmids":["33086033"],"is_preprint":false},{"year":2020,"finding":"FBXW7 inactivation leads to decreased tumor-intrinsic expression of the dsRNA sensors MDA5 and RIG-1 and diminished induction of type I IFN and MHC-I expression, causing resistance to anti-PD-1 immunotherapy. Restoration of dsRNA sensing in Fbxw7-deficient cells sensitizes them to anti-PD-1.","method":"Comparative tumor sequencing, Fbxw7 knockout in murine tumor lines, anti-PD-1 treatment in immunocompetent animals, gene expression analysis, dsRNA sensing pathway reconstitution","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo immunotherapy model with KO and functional rescue, though mechanistic link between FBXW7 and dsRNA sensors is correlative","pmids":["32371478"],"is_preprint":false},{"year":2020,"finding":"FBXW7 inhibits expression of stearoyl-CoA desaturase (SCD1) via inhibiting nuclear receptor NR4A1 (NRA41), which suppresses lipid peroxidation and promotes ferroptosis as well as apoptosis in pancreatic cancer cells.","method":"Gene expression profiling, targeted metabolite analysis, co-expression studies, in vitro ferroptosis and apoptosis assays, xenograft models","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, mechanistic claim based on expression correlation and functional assays without direct ubiquitination of NR4A1 demonstrated","pmids":["33271455"],"is_preprint":false},{"year":2020,"finding":"FBXW7 interacts with and targets p53 for polyubiquitination and proteasomal degradation following ionizing radiation or etoposide. ATM phosphorylates p53 on Ser33 and Ser37 after DNA damage, facilitating FBXW7 binding and subsequent p53 degradation. Inactivation of ATM or SCFFBXW7 extends p53 half-life in an MDM2-independent manner.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, ATM inhibitor, kinase assay, half-life measurements, FBXW7 genetic knockout","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (kinase assay, ubiquitination, genetic KO, pharmacological inhibition) in single study","pmids":["31940492"],"is_preprint":false},{"year":2021,"finding":"FBW7 is identified as a novel E3 ubiquitin ligase for IκBα; FBW7 upregulation promotes IκBα ubiquitin-dependent degradation and NF-κB activation in intestinal epithelial cells, thereby promoting intestinal inflammation.","method":"Co-immunoprecipitation, ubiquitination assay, FBW7 overexpression/knockdown, NF-κB reporter assay, in vivo colitis model","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and ubiquitination assay, single lab, novel substrate claim requires independent replication","pmids":["31945730"],"is_preprint":false},{"year":2021,"finding":"FBW7 suppresses ovarian cancer by targeting the m6A reader YTHDF2 for proteasomal degradation. FBW7 interacts with YTHDF2 and induces its ubiquitination; FBW7 loss stabilizes YTHDF2, which promotes decay of the pro-apoptotic gene BMF mRNA.","method":"IP-MS, co-immunoprecipitation, ubiquitination assay, in vitro and in vivo tumor models, MeRIP-Seq/RNA-Seq","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 / Moderate — IP-MS substrate identification, Co-IP, ubiquitination assay, and downstream m6A-seq analysis with in vivo validation","pmids":["33658012"],"is_preprint":false},{"year":2021,"finding":"Proteasomal degradation of FBW7 requires branched ubiquitylation: SCFFBW7-mediated ubiquitylation of FBW7 on K404 and K412 is necessary but not sufficient for proteasomal degradation. TRIP12 (HECT-domain E3 ligase) additionally mediates branched K11-linked ubiquitylation of FBW7, which is required for its degradation. TRIP12 inactivation causes FBW7 accumulation and increased MCL1 degradation.","method":"shRNA library screen, co-immunoprecipitation, ubiquitin linkage-specific analysis, TRIP12 inactivation, substrate (MCL1) turnover assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — systematic screen plus ubiquitin linkage analysis with multiple orthogonal validations; novel branched ubiquitylation mechanism","pmids":["33824312"],"is_preprint":false},{"year":2022,"finding":"Germline monoallelic FBXW7 missense variants cluster at the substrate-binding surface of the WD40 domain and cause impaired CYCLIN E1 and CYCLIN E2 turnover, as shown by expression of recombinant FBXW7 missense variants in cultured cells. Pan-neuronal knockdown of the Drosophila ortholog archipelago impairs learning and neuronal function, establishing that FBXW7's ubiquitin ligase activity toward cyclin E substrates is essential for normal neurodevelopment.","method":"Structural modeling of WD40 domain, recombinant variant expression with cyclin E turnover assay, Drosophila pan-neuronal RNAi, clinical genetic cohort","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — crystal structure modeling plus functional substrate turnover assay and in vivo Drosophila genetic rescue","pmids":["35395208"],"is_preprint":false},{"year":2022,"finding":"Insulin enhances ERRα activity via a GSK3β/FBXW7 signaling axis: GSK3β phosphorylates ERRα at multiple sites enabling FBXW7-mediated degradation. Liver-specific deletion of GSK3β or FBXW7, or expression of non-degradable ERRα3SA phosphosite mutants, results in accumulated ERRα that no longer responds to fluctuating insulin levels, causing compromised energy homeostasis and reduced insulin sensitivity.","method":"Conditional liver-specific knockouts (GSK3β, FBXW7), phosphosite knock-in mutant mice (ERRα3SA), ubiquitination assay, transcriptome analysis, metabolic phenotyping","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — phosphosite knock-in mutant combined with conditional KO and ubiquitination assay with in vivo metabolic readouts","pmids":["35440636"],"is_preprint":false},{"year":2022,"finding":"Mechanical overloading decreases FBXW7-mediated MKK7 degradation, leading to enhanced JNK signaling and chondrocyte senescence. Intra-articular injection of adenovirus expressing Fbxw7 alleviates osteoarthritis in mice by restoring MKK7 degradation.","method":"Chondrocyte-specific Fbxw7 knockout, intra-articular AAV delivery, substrate (MKK7) analysis, JNK signaling assay, in vitro mechanical stress model, OA scoring","journal":"Annals of the rheumatic diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — conditional KO with substrate readout and in vivo rescue, single lab, novel substrate claim (MKK7)","pmids":["35058228"],"is_preprint":false},{"year":2022,"finding":"FBW7 together with GSK3β recognizes and degrades IGF2BP2 (m6A reader). GSK3β-mediated phosphorylation facilitates FBXW7-dependent ubiquitination of IGF2BP2, which inhibits the IGF2BP2-SLC7A5 positive feedback loop and reduces lung cancer radioresistance.","method":"Co-immunoprecipitation, ubiquitination assay, ChIP-qPCR, RIP/MeRIP-qPCR, RNA pulldown, clonogenic survival assay, xenograft models","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ubiquitination, ChIP, MeRIP) in single lab; novel substrate identification with in vivo validation","pmids":["38281999"],"is_preprint":false},{"year":2022,"finding":"FBXW7-mediated ERK3 ubiquitination and proteasomal degradation requires binding between ERK3's C34D region (specifically Thr417 and Thr421) and the WD40 domain of FBXW7. Double mutation of ERK3 Thr417/Thr421 to alanine abolishes FBXW7-mediated ubiquitination.","method":"Mammalian two-hybrid assay, co-immunoprecipitation, ubiquitination assay, domain mutagenesis, ERK3 knockdown/proliferation assays","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — domain mutagenesis with ubiquitination assay, single lab, novel substrate","pmids":["35022544"],"is_preprint":false},{"year":2007,"finding":"Kaposi's sarcoma-associated herpesvirus (KSHV) LANA directly interacts with Sel10/FBXW7 via LANA's C-terminus with the F-box and WD40 domains of Sel10. LANA-Sel10 complex formation suppresses ICN (intracellular Notch) ubiquitination and degradation by competing with ICN for Sel10 binding, resulting in elevated ICN levels in KSHV-infected cells.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, competition binding assay, KSHV-infected cell analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and ubiquitination assay in KSHV-infected cells, single lab, no independent replication cited","pmids":["17909182"],"is_preprint":false},{"year":2015,"finding":"FBXW7 regulates CCDC6 turnover in a cell-cycle-dependent manner. Mitotic kinases and degron motifs in CCDC6 direct CCDC6 recruitment to FBXW7 E3 ligase; CCDC6 undergoes cyclic phosphorylation and protein level changes peaking at G2 and decreasing in mitosis. The deubiquitinase USP7 fine-tunes CCDC6 stability.","method":"Co-immunoprecipitation, cell cycle synchronization, ubiquitination assay, CCDC6 protein stability analysis, USP7 interaction studies","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and cell cycle analysis, single lab, novel substrate claim","pmids":["25885523"],"is_preprint":false},{"year":2023,"finding":"DYRK2 serine/threonine kinase directly interacts with and phosphorylates FBXW7, causing its proteasome-mediated degradation independent of FBXW7's own ubiquitin ligase activity. DYRK2-dependent FBXW7 destabilization alters levels of key FBXW7 substrates and affects cellular responses to chemotherapy agents (doxorubicin, paclitaxel) and BET inhibitors.","method":"Co-immunoprecipitation, kinase assay, proteasome inhibitor assay, substrate readout, functional drug response assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — kinase assay and Co-IP, single lab, novel regulatory mechanism requiring independent replication","pmids":["36934104"],"is_preprint":false},{"year":2015,"finding":"PKM2 (pyruvate kinase M2) is a bona fide ubiquitin substrate of SCFFBW7 in macrophages. FBW7-deficient macrophages show increased PKM2 levels with decreased pentose phosphate pathway flux (reduced NADPH/GSH), enhanced ROS production, and exacerbated proinflammatory responses and insulin resistance.","method":"Co-immunoprecipitation, ubiquitination assay, myeloid-specific FBW7 knockout, metabolic flux analysis, PKM2 inhibitor, redox measurements","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and ubiquitination assay with functional metabolic readouts in single lab; novel substrate (PKM2)","pmids":["32853822"],"is_preprint":false},{"year":2017,"finding":"FBW7-dependent Mcl-1 degradation is the primary mechanism by which Hsp90 inhibitors kill colorectal cancer cells. Hsp90 inhibition promotes GSK3β-dependent phosphorylation of Mcl-1, which then binds FBW7 and undergoes ubiquitination and proteasomal degradation. Blocking Mcl-1 phosphorylation by genetic knock-in abrogates its degradation and confers resistance to Hsp90 inhibitors.","method":"Co-immunoprecipitation, ubiquitination assay, Mcl-1 phospho knock-in, GSK3β inhibition, in vitro and in vivo Hsp90 inhibitor sensitivity assays","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — phospho knock-in mutagenesis, ubiquitination assay, and in vivo validation provide mechanistically rigorous support","pmids":["28619760"],"is_preprint":false},{"year":2015,"finding":"Fbxw7 deletion in murine bone marrow-derived stromal cells induces accumulation of NOTCH and transcriptional activation of Ccl2, leading to increased serum CCL2. Elevated CCL2 recruits monocytic myeloid-derived suppressor cells and macrophages to promote metastatic tumor growth in a non-cell-autonomous manner.","method":"Conditional Fbxw7 knockout in stromal/BM cells, NOTCH substrate immunoblotting, CCL2 serum measurement, pharmacological CCL2 receptor antagonism, tumor metastasis models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with mechanistic substrate readout, pharmacological rescue, and in vivo metastasis model","pmids":["25555218"],"is_preprint":false}],"current_model":"FBXW7 is the substrate-recognition component of an SCF-type (SKP1-CUL1-F-box) E3 ubiquitin ligase complex that binds phosphorylated degron (CPD) motifs on diverse oncoproteins—including cyclin E, c-MYC, Notch ICDs, c-Jun, Mcl-1, REV-ERBα, SOX9, KLF2, Brg1, GFI1, NDE1, YTHDF2, and TPP1—and mediates their polyubiquitination and proteasomal degradation; substrate recognition requires prior phosphorylation of the degron by kinases such as CDK1, GSK3β, CDK5, or ATM, and the nucleoplasmic Fbxw7α isoform is the dominant active species; FBXW7 activity is antagonized by deubiquitinases (USP9X stabilizes FBXW7 itself; USP28 deubiquitinates Fbw7 substrates), by oncoproteins that trigger FBXW7 self-ubiquitylation (e.g., LSD1), by phosphorylation-triggered FBXW7 degradation (ERK at T205, DYRK2), and by TRIP12-mediated branched K11-ubiquitylation of FBXW7 required for its own proteasomal turnover; through this network FBXW7 controls cell-cycle progression, neural and vascular development, circadian rhythm, senescence, lipid metabolism, immune signaling, and DNA damage responses."},"narrative":{"mechanistic_narrative":"FBXW7 is the substrate-recognition subunit of an SCF (SKP1-CUL1-RBX1)-type E3 ubiquitin ligase that uses its WD40 repeat domain to capture phosphorylated degron motifs on diverse regulatory proteins and target them for polyubiquitination and proteasomal degradation, thereby restraining cell proliferation, differentiation, and tissue homeostasis [PMID:11585921, PMID:19679664, PMID:35395208]. Its earliest characterized substrates were the Notch1 and Notch4 intracellular domains, which it binds in the nucleus in a phosphorylation-dependent manner to terminate Notch transcriptional output [PMID:11461910, PMID:11425854, PMID:11585921]; genetic loss in mouse confirmed Notch4 accumulation as the cause of embryonic vascular remodeling defects [PMID:14672936], and conditional deletions established Notch and N-terminally phosphorylated c-Jun as the critical substrates governing neural, cerebellar, hepatic, and intestinal stem/progenitor cell viability and lineage choice [PMID:20935640, PMID:21123947, PMID:21282377, PMID:21827743]. Substrate engagement is governed by prior phosphorylation of a Cdc4 phosphodegron by upstream kinases — GSK3 for KLF2, SOX9, GFI1, Mcl-1, and ERRα; CDK1 for REV-ERBα; CDK5 for NDE1; CK1δ for Brg1/SMARCA4; ATM for p53; and ERK for the Braf ortholog LIN-45 — extending FBXW7 control to angiogenesis, ciliary length, circadian rhythm, chromatin remodeling, DNA-damage responses, and metabolism [PMID:23507969, PMID:27625374, PMID:31289136, PMID:28619760, PMID:35440636, PMID:27238018, PMID:26206584, PMID:30177679, PMID:31940492, PMID:23154983]. The nucleoplasmic Fbw7α isoform accounts for essentially all activity toward cyclin E, c-Myc, and SREBP1 [PMID:18559665], and germline missense variants clustering at the WD40 substrate-binding surface impair cyclin E turnover and cause a neurodevelopmental disorder [PMID:35395208]. FBXW7 abundance is itself tightly controlled: the deubiquitinase USP9X stabilizes FBXW7 while USP28 removes ubiquitin from FBXW7 substrates [PMID:29346117, PMID:25716680, PMID:25437563], and FBXW7 is destabilized by ERK- and DYRK2-mediated phosphorylation, by LSD1 acting as a dimerization-blocking pseudosubstrate that triggers self-ubiquitylation, and by FBXO45-MYCBP2 and TRIP12-mediated branched K11 ubiquitylation [PMID:25753158, PMID:36934104, PMID:31152129, PMID:31285543, PMID:33824312]. Through this substrate network and layered regulation FBXW7 functions as a broadly acting tumor suppressor whose inactivation promotes oncoprotein accumulation, metastasis, and therapy resistance [PMID:27625374, PMID:25555218, PMID:32371478].","teleology":[{"year":2001,"claim":"Established FBXW7 (SEL-10) as a nuclear ubiquitin ligase component that recognizes the active, phosphorylated intracellular domains of Notch receptors, answering how Notch signaling is terminated.","evidence":"Co-IP, in vitro/in vivo ubiquitination, dominant-negative F-box deletion, and reporter assays for Notch1 and Notch4 ICDs in mammalian cells","pmids":["11461910","11425854","11585921"],"confidence":"High","gaps":["Did not resolve which kinase phosphorylates the Notch degron","SCF complex assembly not biochemically reconstituted at this stage"]},{"year":2002,"claim":"Extended substrate scope to presenilin 1 and APP metabolism, linking FBXW7 to amyloid processing.","evidence":"Co-IP and ubiquitination assays with PS1/APP co-transfection in HEK293 cells","pmids":["12354302"],"confidence":"Medium","gaps":["Single study without independent replication","No degron mapping on PS1","Physiological relevance to amyloid biology not tested in vivo"]},{"year":2003,"claim":"Demonstrated in vivo physiological necessity of FBXW7, showing that embryonic vascular remodeling depends on substrate-specific degradation of Notch4.","evidence":"Fbxw7-null mouse knockout with substrate immunoblotting and explant culture","pmids":["14672936"],"confidence":"High","gaps":["Embryonic lethality precluded analysis of later tissues","Substrate selectivity (Notch4 over Notch1-3/cyclin E) mechanism unexplained"]},{"year":2007,"claim":"Revealed counter-regulation by deubiquitinases and viral antagonism, showing FBXW7 activity is dynamically opposed at the substrate level.","evidence":"Co-IP and substrate stability assays for USP28-Fbw7α with UV; competition binding for KSHV LANA","pmids":["17873522","17909182"],"confidence":"Medium","gaps":["Isoform-specific USP28 interaction not structurally defined","LANA studies limited to single lab in infected cells"]},{"year":2008,"claim":"Defined the three FBXW7 isoforms and established the nucleoplasmic Fbw7α as the dominant active species toward cyclin E, c-Myc, and SREBP1, explaining where ligase activity resides.","evidence":"AAV-mediated isoform-specific gene targeting in human cells with substrate turnover and cell-cycle synchronization","pmids":["18559665"],"confidence":"High","gaps":["Functions of β and γ isoforms left undefined","Cell-cycle modulation of cyclin E sensitivity mechanistically incomplete"]},{"year":2009,"claim":"Showed oncoproteins can inhibit the catalytic core of the SCF(Fbw7) complex directly, a regulatory mode distinct from substrate competition.","evidence":"In vitro reconstituted ubiquitin ligase assay with purified Roc1/Rbx1-CUL1 plus in vivo substrate stability with adenovirus E1A","pmids":["19679664"],"confidence":"High","gaps":["Whether endogenous cellular factors use the same inhibition mode unknown"]},{"year":2011,"claim":"Conditional tissue knockouts identified c-Jun, Notch, and DEK as the physiologically relevant substrates governing neural, cerebellar, hepatic, and intestinal stem/progenitor cell fate and tumorigenesis.","evidence":"Tissue-specific Cre knockouts with genetic epistasis (c-Jun deletion, junAA knock-in, RBP-J deletion, Apc-Min compound) and substrate immunoblotting","pmids":["20935640","21123947","21282377","21827743"],"confidence":"High","gaps":["Relative contribution of each substrate varies by tissue and is not fully partitioned","DEK degron not mapped"]},{"year":2012,"claim":"Defined the Cdc4 phosphodegron logic in vivo, showing ERK-driven phosphorylation creates the degron that recruits the ligase to Braf/LIN-45 in a feedback loop.","evidence":"C. elegans genetics with CPD mutagenesis and sel-10/mpk-1 epistasis","pmids":["23154983"],"confidence":"High","gaps":["Direct mammalian BRAF degradation by FBXW7 not tested here"]},{"year":2016,"claim":"Generalized the kinase-primed degron paradigm across substrates and physiological axes, with distinct upstream kinases dictating recognition of KLF2, SOX9, REV-ERBα, NDE1, and others.","evidence":"Degron/phosphodegron mutagenesis, ubiquitination assays, kinase assays (GSK3, CDK1, CDK5, CK1δ) with functional readouts in angiogenesis, circadian, ciliary, and metastasis models","pmids":["23507969","26206584","27625374","27238018","30177679"],"confidence":"High","gaps":["Structural basis for differential degron affinity across substrates incomplete","Crosstalk between competing substrates not quantified"]},{"year":2017,"claim":"Provided structural/biochemical detail of multisite phosphodegron recognition, showing Pin1-catalyzed proline isomerization tunes c-Jun affinity for the WD40 domain.","evidence":"NMR spectroscopy and fluorescence binding with phosphorylation mapping and Pin1 interaction studies","pmids":["29225075"],"confidence":"High","gaps":["Whether isomerase tuning applies to other FBXW7 substrates not tested"]},{"year":2018,"claim":"Mapped the layered control of FBXW7's own stability, identifying USP9X as a stabilizing deubiquitinase, USP28 as a dual antagonist, and LSD1 as a dimerization-blocking pseudosubstrate driving self-degradation.","evidence":"Proteomics, Co-IP, conditional Usp9x/Usp28 knockouts with c-Myc epistasis, dimerization assays, catalytic mutants, and proteasome/lysosome inhibitors","pmids":["29346117","25716680","25437563","31152129"],"confidence":"High","gaps":["Quantitative balance between stabilizing and destabilizing inputs in normal cells unresolved"]},{"year":2020,"claim":"Identified destabilizing post-translational and E3-ligase inputs (ERK-T205, FBXO45-MYCBP2, TRIP12 branched K11 ubiquitylation) and broadened substrate scope to p53, TPP1, EZH2, and immune/metabolic regulators.","evidence":"Kinase assays, domain mapping, ubiquitin-linkage-specific analysis, shRNA screen, conditional knockouts, and functional models of mitotic slippage, senescence, fibrosis, and immunotherapy response","pmids":["25753158","31285543","33824312","31940492","33086033","31246581","32371478"],"confidence":"High","gaps":["Some substrate claims (e.g., dsRNA sensors) remain correlative","Hierarchy of the multiple FBXW7-destabilizing E3 ligases unclear"]},{"year":2022,"claim":"Established a causative Mendelian link, showing germline WD40 substrate-surface missense variants impair cyclin E turnover and cause a neurodevelopmental disorder.","evidence":"Structural modeling, recombinant variant cyclin E turnover assays, Drosophila pan-neuronal RNAi, and a clinical genetic cohort","pmids":["35395208"],"confidence":"High","gaps":["Which substrate(s) beyond cyclin E drive the neurodevelopmental phenotype not fully defined"]},{"year":null,"claim":"How the dozens of competing phosphodegron substrates are prioritized within a single cell, and how the multiple destabilizing kinases and E3 ligases are integrated to set net FBXW7 activity in a given tissue, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No quantitative model of substrate competition","Tissue-specific regulatory hierarchy of FBXW7 stability inputs undefined","Structural basis of branched-ubiquitin recognition by the proteasome not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,31,33]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[7,19,22,26,34]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,35]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0,5,6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,6]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,15,35,41]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,7,34]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,9,12,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[14,19,35,45]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[20]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,8,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[24,29,32]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[20,36,43]}],"complexes":["SCF(FBXW7) (SKP1-CUL1-RBX1-FBXW7) E3 ubiquitin ligase"],"partners":["CUL1","RBX1","USP28","USP9X","TRIP12","FBXO45","LSD1","DYRK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q969H0","full_name":"F-box/WD repeat-containing protein 7","aliases":["Archipelago homolog","hAgo","F-box and WD-40 domain-containing protein 7","F-box protein FBX30","SEL-10","hCdc4"],"length_aa":707,"mass_kda":79.7,"function":"Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:17434132, PubMed:22748924, PubMed:26976582, PubMed:28727686, PubMed:34741373, PubMed:35395208). Recognizes and binds phosphorylated sites/phosphodegrons within target proteins and thereafter brings them to the SCF complex for ubiquitination (PubMed:17434132, PubMed:22748924, PubMed:26774286, PubMed:26976582, PubMed:28727686, PubMed:34741373). Identified substrates include cyclin-E (CCNE1 or CCNE2), DISC1, JUN, MYC, NOTCH1 released notch intracellular domain (NICD), NFE2L1, NOTCH2, MCL1, MLST8, RICTOR, and probably PSEN1 (PubMed:11565034, PubMed:11585921, PubMed:12354302, PubMed:14739463, PubMed:15103331, PubMed:17558397, PubMed:17873522, PubMed:22608923, PubMed:22748924, PubMed:25775507, PubMed:25897075, PubMed:26976582, PubMed:28007894, PubMed:28727686, PubMed:29149593, PubMed:34102342). Acts as a negative regulator of JNK signaling by binding to phosphorylated JUN and promoting its ubiquitination and subsequent degradation (PubMed:14739463). Involved in bone homeostasis and negative regulation of osteoclast differentiation (PubMed:29149593). Regulates the amplitude of the cyclic expression of hepatic core clock genes and genes involved in lipid and glucose metabolism via ubiquitination and proteasomal degradation of their transcriptional repressor NR1D1; CDK1-dependent phosphorylation of NR1D1 is necessary for SCF(FBXW7)-mediated ubiquitination (PubMed:27238018). Also able to promote 'Lys-63'-linked ubiquitination in response to DNA damage (PubMed:26774286). The SCF(FBXW7) complex facilitates double-strand break repair following phosphorylation by ATM: phosphorylation promotes localization to sites of double-strand breaks and 'Lys-63'-linked ubiquitination of phosphorylated XRCC4, enhancing DNA non-homologous end joining (PubMed:26774286)","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q969H0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBXW7","classification":"Not Classified","n_dependent_lines":64,"n_total_lines":1208,"dependency_fraction":0.052980132450331126},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FBXW7","total_profiled":1310},"omim":[{"mim_id":"620691","title":"BUD13 HOMOLOG; BUD13","url":"https://www.omim.org/entry/620691"},{"mim_id":"620012","title":"DEVELOPMENTAL DELAY, HYPOTONIA, AND IMPAIRED LANGUAGE; DEDHIL","url":"https://www.omim.org/entry/620012"},{"mim_id":"615832","title":"UBIQUITIN-CONJUGATING ENZYME E2 Q FAMILY-LIKE PROTEIN 1; UBE2QL1","url":"https://www.omim.org/entry/615832"},{"mim_id":"613057","title":"MICRO RNA 26A2; MIR26A2","url":"https://www.omim.org/entry/613057"},{"mim_id":"612591","title":"COLORECTAL CANCER, SUSCEPTIBILITY TO, 10; CRCS10","url":"https://www.omim.org/entry/612591"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":58.3},{"tissue":"skin 1","ntpm":57.7}],"url":"https://www.proteinatlas.org/search/FBXW7"},"hgnc":{"alias_symbol":["AGO","FLJ11071","SEL-10","SEL10","FBW7","FBX30","CDC4","FBXW6"],"prev_symbol":[]},"alphafold":{"accession":"Q969H0","domains":[{"cath_id":"1.20.1280.50","chopping":"281-328_350-366","consensus_level":"high","plddt":95.8426,"start":281,"end":366}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969H0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969H0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969H0-F1-predicted_aligned_error_v6.png","plddt_mean":77.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBXW7","jax_strain_url":"https://www.jax.org/strain/search?query=FBXW7"},"sequence":{"accession":"Q969H0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969H0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969H0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969H0"}},"corpus_meta":[{"pmid":"18094723","id":"PMC_18094723","title":"FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation.","date":"2008","source":"Nature reviews. 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SEL-10, an F-box protein, and the nuclear form of activated Notch1 receptor.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11425854","citation_count":317,"is_preprint":false},{"pmid":"25314076","id":"PMC_25314076","title":"Tumor suppression by the Fbw7 ubiquitin ligase: mechanisms and opportunities.","date":"2014","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/25314076","citation_count":305,"is_preprint":false},{"pmid":"11585921","id":"PMC_11585921","title":"SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation.","date":"2001","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11585921","citation_count":290,"is_preprint":false},{"pmid":"14672936","id":"PMC_14672936","title":"Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development.","date":"2003","source":"The Journal of biological 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Ubiquitinated Notch1 IC accumulates in the presence of proteasome inhibitor MG132 but is a less potent transactivator, indicating that ubiquitination itself reduces Notch activity independent of degradation.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, reporter gene assay (HES1 promoter), proteasome inhibitor treatment, nuclear localization by subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction data, in vivo ubiquitination, functional reporter assay; independently replicated in two contemporaneous papers (PMID:11425854, PMID:11585921)\",\n      \"pmids\": [\"11461910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human SEL-10 specifically interacts with nuclear (active transcriptional factor) forms of Notch1, not with inactive membrane-anchored forms, and this interaction requires a phosphorylation event. A dominant-negative SEL-10 (F-box deleted) stabilizes intracellular Notch1 and enhances its transcriptional activity. Notch1 IC undergoes polyubiquitination in vitro and is stabilized by proteasome inhibitors in vivo.\",\n      \"method\": \"Dominant-negative expression, co-immunoprecipitation, in vitro ubiquitination assay, proteasome inhibitor treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (dominant-negative, Co-IP, in vitro ubiquitination), replicated across labs\",\n      \"pmids\": [\"11425854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SEL-10 negatively regulates Notch1 and Notch4 receptor activity by targeting their intracellular domains for ubiquitin-mediated proteasomal degradation via its WD40 repeats. SEL-10 binds preferentially to a phosphorylated form of Notch4 IC; binding requires the C-terminal region of Notch4 downstream of the ankyrin repeats. In vitro ubiquitination of Notch1 and Notch4 IC is dependent on SEL-10.\",\n      \"method\": \"Dominant-negative expression, co-immunoprecipitation, in vitro ubiquitination assay, Notch signaling reporter assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro ubiquitination, domain mapping, multiple substrates tested; replicated across labs\",\n      \"pmids\": [\"11585921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mouse Fbxw7 is required for vascular development; Fbxw7-null embryos die at E10.5-11.5 with impaired vascular remodeling. In Fbxw7-/- embryos, Notch4 (but not Notch1, -2, or -3 or cyclin E) specifically accumulates, resulting in increased expression of Hey1, a downstream Notch transcriptional repressor implicated in vascular development.\",\n      \"method\": \"Genetic knockout (Fbxw7-/- mice), immunoblotting for substrates, in vitro para-aortic explant culture, gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with defined cellular phenotype and substrate-specific mechanistic readout\",\n      \"pmids\": [\"14672936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Human SEL-10 (FBXW7) interacts with presenilin 1 (PS1) and enhances PS1 ubiquitination, altering cellular levels of unprocessed PS1 and its N- and C-terminal fragments. Co-transfection of sel-10 and APP in HEK293 cells alters APP metabolism and increases amyloid beta-peptide production.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, co-transfection in HEK293 cells, western blot\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and ubiquitination assay in a single study, no independent replication cited\",\n      \"pmids\": [\"12354302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Fbw7 mediates proteasomal degradation of the Myc oncoprotein in response to DNA damage (UV irradiation). The ubiquitin-specific protease Usp28 binds to the nucleoplasmic isoform Fbw7alpha and counteracts Fbw7-mediated Myc degradation; UV irradiation causes Usp28 to dissociate from Fbw7alpha, thereby enhancing Fbw7-mediated Myc degradation.\",\n      \"method\": \"Proteasome inhibitor assays, co-immunoprecipitation, western blot following UV irradiation, overexpression/knockdown\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional consequence, mechanistic model supported by multiple experiments in single lab\",\n      \"pmids\": [\"17873522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The Fbxw7 locus encodes three isoforms (alpha, beta, gamma) with distinct subcellular localizations. The nucleoplasmic Fbw7alpha isoform accounts for almost all Fbw7 activity toward cyclin E, c-Myc, and SREBP1. Cyclin E sensitivity to Fbw7 varies during the cell cycle, correlating with changes in cyclin E-CDK2-specific activity, cyclin E autophosphorylation, and CDK2 inhibitory phosphorylation.\",\n      \"method\": \"Isoform-specific gene targeting (AAV-mediated) in human cells, substrate turnover assays, cell-cycle synchronization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — isoform-specific gene targeting with substrate readouts, multiple substrates and cell-cycle-dependent analysis in single rigorous study\",\n      \"pmids\": [\"18559665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Adenovirus E1A oncoprotein inhibits SCF(Fbw7) ubiquitin ligase activity by directly binding to Roc1/Rbx1 and CUL1 subunits of the SCF complex. E1A inhibits the ubiquitin ligase activity of the Roc1/Rbx1-CUL1 complex in vitro (but not that of Mdm2), and decelerates degradation of SCF(Fbw7) substrates in vivo.\",\n      \"method\": \"In vitro ubiquitin ligase assay with purified SCF components, co-immunoprecipitation, in vivo substrate stability assay, viral infection\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted ubiquitin ligase assay with purified components plus functional in vivo confirmation\",\n      \"pmids\": [\"19679664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Fbxw7 controls neural stem and progenitor cell (NSC/NPC) viability and differentiation in the mouse brain. Fbxw7 deficiency causes accumulation of active Notch1 and N-terminally phosphorylated c-Jun. Genetic and pharmacological rescue experiments established that c-Jun is the key Fbxw7 substrate controlling progenitor cell viability, while Notch signaling inhibition alleviates the block in stem cell differentiation.\",\n      \"method\": \"Conditional neural-specific Fbxw7 knockout mice, genetic epistasis (Notch inhibitor, c-Jun deletion), substrate immunoblotting\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with genetic epistasis to dissect specific substrates, multiple orthogonal approaches\",\n      \"pmids\": [\"20935640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Hepatic ablation of Fbxw7 results in hepatomegaly and steatohepatitis with massive triglyceride deposition, and skews liver stem cell differentiation toward the cholangiocyte lineage rather than hepatocyte lineage. Additional loss of Notch cofactor RBP-J corrects the biliary proliferation bias, establishing Notch accumulation as the causal mechanism.\",\n      \"method\": \"Liver-specific conditional knockout (Mx1-Cre and Alb-Cre), substrate immunoblotting, differentiation assays in vitro, genetic epistasis with RBP-J\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent Cre systems, genetic epistasis identifying Notch as the relevant substrate\",\n      \"pmids\": [\"21123947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Intestine-specific deletion of Fbxw7 in mice elevates Notch, c-Jun, and DEK protooncogene expression. DEK accumulation promotes cell division and alters splicing of tropomyosin (TPM) RNA. In the context of APC deficiency, Fbxw7 loss accelerates tumorigenesis and promotes β-catenin accumulation at late time points.\",\n      \"method\": \"Conditional gut-specific knockout (Villin-Cre), compound genetic models (Apc-Min/+), immunoblotting, RNA splicing analysis, genetic epistasis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple substrates identified, genetic epistasis in compound mutant mouse model\",\n      \"pmids\": [\"21282377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Fbxw7 is required for cerebellar development; conditional deletion in the cerebellar anlage reduces Purkinje cell number and causes axonal arborization defects. Protein levels of Notch1 and N-terminally phosphorylated c-Jun are elevated. Concomitant deletion of c-Jun (or junAA knock-in abrogating c-Jun N-terminal phosphorylation) rescues Purkinje cell numbers and arborization, identifying N-terminally phosphorylated c-Jun as an important Fbxw7 substrate during neurogenesis.\",\n      \"method\": \"Conditional cerebellar Fbxw7 knockout, genetic rescue (c-Jun deletion, junAA knock-in), substrate immunoblotting\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with genetic epistasis using both c-Jun deletion and phospho-specific knock-in\",\n      \"pmids\": [\"21827743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In C. elegans, SEL-10 (Fbxw7 ortholog) regulates degradation of LIN-45/Braf through a Cdc4 phosphodegron (CPD). MPK-1/ERK activity is required for LIN-45 protein degradation in a negative feedback loop: where ERK is highly active, LIN-45 is degraded by SEL-10. Mutation of the CPD in LIN-45 or loss of sel-10 results in increased LIN-45 activity and protein stability in vivo.\",\n      \"method\": \"C. elegans genetics, CPD mutant analysis, epistasis with sel-10 and mpk-1, in vivo protein stability assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic epistasis in vivo with CPD mutagenesis identifying substrate degron\",\n      \"pmids\": [\"23154983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FBW7 targets KLF2 for ubiquitination and proteasomal degradation in endothelial cells. GSK3-mediated phosphorylation of KLF2 at two conserved phosphodegron motifs is required for FBW7 binding; mutation of these phosphodegrons abolishes FBW7-mediated KLF2 ubiquitination and degradation. FBW7-mediated KLF2 degradation regulates angiogenesis, leukocyte adhesion, and endothelial barrier integrity in vitro and in vivo (zebrafish).\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, phosphodegron mutagenesis, siRNA knockdown, angiogenesis assays in vitro and in zebrafish\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphodegron mutagenesis, ubiquitination assay, and functional in vivo rescue in zebrafish\",\n      \"pmids\": [\"23507969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ERK directly interacts with FBW7 and phosphorylates FBW7 at Thr205, which promotes FBW7 ubiquitination and proteasomal degradation. A phospho-deficient T205A FBW7 mutant is resistant to ERK-mediated degradation. This mechanism explains how oncogenic KRAS mutations impair FBW7 tumor suppressor function in pancreatic cancer.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (T205A), proteasome inhibitor assays, xenograft tumor models\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay with mutagenesis and in vivo functional validation\",\n      \"pmids\": [\"25753158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FBW7 mediates cell cycle-dependent ubiquitylation and degradation of NDE1, a negative regulator of ciliary length. CDK5, active in G1/G0, primes NDE1 for FBW7-mediated recognition. Cells depleted of FBW7 or CDK5 show elevated NDE1 levels and reduced ciliary length; this phenotype is corrected by co-depletion of NDE1, placing NDE1 downstream of CDK5-FBW7 in the ciliary length regulatory pathway.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, genetic epistasis (FBW7/CDK5/NDE1 siRNA co-depletion), ciliary length measurement, cell cycle synchronization\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with three-way knockdown, ubiquitination assay, and functional ciliary length readout\",\n      \"pmids\": [\"26206584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FBW7 targets ENO1 for ubiquitin-mediated degradation. FBXW7 physically binds ENO1 and its depletion increases ENO1 protein levels; overexpression of FBXW7 suppresses ENO1-induced lactate production, cell proliferation, and migration.\",\n      \"method\": \"2D gel/mass spectrometry to identify substrate, co-immunoprecipitation, in vivo ubiquitination assay, functional proliferation and migration assays\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and ubiquitination assay with functional consequence in a single lab study\",\n      \"pmids\": [\"26097998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Usp28 deubiquitinates Fbw7 substrates (NICD1, c-Jun, c-Myc) independently of Fbw7, recognizing their unphosphorylated phosphodegron motif (while Fbw7 binds the phosphorylated form). Genetic deletion of Usp28 rescues lethality of Fbw7-deficient fibroblasts and corrects substrate accumulation in intestinal cells, indicating direct antagonism between Fbw7 and Usp28 on the same substrates.\",\n      \"method\": \"Genetic deletion of Usp28 in Fbw7-deficient backgrounds, conditional intestine-specific knockouts, substrate immunoblotting, compound mutant mice\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in vivo with mechanistic explanation for reciprocal phosphodegron binding\",\n      \"pmids\": [\"25716680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Usp28 preferentially antagonizes autocatalytic (self-)ubiquitination of Fbw7, thereby stabilizing Fbw7 protein. Monoallelic Usp28 deletion maintains stable Fbw7 and drives substrate degradation; complete Usp28 knockout triggers Fbw7 degradation and substrate accumulation. Overexpression of Usp28 stabilizes both Fbw7 and its substrates. Both loss and overexpression of Usp28 promote Ras-driven oncogenic transformation.\",\n      \"method\": \"Usp28 conditional and complete knockout mice, substrate immunoblotting, oncogenic transformation assays, MEF studies\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mouse models (heterozygous, homozygous, OE) with mechanistic substrate readouts\",\n      \"pmids\": [\"25437563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SOX9 is a direct substrate of FBW7. FBW7 recognizes a conserved degron surrounding Thr236 in SOX9 phosphorylated by GSK3 kinase; SCFFBW7alpha mediates subsequent SOX9 proteasomal degradation. Failure to degrade SOX9 promotes migration, metastasis, and treatment resistance in medulloblastoma. Pharmacological PI3K/AKT/mTOR inhibition destabilizes SOX9 in a GSK3/FBW7-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, degron mutagenesis, conditional knockout, xenograft/migration/metastasis assays, pharmacological rescue\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — degron mutagenesis, ubiquitination assay, and pharmacological epistasis with in vivo validation\",\n      \"pmids\": [\"27625374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CDK1-mediated phosphorylation of REV-ERBα is required for FBXW7 recognition. FBXW7 ubiquitinates REV-ERBα and targets it for degradation, relieving REV-ERBα-dependent repression and enhancing circadian clock gene transcription amplitude. Hepatic disruption of FBXW7 alters circadian expression of core clock genes and perturbs whole-body lipid and glucose levels.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, kinase assay, liver-specific FBXW7 knockout, circadian gene expression profiling, metabolic phenotyping\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay, ubiquitination assay, conditional KO with defined molecular and metabolic phenotypes\",\n      \"pmids\": [\"27238018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Multisite phosphorylation of c-Jun is required for high-affinity interaction with the WD40 domain of Fbw7. Pin1 (prolyl isomerase) interacts with the multiply phosphorylated disordered region of c-Jun and isomerizes a pSer-Pro peptide bond at the c-Jun N-terminus, which modulates c-Jun binding to Fbw7 and thereby regulates ubiquitin-mediated c-Jun degradation.\",\n      \"method\": \"NMR spectroscopy, fluorescence binding assays, c-Jun phosphorylation mapping, Pin1 domain interaction studies\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR with fluorescence validation and mechanistic mutagenesis in a single rigorous structural study\",\n      \"pmids\": [\"29225075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SCFFBW7 targets Brg1/SMARCA4 (ATPase subunit of SWI/SNF) for ubiquitination and proteasomal degradation. CK1δ phosphorylates Brg1 at Ser31/Ser35 to facilitate FBW7 binding; phospho-deficient mutations abolish FBW7-mediated Brg1 degradation. Brg1 stabilization in gastric cancer cells suppresses E-cadherin expression, promoting metastasis.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, CK1δ kinase assay, phosphodegron mutagenesis, E-cadherin expression analysis, clinical sample correlation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — kinase assay, ubiquitination assay, phosphodegron mutagenesis, with functional metastasis readout\",\n      \"pmids\": [\"30177679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The deubiquitinase USP9X interacts with FBW7, antagonizes FBW7 ubiquitylation, and stabilizes FBW7 protein. Deletion of Usp9x causes Fbw7 destabilization, increased c-Myc levels, reduced secretory cell differentiation, and increased intestinal tumor burden. c-Myc heterozygosity abrogates the increased proliferation and tumor burden in Usp9x-deficient mice, placing USP9X upstream of FBW7 and c-Myc.\",\n      \"method\": \"Proteomics/MS to identify USP9X, co-immunoprecipitation, conditional gut-specific Usp9x knockout, genetic epistasis with c-Myc heterozygosity, tumor burden analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics-identified interaction, conditional KO with genetic epistasis in vivo\",\n      \"pmids\": [\"29346117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FBXW7 degrades EZH2 in macrophages, suppressing H3K27me3 modification and thereby promoting Ccl2 and Ccl7 expression. In CX3CR1hi resident macrophages, FBXW7 deficiency results in decreased CCL2/CCL7 production and reduced accumulation of pro-inflammatory macrophages in colitis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, myeloid-specific conditional knockout, colitis models (DSS and TNBS), AAV-shFbxw7 in vivo, chromatin analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional myeloid-specific KO with mechanistic substrate (EZH2) and downstream histone mark analysis\",\n      \"pmids\": [\"31246581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FBXO45-MYCBP2 E3 ubiquitin ligase targets FBXW7 for ubiquitylation and proteasomal degradation during prolonged mitotic arrest. FBXO45 binds a conserved acidic N-terminal motif of FBXW7 specifically under conditions of extended mitotic delay, reducing FBXW7 levels and thereby promoting mitotic slippage over cell death.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, FBXW7 domain mapping, overexpression/knockdown, mitotic slippage assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, ubiquitination assay, functional mitotic outcome assay\",\n      \"pmids\": [\"31285543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SCFFBXW7/GSK3β targets GFI1 transcription factor for degradation. GSK3β-mediated GFI1 phosphorylation at S94/S98 triggers interaction with FBXW7 and subsequent SCFFBW7-mediated ubiquitination and degradation. A non-degradable GFI1 S94A/S98A mutant more potently drives gastric cancer cell proliferation than wild-type GFI1.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, phosphodegron mutagenesis (S94A/S98A), kinase assay, proliferation/tumorigenesis assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — kinase assay, phosphodegron mutagenesis, ubiquitination assay, and functional in vivo readout\",\n      \"pmids\": [\"31289136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LSD1 (KDM1A) directly binds FBXW7 and acts as a pseudosubstrate, promoting FBXW7 self-ubiquitylation by preventing FBXW7 dimerization. LSD1-FBXW7 binding does not trigger LSD1 ubiquitylation but destabilizes FBXW7 in a manner independent of LSD1 demethylase activity. Self-ubiquitylated FBXW7 is degraded by both proteasome and lysosome/autophagy (p62/SQSTM1-dependent).\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, dimerization assays, LSD1 catalytic mutant, proteasome and lysosome inhibitors, autophagy pathway analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — catalytic mutant, multiple degradation pathway inhibitors, dimerization assay; mechanistically rigorous\",\n      \"pmids\": [\"31152129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FBXW7 binds to telomere protection protein 1 (TPP1) and facilitates TPP1 multisite polyubiquitination and degradation, triggering telomere uncapping and DNA damage response. This mechanism underlies stress-induced cell senescence and pulmonary fibrosis. Overexpressing TPP1 or inhibiting FBW7 reduces telomere uncapping and shortening.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, FBW7 genetic ablation, telomere dysfunction assays, mouse pulmonary fibrosis models\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with ubiquitination assay, genetic rescue, and in vivo fibrosis model with mechanistic substrate identification\",\n      \"pmids\": [\"33086033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FBXW7 inactivation leads to decreased tumor-intrinsic expression of the dsRNA sensors MDA5 and RIG-1 and diminished induction of type I IFN and MHC-I expression, causing resistance to anti-PD-1 immunotherapy. Restoration of dsRNA sensing in Fbxw7-deficient cells sensitizes them to anti-PD-1.\",\n      \"method\": \"Comparative tumor sequencing, Fbxw7 knockout in murine tumor lines, anti-PD-1 treatment in immunocompetent animals, gene expression analysis, dsRNA sensing pathway reconstitution\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo immunotherapy model with KO and functional rescue, though mechanistic link between FBXW7 and dsRNA sensors is correlative\",\n      \"pmids\": [\"32371478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FBXW7 inhibits expression of stearoyl-CoA desaturase (SCD1) via inhibiting nuclear receptor NR4A1 (NRA41), which suppresses lipid peroxidation and promotes ferroptosis as well as apoptosis in pancreatic cancer cells.\",\n      \"method\": \"Gene expression profiling, targeted metabolite analysis, co-expression studies, in vitro ferroptosis and apoptosis assays, xenograft models\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, mechanistic claim based on expression correlation and functional assays without direct ubiquitination of NR4A1 demonstrated\",\n      \"pmids\": [\"33271455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FBXW7 interacts with and targets p53 for polyubiquitination and proteasomal degradation following ionizing radiation or etoposide. ATM phosphorylates p53 on Ser33 and Ser37 after DNA damage, facilitating FBXW7 binding and subsequent p53 degradation. Inactivation of ATM or SCFFBXW7 extends p53 half-life in an MDM2-independent manner.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, ATM inhibitor, kinase assay, half-life measurements, FBXW7 genetic knockout\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (kinase assay, ubiquitination, genetic KO, pharmacological inhibition) in single study\",\n      \"pmids\": [\"31940492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBW7 is identified as a novel E3 ubiquitin ligase for IκBα; FBW7 upregulation promotes IκBα ubiquitin-dependent degradation and NF-κB activation in intestinal epithelial cells, thereby promoting intestinal inflammation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, FBW7 overexpression/knockdown, NF-κB reporter assay, in vivo colitis model\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and ubiquitination assay, single lab, novel substrate claim requires independent replication\",\n      \"pmids\": [\"31945730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBW7 suppresses ovarian cancer by targeting the m6A reader YTHDF2 for proteasomal degradation. FBW7 interacts with YTHDF2 and induces its ubiquitination; FBW7 loss stabilizes YTHDF2, which promotes decay of the pro-apoptotic gene BMF mRNA.\",\n      \"method\": \"IP-MS, co-immunoprecipitation, ubiquitination assay, in vitro and in vivo tumor models, MeRIP-Seq/RNA-Seq\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS substrate identification, Co-IP, ubiquitination assay, and downstream m6A-seq analysis with in vivo validation\",\n      \"pmids\": [\"33658012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Proteasomal degradation of FBW7 requires branched ubiquitylation: SCFFBW7-mediated ubiquitylation of FBW7 on K404 and K412 is necessary but not sufficient for proteasomal degradation. TRIP12 (HECT-domain E3 ligase) additionally mediates branched K11-linked ubiquitylation of FBW7, which is required for its degradation. TRIP12 inactivation causes FBW7 accumulation and increased MCL1 degradation.\",\n      \"method\": \"shRNA library screen, co-immunoprecipitation, ubiquitin linkage-specific analysis, TRIP12 inactivation, substrate (MCL1) turnover assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — systematic screen plus ubiquitin linkage analysis with multiple orthogonal validations; novel branched ubiquitylation mechanism\",\n      \"pmids\": [\"33824312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Germline monoallelic FBXW7 missense variants cluster at the substrate-binding surface of the WD40 domain and cause impaired CYCLIN E1 and CYCLIN E2 turnover, as shown by expression of recombinant FBXW7 missense variants in cultured cells. Pan-neuronal knockdown of the Drosophila ortholog archipelago impairs learning and neuronal function, establishing that FBXW7's ubiquitin ligase activity toward cyclin E substrates is essential for normal neurodevelopment.\",\n      \"method\": \"Structural modeling of WD40 domain, recombinant variant expression with cyclin E turnover assay, Drosophila pan-neuronal RNAi, clinical genetic cohort\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — crystal structure modeling plus functional substrate turnover assay and in vivo Drosophila genetic rescue\",\n      \"pmids\": [\"35395208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Insulin enhances ERRα activity via a GSK3β/FBXW7 signaling axis: GSK3β phosphorylates ERRα at multiple sites enabling FBXW7-mediated degradation. Liver-specific deletion of GSK3β or FBXW7, or expression of non-degradable ERRα3SA phosphosite mutants, results in accumulated ERRα that no longer responds to fluctuating insulin levels, causing compromised energy homeostasis and reduced insulin sensitivity.\",\n      \"method\": \"Conditional liver-specific knockouts (GSK3β, FBXW7), phosphosite knock-in mutant mice (ERRα3SA), ubiquitination assay, transcriptome analysis, metabolic phenotyping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — phosphosite knock-in mutant combined with conditional KO and ubiquitination assay with in vivo metabolic readouts\",\n      \"pmids\": [\"35440636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mechanical overloading decreases FBXW7-mediated MKK7 degradation, leading to enhanced JNK signaling and chondrocyte senescence. Intra-articular injection of adenovirus expressing Fbxw7 alleviates osteoarthritis in mice by restoring MKK7 degradation.\",\n      \"method\": \"Chondrocyte-specific Fbxw7 knockout, intra-articular AAV delivery, substrate (MKK7) analysis, JNK signaling assay, in vitro mechanical stress model, OA scoring\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — conditional KO with substrate readout and in vivo rescue, single lab, novel substrate claim (MKK7)\",\n      \"pmids\": [\"35058228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBW7 together with GSK3β recognizes and degrades IGF2BP2 (m6A reader). GSK3β-mediated phosphorylation facilitates FBXW7-dependent ubiquitination of IGF2BP2, which inhibits the IGF2BP2-SLC7A5 positive feedback loop and reduces lung cancer radioresistance.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, ChIP-qPCR, RIP/MeRIP-qPCR, RNA pulldown, clonogenic survival assay, xenograft models\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ubiquitination, ChIP, MeRIP) in single lab; novel substrate identification with in vivo validation\",\n      \"pmids\": [\"38281999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBXW7-mediated ERK3 ubiquitination and proteasomal degradation requires binding between ERK3's C34D region (specifically Thr417 and Thr421) and the WD40 domain of FBXW7. Double mutation of ERK3 Thr417/Thr421 to alanine abolishes FBXW7-mediated ubiquitination.\",\n      \"method\": \"Mammalian two-hybrid assay, co-immunoprecipitation, ubiquitination assay, domain mutagenesis, ERK3 knockdown/proliferation assays\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — domain mutagenesis with ubiquitination assay, single lab, novel substrate\",\n      \"pmids\": [\"35022544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Kaposi's sarcoma-associated herpesvirus (KSHV) LANA directly interacts with Sel10/FBXW7 via LANA's C-terminus with the F-box and WD40 domains of Sel10. LANA-Sel10 complex formation suppresses ICN (intracellular Notch) ubiquitination and degradation by competing with ICN for Sel10 binding, resulting in elevated ICN levels in KSHV-infected cells.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, competition binding assay, KSHV-infected cell analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and ubiquitination assay in KSHV-infected cells, single lab, no independent replication cited\",\n      \"pmids\": [\"17909182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FBXW7 regulates CCDC6 turnover in a cell-cycle-dependent manner. Mitotic kinases and degron motifs in CCDC6 direct CCDC6 recruitment to FBXW7 E3 ligase; CCDC6 undergoes cyclic phosphorylation and protein level changes peaking at G2 and decreasing in mitosis. The deubiquitinase USP7 fine-tunes CCDC6 stability.\",\n      \"method\": \"Co-immunoprecipitation, cell cycle synchronization, ubiquitination assay, CCDC6 protein stability analysis, USP7 interaction studies\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and cell cycle analysis, single lab, novel substrate claim\",\n      \"pmids\": [\"25885523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DYRK2 serine/threonine kinase directly interacts with and phosphorylates FBXW7, causing its proteasome-mediated degradation independent of FBXW7's own ubiquitin ligase activity. DYRK2-dependent FBXW7 destabilization alters levels of key FBXW7 substrates and affects cellular responses to chemotherapy agents (doxorubicin, paclitaxel) and BET inhibitors.\",\n      \"method\": \"Co-immunoprecipitation, kinase assay, proteasome inhibitor assay, substrate readout, functional drug response assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — kinase assay and Co-IP, single lab, novel regulatory mechanism requiring independent replication\",\n      \"pmids\": [\"36934104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PKM2 (pyruvate kinase M2) is a bona fide ubiquitin substrate of SCFFBW7 in macrophages. FBW7-deficient macrophages show increased PKM2 levels with decreased pentose phosphate pathway flux (reduced NADPH/GSH), enhanced ROS production, and exacerbated proinflammatory responses and insulin resistance.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, myeloid-specific FBW7 knockout, metabolic flux analysis, PKM2 inhibitor, redox measurements\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and ubiquitination assay with functional metabolic readouts in single lab; novel substrate (PKM2)\",\n      \"pmids\": [\"32853822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FBW7-dependent Mcl-1 degradation is the primary mechanism by which Hsp90 inhibitors kill colorectal cancer cells. Hsp90 inhibition promotes GSK3β-dependent phosphorylation of Mcl-1, which then binds FBW7 and undergoes ubiquitination and proteasomal degradation. Blocking Mcl-1 phosphorylation by genetic knock-in abrogates its degradation and confers resistance to Hsp90 inhibitors.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Mcl-1 phospho knock-in, GSK3β inhibition, in vitro and in vivo Hsp90 inhibitor sensitivity assays\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — phospho knock-in mutagenesis, ubiquitination assay, and in vivo validation provide mechanistically rigorous support\",\n      \"pmids\": [\"28619760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Fbxw7 deletion in murine bone marrow-derived stromal cells induces accumulation of NOTCH and transcriptional activation of Ccl2, leading to increased serum CCL2. Elevated CCL2 recruits monocytic myeloid-derived suppressor cells and macrophages to promote metastatic tumor growth in a non-cell-autonomous manner.\",\n      \"method\": \"Conditional Fbxw7 knockout in stromal/BM cells, NOTCH substrate immunoblotting, CCL2 serum measurement, pharmacological CCL2 receptor antagonism, tumor metastasis models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with mechanistic substrate readout, pharmacological rescue, and in vivo metastasis model\",\n      \"pmids\": [\"25555218\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXW7 is the substrate-recognition component of an SCF-type (SKP1-CUL1-F-box) E3 ubiquitin ligase complex that binds phosphorylated degron (CPD) motifs on diverse oncoproteins—including cyclin E, c-MYC, Notch ICDs, c-Jun, Mcl-1, REV-ERBα, SOX9, KLF2, Brg1, GFI1, NDE1, YTHDF2, and TPP1—and mediates their polyubiquitination and proteasomal degradation; substrate recognition requires prior phosphorylation of the degron by kinases such as CDK1, GSK3β, CDK5, or ATM, and the nucleoplasmic Fbxw7α isoform is the dominant active species; FBXW7 activity is antagonized by deubiquitinases (USP9X stabilizes FBXW7 itself; USP28 deubiquitinates Fbw7 substrates), by oncoproteins that trigger FBXW7 self-ubiquitylation (e.g., LSD1), by phosphorylation-triggered FBXW7 degradation (ERK at T205, DYRK2), and by TRIP12-mediated branched K11-ubiquitylation of FBXW7 required for its own proteasomal turnover; through this network FBXW7 controls cell-cycle progression, neural and vascular development, circadian rhythm, senescence, lipid metabolism, immune signaling, and DNA damage responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBXW7 is the substrate-recognition subunit of an SCF (SKP1-CUL1-RBX1)-type E3 ubiquitin ligase that uses its WD40 repeat domain to capture phosphorylated degron motifs on diverse regulatory proteins and target them for polyubiquitination and proteasomal degradation, thereby restraining cell proliferation, differentiation, and tissue homeostasis [#2, #7, #35]. Its earliest characterized substrates were the Notch1 and Notch4 intracellular domains, which it binds in the nucleus in a phosphorylation-dependent manner to terminate Notch transcriptional output [#0, #1, #2]; genetic loss in mouse confirmed Notch4 accumulation as the cause of embryonic vascular remodeling defects [#3], and conditional deletions established Notch and N-terminally phosphorylated c-Jun as the critical substrates governing neural, cerebellar, hepatic, and intestinal stem/progenitor cell viability and lineage choice [#8, #9, #10, #11]. Substrate engagement is governed by prior phosphorylation of a Cdc4 phosphodegron by upstream kinases — GSK3 for KLF2, SOX9, GFI1, Mcl-1, and ERRα; CDK1 for REV-ERBα; CDK5 for NDE1; CK1δ for Brg1/SMARCA4; ATM for p53; and ERK for the Braf ortholog LIN-45 — extending FBXW7 control to angiogenesis, ciliary length, circadian rhythm, chromatin remodeling, DNA-damage responses, and metabolism [#13, #19, #26, #44, #36, #20, #15, #22, #31, #12]. The nucleoplasmic Fbw7α isoform accounts for essentially all activity toward cyclin E, c-Myc, and SREBP1 [#6], and germline missense variants clustering at the WD40 substrate-binding surface impair cyclin E turnover and cause a neurodevelopmental disorder [#35]. FBXW7 abundance is itself tightly controlled: the deubiquitinase USP9X stabilizes FBXW7 while USP28 removes ubiquitin from FBXW7 substrates [#23, #17, #18], and FBXW7 is destabilized by ERK- and DYRK2-mediated phosphorylation, by LSD1 acting as a dimerization-blocking pseudosubstrate that triggers self-ubiquitylation, and by FBXO45-MYCBP2 and TRIP12-mediated branched K11 ubiquitylation [#14, #42, #27, #25, #34]. Through this substrate network and layered regulation FBXW7 functions as a broadly acting tumor suppressor whose inactivation promotes oncoprotein accumulation, metastasis, and therapy resistance [#19, #45, #29].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established FBXW7 (SEL-10) as a nuclear ubiquitin ligase component that recognizes the active, phosphorylated intracellular domains of Notch receptors, answering how Notch signaling is terminated.\",\n      \"evidence\": \"Co-IP, in vitro/in vivo ubiquitination, dominant-negative F-box deletion, and reporter assays for Notch1 and Notch4 ICDs in mammalian cells\",\n      \"pmids\": [\"11461910\", \"11425854\", \"11585921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which kinase phosphorylates the Notch degron\", \"SCF complex assembly not biochemically reconstituted at this stage\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Extended substrate scope to presenilin 1 and APP metabolism, linking FBXW7 to amyloid processing.\",\n      \"evidence\": \"Co-IP and ubiquitination assays with PS1/APP co-transfection in HEK293 cells\",\n      \"pmids\": [\"12354302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study without independent replication\", \"No degron mapping on PS1\", \"Physiological relevance to amyloid biology not tested in vivo\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated in vivo physiological necessity of FBXW7, showing that embryonic vascular remodeling depends on substrate-specific degradation of Notch4.\",\n      \"evidence\": \"Fbxw7-null mouse knockout with substrate immunoblotting and explant culture\",\n      \"pmids\": [\"14672936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Embryonic lethality precluded analysis of later tissues\", \"Substrate selectivity (Notch4 over Notch1-3/cyclin E) mechanism unexplained\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed counter-regulation by deubiquitinases and viral antagonism, showing FBXW7 activity is dynamically opposed at the substrate level.\",\n      \"evidence\": \"Co-IP and substrate stability assays for USP28-Fbw7α with UV; competition binding for KSHV LANA\",\n      \"pmids\": [\"17873522\", \"17909182\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Isoform-specific USP28 interaction not structurally defined\", \"LANA studies limited to single lab in infected cells\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the three FBXW7 isoforms and established the nucleoplasmic Fbw7α as the dominant active species toward cyclin E, c-Myc, and SREBP1, explaining where ligase activity resides.\",\n      \"evidence\": \"AAV-mediated isoform-specific gene targeting in human cells with substrate turnover and cell-cycle synchronization\",\n      \"pmids\": [\"18559665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functions of β and γ isoforms left undefined\", \"Cell-cycle modulation of cyclin E sensitivity mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed oncoproteins can inhibit the catalytic core of the SCF(Fbw7) complex directly, a regulatory mode distinct from substrate competition.\",\n      \"evidence\": \"In vitro reconstituted ubiquitin ligase assay with purified Roc1/Rbx1-CUL1 plus in vivo substrate stability with adenovirus E1A\",\n      \"pmids\": [\"19679664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether endogenous cellular factors use the same inhibition mode unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Conditional tissue knockouts identified c-Jun, Notch, and DEK as the physiologically relevant substrates governing neural, cerebellar, hepatic, and intestinal stem/progenitor cell fate and tumorigenesis.\",\n      \"evidence\": \"Tissue-specific Cre knockouts with genetic epistasis (c-Jun deletion, junAA knock-in, RBP-J deletion, Apc-Min compound) and substrate immunoblotting\",\n      \"pmids\": [\"20935640\", \"21123947\", \"21282377\", \"21827743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each substrate varies by tissue and is not fully partitioned\", \"DEK degron not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the Cdc4 phosphodegron logic in vivo, showing ERK-driven phosphorylation creates the degron that recruits the ligase to Braf/LIN-45 in a feedback loop.\",\n      \"evidence\": \"C. elegans genetics with CPD mutagenesis and sel-10/mpk-1 epistasis\",\n      \"pmids\": [\"23154983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mammalian BRAF degradation by FBXW7 not tested here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Generalized the kinase-primed degron paradigm across substrates and physiological axes, with distinct upstream kinases dictating recognition of KLF2, SOX9, REV-ERBα, NDE1, and others.\",\n      \"evidence\": \"Degron/phosphodegron mutagenesis, ubiquitination assays, kinase assays (GSK3, CDK1, CDK5, CK1δ) with functional readouts in angiogenesis, circadian, ciliary, and metastasis models\",\n      \"pmids\": [\"23507969\", \"26206584\", \"27625374\", \"27238018\", \"30177679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for differential degron affinity across substrates incomplete\", \"Crosstalk between competing substrates not quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided structural/biochemical detail of multisite phosphodegron recognition, showing Pin1-catalyzed proline isomerization tunes c-Jun affinity for the WD40 domain.\",\n      \"evidence\": \"NMR spectroscopy and fluorescence binding with phosphorylation mapping and Pin1 interaction studies\",\n      \"pmids\": [\"29225075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether isomerase tuning applies to other FBXW7 substrates not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped the layered control of FBXW7's own stability, identifying USP9X as a stabilizing deubiquitinase, USP28 as a dual antagonist, and LSD1 as a dimerization-blocking pseudosubstrate driving self-degradation.\",\n      \"evidence\": \"Proteomics, Co-IP, conditional Usp9x/Usp28 knockouts with c-Myc epistasis, dimerization assays, catalytic mutants, and proteasome/lysosome inhibitors\",\n      \"pmids\": [\"29346117\", \"25716680\", \"25437563\", \"31152129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative balance between stabilizing and destabilizing inputs in normal cells unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified destabilizing post-translational and E3-ligase inputs (ERK-T205, FBXO45-MYCBP2, TRIP12 branched K11 ubiquitylation) and broadened substrate scope to p53, TPP1, EZH2, and immune/metabolic regulators.\",\n      \"evidence\": \"Kinase assays, domain mapping, ubiquitin-linkage-specific analysis, shRNA screen, conditional knockouts, and functional models of mitotic slippage, senescence, fibrosis, and immunotherapy response\",\n      \"pmids\": [\"25753158\", \"31285543\", \"33824312\", \"31940492\", \"33086033\", \"31246581\", \"32371478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Some substrate claims (e.g., dsRNA sensors) remain correlative\", \"Hierarchy of the multiple FBXW7-destabilizing E3 ligases unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a causative Mendelian link, showing germline WD40 substrate-surface missense variants impair cyclin E turnover and cause a neurodevelopmental disorder.\",\n      \"evidence\": \"Structural modeling, recombinant variant cyclin E turnover assays, Drosophila pan-neuronal RNAi, and a clinical genetic cohort\",\n      \"pmids\": [\"35395208\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which substrate(s) beyond cyclin E drive the neurodevelopmental phenotype not fully defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the dozens of competing phosphodegron substrates are prioritized within a single cell, and how the multiple destabilizing kinases and E3 ligases are integrated to set net FBXW7 activity in a given tissue, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No quantitative model of substrate competition\", \"Tissue-specific regulatory hierarchy of FBXW7 stability inputs undefined\", \"Structural basis of branched-ubiquitin recognition by the proteasome not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 31, 33]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [7, 19, 22, 26, 34]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 35]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 15, 35, 41]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 7, 34]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 9, 12, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [14, 19, 35, 45]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 8, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [24, 29, 32]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [20, 36, 43]}\n    ],\n    \"complexes\": [\"SCF(FBXW7) (SKP1-CUL1-RBX1-FBXW7) E3 ubiquitin ligase\"],\n    \"partners\": [\"CUL1\", \"RBX1\", \"USP28\", \"USP9X\", \"TRIP12\", \"FBXO45\", \"LSD1\", \"DYRK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}