{"gene":"FBXW5","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2008,"finding":"FBXW5 (FBW5) acts as a DDB1-binding WD40 substrate receptor that recruits TSC2 to the DDB1-CUL4-ROC1 E3 ubiquitin ligase complex, promoting TSC2 ubiquitination and proteasomal degradation. TSC1 co-expression abrogates this degradation. In Drosophila, Ddb1 or Cul4 mutations cause Gigas/TSC2 accumulation and growth defects partially rescued by Gigas/Tsc2 reduction.","method":"Co-immunoprecipitation, overexpression/depletion assays, in vivo ubiquitination, Drosophila genetic epistasis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, gain/loss-of-function, and genetic epistasis in Drosophila; replicated by subsequent studies","pmids":["18381890"],"is_preprint":false},{"year":2011,"finding":"FBXW5 functions as the F-box/substrate-targeting subunit of SCF-FBXW5 E3 ubiquitin ligase that binds and ubiquitylates the centriolar protein HsSAS-6, targeting it for proteasomal degradation to limit centrosome duplication. PLK4 phosphorylates FBXW5 at Ser151 to suppress its ability to ubiquitylate HsSAS-6. FBXW5 itself is a substrate of APC/C, which degrades it during mitosis and G1 to reset the centrosome duplication machinery.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, siRNA depletion/overexpression, phosphorylation mapping, cell cycle analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (Co-IP, ubiquitination assay, mutagenesis of phosphosite, APC/C substrate validation); single high-impact study with rigorous controls","pmids":["21725316"],"is_preprint":false},{"year":2009,"finding":"FBXW5 associates with endogenous TAK1 in an IL-1β-dependent manner, identified by tandem affinity purification. Overexpression of FBXW5 inhibits IL-1β-induced JNK/p38 MAPK and NF-κB activation and TAK1 phosphorylation at Thr187, while FBXW5 knockdown prolongs TAK1 activation, indicating FBXW5 negatively regulates TAK1 signaling.","method":"Tandem affinity purification (TAP), Co-immunoprecipitation, overexpression/knockdown with signaling readouts","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — TAP identification plus functional gain/loss-of-function; single lab study","pmids":["19232515"],"is_preprint":false},{"year":2012,"finding":"FBXW5, acting via the DDB1-CUL4A-RBX1 complex, enhances sumoylation of nuclear c-Myb rather than ubiquitination, localizing c-Myb to nuclear dot-like domains and suppressing its transactivation of the c-myc promoter. This demonstrates the DDB1-CUL4A-RBX1 complex can function as a dual SUMO/ubiquitin ligase depending on substrate.","method":"Co-immunoprecipitation, sumoylation assay, transcriptional reporter assay, subcellular localization imaging","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 — functional sumoylation assay with transcriptional readout; single lab, moderate mechanistic depth","pmids":["22910413"],"is_preprint":false},{"year":2013,"finding":"FBXW5 acts as the substrate receptor of the CRL4A (CUL4A-DDB1-RBX1) ubiquitin ligase to ubiquitinate and degrade the RhoGAP tumor suppressor DLC1, suppressing RhoA-GTP levels and RhoA effector signaling. siRNA knockdown of CUL4A, DDB1, or FBXW5 restores DLC1 protein and reduces RhoA activity in NSCLC cells.","method":"siRNA knockdown, Co-immunoprecipitation, ubiquitination assay, RhoA-GTP pulldown, proliferation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, ubiquitination assay, RhoA activity assay, rescue experiments); published in high-impact journal","pmids":["24082123"],"is_preprint":false},{"year":2014,"finding":"Tnfaip8l1/Oxi-β competes with TSC2 for binding to FBXW5, preventing FBXW5-mediated ubiquitination of TSC2 and thereby stabilizing TSC2 to decrease mTOR phosphorylation and enhance autophagy in dopaminergic neurons under oxidative stress.","method":"Co-immunoprecipitation, protein stability assay, mTOR phosphorylation readout, autophagy markers","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP and functional readouts; single lab, partial mechanistic follow-up on known FBXW5-TSC2 axis","pmids":["24444419","24372178"],"is_preprint":false},{"year":2018,"finding":"FBXW5 targets SEC23B, a component of the COPII coat complex, for proteasomal degradation via the SCF-FBXW5 complex, limiting autophagic flux in nutrient-replete conditions. ULK1 phosphorylates SEC23B on Serine 186 in response to starvation, preventing SEC23B-FBXW5 interaction and stabilizing SEC23B. Stabilized, phosphorylated SEC23B associates selectively with SEC24A and SEC24B and relocalizes to the ER-Golgi intermediate compartment to promote autophagosome biogenesis.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, phosphorylation site mutagenesis, mass spectrometry, subcellular fractionation/localization, autophagic flux assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including Co-IP, ubiquitination assay, site-specific mutagenesis, and localization; rigorous single-study with strong mechanistic resolution","pmids":["30596474"],"is_preprint":false},{"year":2020,"finding":"FBXW5 directly interacts with TAK1 and negatively regulates pathological cardiac hypertrophy by blocking MAPK signaling downstream of TAK1. FBXW5 knockout mice show aggravated pressure-overload-induced hypertrophy, while AAV9-mediated overexpression is protective. TAK1 inhibition prevents the pro-hypertrophic effects of FBXW5 loss.","method":"Co-immunoprecipitation, FBXW5 knockout mice, AAV9 overexpression, pressure-overload model, MAPK phosphorylation readouts","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus in vivo KO and OE with genetic rescue; single lab","pmids":["32971071"],"is_preprint":false},{"year":2021,"finding":"SCFFbxw5 ubiquitylates kinesin-13 microtubule depolymerases MCAK (Kif2c), Kif2a, and Kif2b in vitro without requiring preceding substrate modifications, using neddylated SCFFbxw5 and Cdc34. In cells, SCFFbxw5 targets MCAK for proteasomal degradation predominantly during G2. Loss of Fbxw5 increases MCAK levels at basal bodies and impairs ciliogenesis in G1/G0, which is rescued by co-knockdown of MCAK, Kif2a, or Kif2b.","method":"Protein microarray screening, in vitro reconstituted ubiquitylation assay, siRNA knockdown, co-knockdown rescue, ciliogenesis assay, cell cycle staging","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution assay plus epistasis rescue in cells; multiple substrates tested","pmids":["34368969"],"is_preprint":false},{"year":2022,"finding":"FBXW5 binds to the PPxY motif in the LATS1/2 kinase domain and promotes their ubiquitination and proteasomal degradation, thereby inactivating the Hippo pathway and increasing YAP1 activity in gastric cancer cells.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown, xenograft mouse model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP and ubiquitination assay with functional validation; single lab","pmids":["35210431"],"is_preprint":false},{"year":2024,"finding":"FBXW5 targets AQP3 (aquaporin 3) for ubiquitination and proteasomal degradation via the SCF-FBXW5 complex. FBXW5 knockdown stabilizes AQP3, which leads to lysosomal-dependent degradation of PDPK1, inactivating the AKT-mTOR pathway and inducing autophagic cell death in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, lysosomal inhibitor experiments, AKT-mTOR pathway readouts","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP and ubiquitination assay with pathway mechanistic follow-up; single lab","pmids":["38726865"],"is_preprint":false},{"year":2025,"finding":"FBXW5 promotes ubiquitination and degradation of KLF13, which in turn relieves KLF13-mediated transcriptional suppression of TROAP, facilitating EMT in lung adenocarcinoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, ChIP, luciferase reporter assay, siRNA knockdown, xenograft model","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ubiquitination, ChIP, and transcriptional reporter in a single study; single lab","pmids":["40696794"],"is_preprint":false}],"current_model":"FBXW5 is an F-box/WD40 substrate receptor that functions in two distinct E3 ubiquitin ligase complexes — SCF-FBXW5 (SKP1-CUL1-RBX1-FBXW5) and CRL4-FBXW5 (DDB1-CUL4-ROC1-FBXW5) — to ubiquitinate and degrade diverse substrates including TSC2, HsSAS-6, SEC23B, DLC1, MCAK/Kif2a/Kif2b, LATS1/2, AQP3, and KLF13, thereby regulating mTOR/autophagy signaling, centrosome duplication, ciliogenesis, Hippo pathway activity, and cytoskeletal dynamics; its own activity is controlled by PLK4 phosphorylation (Ser151) and APC/C-mediated degradation during the cell cycle, and it additionally associates with TAK1 to negatively regulate IL-1β/MAPK/NF-κB signaling."},"narrative":{"teleology":[{"year":2008,"claim":"Establishing that FBXW5 is not solely an SCF component but also a DDB1-binding WD40 receptor for the CRL4 E3 ligase, with TSC2 identified as its first substrate—linking FBXW5 to growth control via the TSC/mTOR axis.","evidence":"Co-IP, in vivo ubiquitination, and Drosophila genetic epistasis showing Gigas/TSC2 accumulation upon Ddb1/Cul4 loss","pmids":["18381890"],"confidence":"High","gaps":["Whether SCF-FBXW5 also targets TSC2 was not tested","Structural basis for FBXW5-TSC2 recognition unknown","Physiological contexts beyond Drosophila growth not explored"]},{"year":2009,"claim":"Revealing a ligase-independent function: FBXW5 associates with TAK1 and acts as a negative regulator of IL-1β-induced MAPK and NF-κB signaling, expanding its role beyond substrate-targeted ubiquitination.","evidence":"Tandem affinity purification identifying endogenous TAK1 association; overexpression/knockdown modulating JNK/p38/NF-κB activation","pmids":["19232515"],"confidence":"Medium","gaps":["Whether FBXW5 ubiquitinates TAK1 or acts through a non-catalytic mechanism was not resolved","Single-lab study without independent confirmation","Downstream effector specificity unclear"]},{"year":2011,"claim":"Demonstrating that FBXW5 functions in the SCF complex to ubiquitinate HsSAS-6 and limit centrosome duplication, while itself being regulated by PLK4 phosphorylation and APC/C-mediated degradation—establishing a cell-cycle-integrated control circuit for centriole copy number.","evidence":"Co-IP, in vivo ubiquitination, Ser151 phosphosite mutagenesis, APC/C substrate validation, cell cycle analysis","pmids":["21725316"],"confidence":"High","gaps":["Crystal structure of FBXW5-HsSAS-6 interface not determined","Whether PLK4 phosphorylation affects other FBXW5 substrates untested"]},{"year":2012,"claim":"Unexpectedly showing that the CRL4-FBXW5 complex can promote sumoylation rather than ubiquitination of c-Myb, suppressing its transactivation—raising the possibility that FBXW5-containing ligases have dual SUMO/ubiquitin activity.","evidence":"Co-IP, sumoylation assay, transcriptional reporter, subcellular localization imaging","pmids":["22910413"],"confidence":"Medium","gaps":["Mechanism by which a CRL promotes sumoylation instead of ubiquitination not explained","Not independently replicated","Endogenous c-Myb sumoylation dependence on FBXW5 not shown"]},{"year":2013,"claim":"Identifying DLC1, a RhoGAP tumor suppressor, as a CRL4A-FBXW5 substrate, thereby linking FBXW5 to Rho GTPase signaling and cancer cell proliferation.","evidence":"siRNA of CUL4A/DDB1/FBXW5 restoring DLC1 and reducing RhoA-GTP; Co-IP and ubiquitination assay in NSCLC cells","pmids":["24082123"],"confidence":"High","gaps":["DLC1 degron recognized by FBXW5 not mapped","Whether FBXW5-DLC1 axis operates in non-cancer contexts not addressed"]},{"year":2014,"claim":"Demonstrating that Tnfaip8l1/Oxi-β competes with TSC2 for FBXW5 binding, providing the first example of a competitive inhibitor of FBXW5 substrate recognition and linking the FBXW5-TSC2 axis to autophagy and dopaminergic neuron survival under oxidative stress.","evidence":"Co-IP competition assay, protein stability, mTOR phosphorylation, and autophagy marker readouts","pmids":["24444419","24372178"],"confidence":"Medium","gaps":["Direct binding competition not shown with purified proteins","In vivo neuronal relevance not confirmed in animal models"]},{"year":2018,"claim":"Showing that SCF-FBXW5 ubiquitinates SEC23B to limit autophagosome biogenesis in fed conditions, and that ULK1 phosphorylation of SEC23B at Ser186 blocks FBXW5 recognition upon starvation—revealing FBXW5 as a nutrient-sensitive gatekeeper of COPII-dependent autophagy.","evidence":"Co-IP, ubiquitination assay, phosphosite mutagenesis, mass spectrometry, autophagic flux assays, ERGIC localization","pmids":["30596474"],"confidence":"High","gaps":["Whether other COPII components are also FBXW5 substrates unknown","Structural basis for phospho-switch disrupting FBXW5-SEC23B interaction unresolved"]},{"year":2020,"claim":"Extending the FBXW5-TAK1 axis in vivo: FBXW5 knockout mice develop aggravated cardiac hypertrophy via enhanced TAK1-MAPK signaling, and AAV9-mediated overexpression is protective—validating a physiological role for FBXW5 in cardiac stress responses.","evidence":"FBXW5 knockout mice, AAV9 overexpression, pressure-overload model, TAK1 inhibitor rescue","pmids":["32971071"],"confidence":"Medium","gaps":["Whether FBXW5 ubiquitinates TAK1 or acts non-catalytically still unresolved","Cardiac-specific versus systemic effects not dissected"]},{"year":2021,"claim":"Identifying kinesin-13 microtubule depolymerases (MCAK, Kif2a, Kif2b) as direct modification-independent substrates of SCF-FBXW5, and establishing that their degradation during G2 is required for subsequent ciliogenesis in G0/G1.","evidence":"Protein microarray, reconstituted in vitro ubiquitylation with neddylated SCF-FBXW5 and Cdc34, co-knockdown rescue of ciliogenesis defect","pmids":["34368969"],"confidence":"High","gaps":["How FBXW5 recognizes these substrates without prior modification is structurally unexplained","Whether this pathway operates in multiciliated cells unknown"]},{"year":2022,"claim":"Showing FBXW5 binds the PPxY motif of LATS1/2 kinases and promotes their ubiquitination and degradation, inactivating the Hippo pathway and enhancing YAP1-driven transcription in gastric cancer.","evidence":"Co-IP, ubiquitination assay, siRNA, xenograft model","pmids":["35210431"],"confidence":"Medium","gaps":["Which E3 complex (SCF or CRL4) mediates LATS1/2 degradation not specified","PPxY motif recognition by WD40 repeats not structurally characterized","Single-lab finding"]},{"year":2024,"claim":"Identifying AQP3 as an SCF-FBXW5 substrate whose stabilization upon FBXW5 loss triggers lysosomal PDPK1 degradation, AKT-mTOR pathway inactivation, and autophagic cell death in hepatocellular carcinoma—revealing a non-canonical route by which FBXW5 controls mTOR signaling.","evidence":"Co-IP, ubiquitination assay, siRNA, lysosomal inhibitor experiments, AKT-mTOR readouts","pmids":["38726865"],"confidence":"Medium","gaps":["Mechanism by which AQP3 stabilization causes PDPK1 lysosomal targeting is indirect","Single-lab study"]},{"year":2025,"claim":"Extending FBXW5 substrates to transcription factor KLF13, whose degradation de-represses TROAP transcription and promotes EMT in lung adenocarcinoma.","evidence":"Co-IP, ubiquitination assay, ChIP, luciferase reporter, xenograft model","pmids":["40696794"],"confidence":"Medium","gaps":["KLF13 degron not mapped","Which CRL complex is involved not specified","Single-lab finding"]},{"year":null,"claim":"No high-resolution structural information exists for FBXW5 in complex with any substrate, leaving the molecular determinants of its unusually broad substrate recognition—spanning modification-dependent and modification-independent modes—unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of FBXW5 alone or in complex","Rules governing SCF versus CRL4 complex assembly choice unclear","Comprehensive substrate landscape under physiological conditions not systematically defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,4,6,8,9,10,11]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[1,8]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,4,6,8,9,10,11]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,8]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[5,6,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,9,10]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,8]}],"complexes":["SCF-FBXW5 (SKP1-CUL1-RBX1-FBXW5)","CRL4-FBXW5 (DDB1-CUL4-ROC1-FBXW5)"],"partners":["DDB1","CUL4A","SKP1","CUL1","TAK1","PLK4","HSSAS-6","TSC2"],"other_free_text":[]},"mechanistic_narrative":"FBXW5 is an F-box and WD40-repeat substrate receptor that assembles into two distinct cullin-RING E3 ubiquitin ligase complexes—SCF-FBXW5 (SKP1-CUL1-RBX1) and CRL4-FBXW5 (DDB1-CUL4-ROC1)—to ubiquitinate and target diverse substrates for proteasomal degradation, thereby regulating centrosome duplication, ciliogenesis, mTOR/autophagy signaling, Rho GTPase activity, Hippo pathway output, and COPII-dependent membrane trafficking [PMID:18381890, PMID:21725316, PMID:24082123, PMID:30596474, PMID:34368969, PMID:35210431]. Through the CRL4 complex, FBXW5 degrades TSC2 to activate mTOR and degrades the RhoGAP DLC1 to sustain RhoA signaling, while through SCF it targets HsSAS-6 to restrict centrosome number, SEC23B to limit autophagosome biogenesis under nutrient-replete conditions, and kinesin-13 depolymerases (MCAK/Kif2a/Kif2b) to permit ciliogenesis [PMID:18381890, PMID:24082123, PMID:21725316, PMID:30596474, PMID:34368969]. FBXW5 activity is itself cell-cycle regulated: PLK4 phosphorylation at Ser151 inhibits its ubiquitin ligase function toward HsSAS-6 during S phase, and APC/C-mediated degradation eliminates FBXW5 during mitosis and G1 [PMID:21725316]. Independent of its ligase function, FBXW5 binds TAK1 and negatively regulates IL-1β-induced MAPK/NF-κB signaling and pathological cardiac hypertrophy [PMID:19232515, PMID:32971071]."},"prefetch_data":{"uniprot":{"accession":"Q969U6","full_name":"F-box/WD repeat-containing protein 5","aliases":["F-box and WD-40 domain-containing protein 5"],"length_aa":566,"mass_kda":63.9,"function":"Substrate recognition component of both SCF (SKP1-CUL1-F-box protein) and DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes. Substrate recognition component of the SCF(FBXW5) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of SASS6 during S phase, leading to prevent centriole reduplication. The SCF(FBXW5) complex also mediates ubiquitination and degradation of actin-regulator EPS8 during G2 phase, leading to the transient degradation of EPS8 and subsequent cell shape changes required to allow mitotic progression. Substrate-specific adapter of the DCX(FBXW5) E3 ubiquitin-protein ligase complex which mediates the polyubiquitination and subsequent degradation of TSC2. May also act as a negative regulator of MAP3K7/TAK1 signaling in the interleukin-1B (IL1B) signaling pathway","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q969U6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBXW5","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FBXW5","total_profiled":1310},"omim":[{"mim_id":"615869","title":"TUMOR NECROSIS FACTOR-ALPHA-INDUCED PROTEIN 8-LIKE 1; TNFAIP8L1","url":"https://www.omim.org/entry/615869"},{"mim_id":"609072","title":"F-BOX AND WD40 DOMAIN PROTEIN 5; FBXW5","url":"https://www.omim.org/entry/609072"},{"mim_id":"191092","title":"TSC COMPLEX SUBUNIT 2; TSC2","url":"https://www.omim.org/entry/191092"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"testis","ntpm":219.8}],"url":"https://www.proteinatlas.org/search/FBXW5"},"hgnc":{"alias_symbol":["DKFZP434B205","MGC20962","Fbw5"],"prev_symbol":[]},"alphafold":{"accession":"Q969U6","domains":[{"cath_id":"1.20.1280.50","chopping":"10-78","consensus_level":"high","plddt":94.4139,"start":10,"end":78},{"cath_id":"2.130.10.10","chopping":"82-260_331-337_347-378_389-547","consensus_level":"medium","plddt":92.6813,"start":82,"end":547}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969U6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969U6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969U6-F1-predicted_aligned_error_v6.png","plddt_mean":84.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBXW5","jax_strain_url":"https://www.jax.org/strain/search?query=FBXW5"},"sequence":{"accession":"Q969U6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969U6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969U6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969U6"}},"corpus_meta":[{"pmid":"18381890","id":"PMC_18381890","title":"WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by DDB1-CUL4-ROC1 ligase.","date":"2008","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/18381890","citation_count":141,"is_preprint":false},{"pmid":"21725316","id":"PMC_21725316","title":"The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication.","date":"2011","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21725316","citation_count":125,"is_preprint":false},{"pmid":"30596474","id":"PMC_30596474","title":"The ULK1-FBXW5-SEC23B nexus controls autophagy.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/30596474","citation_count":71,"is_preprint":false},{"pmid":"24082123","id":"PMC_24082123","title":"CRL4A-FBXW5-mediated degradation of DLC1 Rho GTPase-activating protein tumor suppressor promotes non-small cell lung cancer cell growth.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24082123","citation_count":58,"is_preprint":false},{"pmid":"24444419","id":"PMC_24444419","title":"Tnfaip8 l1/Oxi-β binds to FBXW5, increasing autophagy through activation of TSC2 in a Parkinson's disease model.","date":"2014","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24444419","citation_count":51,"is_preprint":false},{"pmid":"34217994","id":"PMC_34217994","title":"FBXW5 aggravates hepatic ischemia/reperfusion injury via promoting phosphorylation of ASK1 in a TRAF6-dependent manner.","date":"2021","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34217994","citation_count":44,"is_preprint":false},{"pmid":"35210431","id":"PMC_35210431","title":"The E3 ubiquitin ligase, FBXW5, promotes the migration and invasion of gastric cancer through the dysregulation of the Hippo pathway.","date":"2022","source":"Cell death 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Epithelial-Mesenchymal Transition in Lung Adenocarcinoma Through the KLF13/TROAP Signaling Pathway.","date":"2025","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/40696794","citation_count":1,"is_preprint":false},{"pmid":"40989716","id":"PMC_40989716","title":"The structure and function of FBXW5 in human diseases.","date":"2025","source":"Biochemistry and biophysics reports","url":"https://pubmed.ncbi.nlm.nih.gov/40989716","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10477,"output_tokens":3406,"usd":0.04126},"stage2":{"model":"claude-opus-4-6","input_tokens":6793,"output_tokens":3575,"usd":0.18501},"total_usd":0.22627,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"FBXW5 (FBW5) acts as a DDB1-binding WD40 substrate receptor that recruits TSC2 to the DDB1-CUL4-ROC1 E3 ubiquitin ligase complex, promoting TSC2 ubiquitination and proteasomal degradation. TSC1 co-expression abrogates this degradation. In Drosophila, Ddb1 or Cul4 mutations cause Gigas/TSC2 accumulation and growth defects partially rescued by Gigas/Tsc2 reduction.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/depletion assays, in vivo ubiquitination, Drosophila genetic epistasis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, gain/loss-of-function, and genetic epistasis in Drosophila; replicated by subsequent studies\",\n      \"pmids\": [\"18381890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FBXW5 functions as the F-box/substrate-targeting subunit of SCF-FBXW5 E3 ubiquitin ligase that binds and ubiquitylates the centriolar protein HsSAS-6, targeting it for proteasomal degradation to limit centrosome duplication. PLK4 phosphorylates FBXW5 at Ser151 to suppress its ability to ubiquitylate HsSAS-6. FBXW5 itself is a substrate of APC/C, which degrades it during mitosis and G1 to reset the centrosome duplication machinery.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, siRNA depletion/overexpression, phosphorylation mapping, cell cycle analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Co-IP, ubiquitination assay, mutagenesis of phosphosite, APC/C substrate validation); single high-impact study with rigorous controls\",\n      \"pmids\": [\"21725316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FBXW5 associates with endogenous TAK1 in an IL-1β-dependent manner, identified by tandem affinity purification. Overexpression of FBXW5 inhibits IL-1β-induced JNK/p38 MAPK and NF-κB activation and TAK1 phosphorylation at Thr187, while FBXW5 knockdown prolongs TAK1 activation, indicating FBXW5 negatively regulates TAK1 signaling.\",\n      \"method\": \"Tandem affinity purification (TAP), Co-immunoprecipitation, overexpression/knockdown with signaling readouts\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — TAP identification plus functional gain/loss-of-function; single lab study\",\n      \"pmids\": [\"19232515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FBXW5, acting via the DDB1-CUL4A-RBX1 complex, enhances sumoylation of nuclear c-Myb rather than ubiquitination, localizing c-Myb to nuclear dot-like domains and suppressing its transactivation of the c-myc promoter. This demonstrates the DDB1-CUL4A-RBX1 complex can function as a dual SUMO/ubiquitin ligase depending on substrate.\",\n      \"method\": \"Co-immunoprecipitation, sumoylation assay, transcriptional reporter assay, subcellular localization imaging\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — functional sumoylation assay with transcriptional readout; single lab, moderate mechanistic depth\",\n      \"pmids\": [\"22910413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FBXW5 acts as the substrate receptor of the CRL4A (CUL4A-DDB1-RBX1) ubiquitin ligase to ubiquitinate and degrade the RhoGAP tumor suppressor DLC1, suppressing RhoA-GTP levels and RhoA effector signaling. siRNA knockdown of CUL4A, DDB1, or FBXW5 restores DLC1 protein and reduces RhoA activity in NSCLC cells.\",\n      \"method\": \"siRNA knockdown, Co-immunoprecipitation, ubiquitination assay, RhoA-GTP pulldown, proliferation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, ubiquitination assay, RhoA activity assay, rescue experiments); published in high-impact journal\",\n      \"pmids\": [\"24082123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Tnfaip8l1/Oxi-β competes with TSC2 for binding to FBXW5, preventing FBXW5-mediated ubiquitination of TSC2 and thereby stabilizing TSC2 to decrease mTOR phosphorylation and enhance autophagy in dopaminergic neurons under oxidative stress.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assay, mTOR phosphorylation readout, autophagy markers\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and functional readouts; single lab, partial mechanistic follow-up on known FBXW5-TSC2 axis\",\n      \"pmids\": [\"24444419\", \"24372178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FBXW5 targets SEC23B, a component of the COPII coat complex, for proteasomal degradation via the SCF-FBXW5 complex, limiting autophagic flux in nutrient-replete conditions. ULK1 phosphorylates SEC23B on Serine 186 in response to starvation, preventing SEC23B-FBXW5 interaction and stabilizing SEC23B. Stabilized, phosphorylated SEC23B associates selectively with SEC24A and SEC24B and relocalizes to the ER-Golgi intermediate compartment to promote autophagosome biogenesis.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, phosphorylation site mutagenesis, mass spectrometry, subcellular fractionation/localization, autophagic flux assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including Co-IP, ubiquitination assay, site-specific mutagenesis, and localization; rigorous single-study with strong mechanistic resolution\",\n      \"pmids\": [\"30596474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FBXW5 directly interacts with TAK1 and negatively regulates pathological cardiac hypertrophy by blocking MAPK signaling downstream of TAK1. FBXW5 knockout mice show aggravated pressure-overload-induced hypertrophy, while AAV9-mediated overexpression is protective. TAK1 inhibition prevents the pro-hypertrophic effects of FBXW5 loss.\",\n      \"method\": \"Co-immunoprecipitation, FBXW5 knockout mice, AAV9 overexpression, pressure-overload model, MAPK phosphorylation readouts\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus in vivo KO and OE with genetic rescue; single lab\",\n      \"pmids\": [\"32971071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SCFFbxw5 ubiquitylates kinesin-13 microtubule depolymerases MCAK (Kif2c), Kif2a, and Kif2b in vitro without requiring preceding substrate modifications, using neddylated SCFFbxw5 and Cdc34. In cells, SCFFbxw5 targets MCAK for proteasomal degradation predominantly during G2. Loss of Fbxw5 increases MCAK levels at basal bodies and impairs ciliogenesis in G1/G0, which is rescued by co-knockdown of MCAK, Kif2a, or Kif2b.\",\n      \"method\": \"Protein microarray screening, in vitro reconstituted ubiquitylation assay, siRNA knockdown, co-knockdown rescue, ciliogenesis assay, cell cycle staging\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution assay plus epistasis rescue in cells; multiple substrates tested\",\n      \"pmids\": [\"34368969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBXW5 binds to the PPxY motif in the LATS1/2 kinase domain and promotes their ubiquitination and proteasomal degradation, thereby inactivating the Hippo pathway and increasing YAP1 activity in gastric cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown, xenograft mouse model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP and ubiquitination assay with functional validation; single lab\",\n      \"pmids\": [\"35210431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXW5 targets AQP3 (aquaporin 3) for ubiquitination and proteasomal degradation via the SCF-FBXW5 complex. FBXW5 knockdown stabilizes AQP3, which leads to lysosomal-dependent degradation of PDPK1, inactivating the AKT-mTOR pathway and inducing autophagic cell death in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, lysosomal inhibitor experiments, AKT-mTOR pathway readouts\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP and ubiquitination assay with pathway mechanistic follow-up; single lab\",\n      \"pmids\": [\"38726865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXW5 promotes ubiquitination and degradation of KLF13, which in turn relieves KLF13-mediated transcriptional suppression of TROAP, facilitating EMT in lung adenocarcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, ChIP, luciferase reporter assay, siRNA knockdown, xenograft model\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination, ChIP, and transcriptional reporter in a single study; single lab\",\n      \"pmids\": [\"40696794\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXW5 is an F-box/WD40 substrate receptor that functions in two distinct E3 ubiquitin ligase complexes — SCF-FBXW5 (SKP1-CUL1-RBX1-FBXW5) and CRL4-FBXW5 (DDB1-CUL4-ROC1-FBXW5) — to ubiquitinate and degrade diverse substrates including TSC2, HsSAS-6, SEC23B, DLC1, MCAK/Kif2a/Kif2b, LATS1/2, AQP3, and KLF13, thereby regulating mTOR/autophagy signaling, centrosome duplication, ciliogenesis, Hippo pathway activity, and cytoskeletal dynamics; its own activity is controlled by PLK4 phosphorylation (Ser151) and APC/C-mediated degradation during the cell cycle, and it additionally associates with TAK1 to negatively regulate IL-1β/MAPK/NF-κB signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FBXW5 is an F-box and WD40-repeat substrate receptor that assembles into two distinct cullin-RING E3 ubiquitin ligase complexes—SCF-FBXW5 (SKP1-CUL1-RBX1) and CRL4-FBXW5 (DDB1-CUL4-ROC1)—to ubiquitinate and target diverse substrates for proteasomal degradation, thereby regulating centrosome duplication, ciliogenesis, mTOR/autophagy signaling, Rho GTPase activity, Hippo pathway output, and COPII-dependent membrane trafficking [PMID:18381890, PMID:21725316, PMID:24082123, PMID:30596474, PMID:34368969, PMID:35210431]. Through the CRL4 complex, FBXW5 degrades TSC2 to activate mTOR and degrades the RhoGAP DLC1 to sustain RhoA signaling, while through SCF it targets HsSAS-6 to restrict centrosome number, SEC23B to limit autophagosome biogenesis under nutrient-replete conditions, and kinesin-13 depolymerases (MCAK/Kif2a/Kif2b) to permit ciliogenesis [PMID:18381890, PMID:24082123, PMID:21725316, PMID:30596474, PMID:34368969]. FBXW5 activity is itself cell-cycle regulated: PLK4 phosphorylation at Ser151 inhibits its ubiquitin ligase function toward HsSAS-6 during S phase, and APC/C-mediated degradation eliminates FBXW5 during mitosis and G1 [PMID:21725316]. Independent of its ligase function, FBXW5 binds TAK1 and negatively regulates IL-1β-induced MAPK/NF-κB signaling and pathological cardiac hypertrophy [PMID:19232515, PMID:32971071].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing that FBXW5 is not solely an SCF component but also a DDB1-binding WD40 receptor for the CRL4 E3 ligase, with TSC2 identified as its first substrate—linking FBXW5 to growth control via the TSC/mTOR axis.\",\n      \"evidence\": \"Co-IP, in vivo ubiquitination, and Drosophila genetic epistasis showing Gigas/TSC2 accumulation upon Ddb1/Cul4 loss\",\n      \"pmids\": [\"18381890\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SCF-FBXW5 also targets TSC2 was not tested\", \"Structural basis for FBXW5-TSC2 recognition unknown\", \"Physiological contexts beyond Drosophila growth not explored\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealing a ligase-independent function: FBXW5 associates with TAK1 and acts as a negative regulator of IL-1β-induced MAPK and NF-κB signaling, expanding its role beyond substrate-targeted ubiquitination.\",\n      \"evidence\": \"Tandem affinity purification identifying endogenous TAK1 association; overexpression/knockdown modulating JNK/p38/NF-κB activation\",\n      \"pmids\": [\"19232515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FBXW5 ubiquitinates TAK1 or acts through a non-catalytic mechanism was not resolved\", \"Single-lab study without independent confirmation\", \"Downstream effector specificity unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that FBXW5 functions in the SCF complex to ubiquitinate HsSAS-6 and limit centrosome duplication, while itself being regulated by PLK4 phosphorylation and APC/C-mediated degradation—establishing a cell-cycle-integrated control circuit for centriole copy number.\",\n      \"evidence\": \"Co-IP, in vivo ubiquitination, Ser151 phosphosite mutagenesis, APC/C substrate validation, cell cycle analysis\",\n      \"pmids\": [\"21725316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of FBXW5-HsSAS-6 interface not determined\", \"Whether PLK4 phosphorylation affects other FBXW5 substrates untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Unexpectedly showing that the CRL4-FBXW5 complex can promote sumoylation rather than ubiquitination of c-Myb, suppressing its transactivation—raising the possibility that FBXW5-containing ligases have dual SUMO/ubiquitin activity.\",\n      \"evidence\": \"Co-IP, sumoylation assay, transcriptional reporter, subcellular localization imaging\",\n      \"pmids\": [\"22910413\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which a CRL promotes sumoylation instead of ubiquitination not explained\", \"Not independently replicated\", \"Endogenous c-Myb sumoylation dependence on FBXW5 not shown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying DLC1, a RhoGAP tumor suppressor, as a CRL4A-FBXW5 substrate, thereby linking FBXW5 to Rho GTPase signaling and cancer cell proliferation.\",\n      \"evidence\": \"siRNA of CUL4A/DDB1/FBXW5 restoring DLC1 and reducing RhoA-GTP; Co-IP and ubiquitination assay in NSCLC cells\",\n      \"pmids\": [\"24082123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DLC1 degron recognized by FBXW5 not mapped\", \"Whether FBXW5-DLC1 axis operates in non-cancer contexts not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that Tnfaip8l1/Oxi-β competes with TSC2 for FBXW5 binding, providing the first example of a competitive inhibitor of FBXW5 substrate recognition and linking the FBXW5-TSC2 axis to autophagy and dopaminergic neuron survival under oxidative stress.\",\n      \"evidence\": \"Co-IP competition assay, protein stability, mTOR phosphorylation, and autophagy marker readouts\",\n      \"pmids\": [\"24444419\", \"24372178\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding competition not shown with purified proteins\", \"In vivo neuronal relevance not confirmed in animal models\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing that SCF-FBXW5 ubiquitinates SEC23B to limit autophagosome biogenesis in fed conditions, and that ULK1 phosphorylation of SEC23B at Ser186 blocks FBXW5 recognition upon starvation—revealing FBXW5 as a nutrient-sensitive gatekeeper of COPII-dependent autophagy.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, phosphosite mutagenesis, mass spectrometry, autophagic flux assays, ERGIC localization\",\n      \"pmids\": [\"30596474\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other COPII components are also FBXW5 substrates unknown\", \"Structural basis for phospho-switch disrupting FBXW5-SEC23B interaction unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extending the FBXW5-TAK1 axis in vivo: FBXW5 knockout mice develop aggravated cardiac hypertrophy via enhanced TAK1-MAPK signaling, and AAV9-mediated overexpression is protective—validating a physiological role for FBXW5 in cardiac stress responses.\",\n      \"evidence\": \"FBXW5 knockout mice, AAV9 overexpression, pressure-overload model, TAK1 inhibitor rescue\",\n      \"pmids\": [\"32971071\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FBXW5 ubiquitinates TAK1 or acts non-catalytically still unresolved\", \"Cardiac-specific versus systemic effects not dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying kinesin-13 microtubule depolymerases (MCAK, Kif2a, Kif2b) as direct modification-independent substrates of SCF-FBXW5, and establishing that their degradation during G2 is required for subsequent ciliogenesis in G0/G1.\",\n      \"evidence\": \"Protein microarray, reconstituted in vitro ubiquitylation with neddylated SCF-FBXW5 and Cdc34, co-knockdown rescue of ciliogenesis defect\",\n      \"pmids\": [\"34368969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FBXW5 recognizes these substrates without prior modification is structurally unexplained\", \"Whether this pathway operates in multiciliated cells unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing FBXW5 binds the PPxY motif of LATS1/2 kinases and promotes their ubiquitination and degradation, inactivating the Hippo pathway and enhancing YAP1-driven transcription in gastric cancer.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, siRNA, xenograft model\",\n      \"pmids\": [\"35210431\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which E3 complex (SCF or CRL4) mediates LATS1/2 degradation not specified\", \"PPxY motif recognition by WD40 repeats not structurally characterized\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying AQP3 as an SCF-FBXW5 substrate whose stabilization upon FBXW5 loss triggers lysosomal PDPK1 degradation, AKT-mTOR pathway inactivation, and autophagic cell death in hepatocellular carcinoma—revealing a non-canonical route by which FBXW5 controls mTOR signaling.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, siRNA, lysosomal inhibitor experiments, AKT-mTOR readouts\",\n      \"pmids\": [\"38726865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which AQP3 stabilization causes PDPK1 lysosomal targeting is indirect\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extending FBXW5 substrates to transcription factor KLF13, whose degradation de-represses TROAP transcription and promotes EMT in lung adenocarcinoma.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, ChIP, luciferase reporter, xenograft model\",\n      \"pmids\": [\"40696794\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"KLF13 degron not mapped\", \"Which CRL complex is involved not specified\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No high-resolution structural information exists for FBXW5 in complex with any substrate, leaving the molecular determinants of its unusually broad substrate recognition—spanning modification-dependent and modification-independent modes—unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of FBXW5 alone or in complex\", \"Rules governing SCF versus CRL4 complex assembly choice unclear\", \"Comprehensive substrate landscape under physiological conditions not systematically defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 4, 6, 8, 9, 10, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 4, 6, 8, 9, 10, 11]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5, 6, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 9, 10]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 8]}\n    ],\n    \"complexes\": [\n      \"SCF-FBXW5 (SKP1-CUL1-RBX1-FBXW5)\",\n      \"CRL4-FBXW5 (DDB1-CUL4-ROC1-FBXW5)\"\n    ],\n    \"partners\": [\n      \"DDB1\",\n      \"CUL4A\",\n      \"SKP1\",\n      \"CUL1\",\n      \"TAK1\",\n      \"PLK4\",\n      \"HsSAS-6\",\n      \"TSC2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}