{"gene":"FBXW5","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2008,"finding":"FBXW5 (FBW5) binds TSC2 and recruits it to the DDB1-CUL4-ROC1 E3 ubiquitin ligase complex, promoting TSC2 ubiquitination and proteasomal degradation. TSC1 co-expression abrogates this degradation. Drosophila Ddb1 or Cul4 mutations cause Gigas/TSC2 accumulation and growth defects rescuable by Gigas/Tsc2 reduction, confirming epistatic relationship.","method":"Co-IP, overexpression/depletion assays, in vivo ubiquitination, Drosophila genetic epistasis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic epistasis in Drosophila, and multiple orthogonal loss/gain-of-function experiments across two organisms","pmids":["18381890"],"is_preprint":false},{"year":2011,"finding":"FBXW5 acts as the substrate-targeting subunit of the SCF-FBXW5 E3 ubiquitin ligase that ubiquitylates and degrades the centriolar protein HsSAS-6, thereby limiting centrosome duplication. PLK4 phosphorylates FBXW5 at Ser151 to suppress its ubiquitylation activity toward HsSAS-6. APC/C targets FBXW5 for degradation during mitosis and G1, restricting centrosome re-duplication. FBXW5 levels peak at the G1/S transition.","method":"Co-IP, in vivo ubiquitination assay, depletion/overexpression with centrosome counting, phosphorylation site mutagenesis, cell-cycle staging","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination assay, phospho-mutagenesis, cell-cycle analysis) in a single focused study with clear mechanistic dissection","pmids":["21725316"],"is_preprint":false},{"year":2018,"finding":"FBXW5 targets SEC23B (a COPII component) for proteasomal degradation, limiting autophagic flux under nutrient-replete conditions. ULK1 phosphorylates SEC23B on Ser186 during starvation, blocking the FBXW5–SEC23B interaction and stabilizing SEC23B, which then associates with SEC24A/B (not SEC24C/D) and re-localizes to the ERGIC to promote autophagosome biogenesis.","method":"Co-IP, in vivo ubiquitination, phosphorylation site mapping, ULK1 kinase assay, co-localization imaging, autophagy flux assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, kinase assay, phospho-mutagenesis, flux assay, imaging) demonstrating a complete regulatory axis in one rigorous study","pmids":["30596474"],"is_preprint":false},{"year":2013,"finding":"FBXW5 is the substrate receptor of the CRL4A (CUL4A-DDB1-ROC1) complex that ubiquitinates and degrades the RhoA-GAP tumor suppressor DLC1. siRNA knockdown of CUL4A, DDB1, or FBXW5 restores DLC1 protein and reduces active RhoA-GTP levels and RhoA effector signaling in NSCLC cells.","method":"siRNA knockdown, Co-IP, in vivo ubiquitination assay, RhoA-GTP pulldown, proliferation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assays with functional readout, single lab","pmids":["24082123"],"is_preprint":false},{"year":2009,"finding":"FBXW5 associates with endogenous TAK1 in an IL-1β-dependent manner (identified by TAP-MS in HeLa cells). Overexpression of FBXW5 inhibits IL-1β-induced JNK/p38 MAPK and NF-κB activation and blocks TAK1 phosphorylation at Thr187; knockdown prolongs TAK1 activation, establishing FBXW5 as a negative regulator of TAK1 in the IL-1β signaling pathway.","method":"Tandem affinity purification / mass spectrometry, Co-IP, overexpression and siRNA knockdown with kinase activity and pathway readouts","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TAP-MS identification followed by Co-IP validation and functional gain/loss-of-function, single lab","pmids":["19232515"],"is_preprint":false},{"year":2012,"finding":"FBXW5, via the DDB1-CUL4A-RBX1 complex, enhances sumoylation (rather than ubiquitination) of nuclear c-Myb, causing c-Myb re-localization to nuclear dot-like domains and suppression of c-Myc promoter transactivation. FBXW5 localizes to both nucleus and cytosol.","method":"Co-IP, sumoylation assays, reporter gene assays, immunofluorescence localization","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sumoylation assay with functional reporter readout and localization, single lab","pmids":["22910413"],"is_preprint":false},{"year":2014,"finding":"Tnfaip8l1/Oxi-β binds FBXW5 and competes with TSC2 for FBXW5 binding, thereby preventing TSC2 ubiquitination and degradation by the CUL4 E3 ligase complex. This stabilizes TSC2, reduces mTOR phosphorylation, and increases autophagy in dopaminergic neurons under oxidative stress.","method":"Co-IP, competition binding assay, ubiquitination assay, siRNA knockdown, autophagy markers","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and functional assays replicated across two publications from the same lab (PMIDs 24444419 and 24372178)","pmids":["24444419","24372178"],"is_preprint":false},{"year":2021,"finding":"SCF-FBXW5 targets kinesin-13 family members MCAK (Kif2c), Kif2a, and Kif2b for proteasomal degradation. In vitro reconstitution with neddylated SCF-FBXW5 and Cdc34 demonstrates efficient polyubiquitylation of MCAK without requiring prior modifications. Loss of Fbxw5 elevates MCAK levels at basal bodies and impairs ciliogenesis in G1/G0; concomitant knockdown of MCAK, Kif2a, or Kif2b rescues ciliogenesis.","method":"Protein microarray screening, in vitro ubiquitination reconstitution, siRNA knockdown, ciliogenesis assay, rescue experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution assay demonstrating ubiquitylation without cofactors, combined with genetic rescue experiments, single lab","pmids":["34368969"],"is_preprint":false},{"year":2022,"finding":"FBXW5 binds the PPxY sequence in the LATS1/2 kinase domain and promotes LATS1/2 ubiquitination and degradation, thereby inactivating the Hippo pathway and increasing YAP1 activity in gastric cancer cells. Blocking LATS1-YAP1 signaling abolishes FBXW5-mediated effects on invasion and chemoresistance.","method":"Co-IP, in vivo ubiquitination assay, siRNA/overexpression, mouse xenograft","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay with functional epistasis (LATS1-YAP1 blocking rescue), single lab","pmids":["35210431"],"is_preprint":false},{"year":2024,"finding":"FBXW5 (as part of the SCF complex) directly ubiquitinates AQP3 (aquaporin 3), targeting it for proteasomal degradation. FBXW5 knockdown stabilizes AQP3, which then promotes lysosomal degradation of PDPK1, inactivating the AKT-mTOR pathway and inducing autophagic cell death in hepatocellular carcinoma cells.","method":"Co-IP, in vivo ubiquitination assay, siRNA knockdown, lysosomal inhibitor experiments, autophagy assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, and mechanistic pathway dissection with pharmacological inhibitors, single lab","pmids":["38726865"],"is_preprint":false},{"year":2020,"finding":"FBXW5 directly interacts with TAK1 and blocks MAPK signaling in cardiomyocytes. FBXW5 knockout mice develop aggravated pressure overload-induced cardiac hypertrophy, while AAV9-mediated FBXW5 overexpression is protective. TAK1 inhibition prevents the hypertrophic effects of FBXW5 loss, placing FBXW5 upstream of TAK1-MAPK in pathological cardiac hypertrophy.","method":"Co-IP, FBXW5 knockout mice, AAV9-mediated overexpression, pressure overload model, TAK1 inhibitor epistasis","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss and gain of function in vivo with epistasis via TAK1 inhibition, Co-IP for interaction, single lab","pmids":["32971071"],"is_preprint":false},{"year":2025,"finding":"FBXW5 promotes ubiquitinated degradation of KLF13, a transcriptional repressor. Loss of KLF13 protein relieves transcriptional repression of TROAP, facilitating EMT in lung adenocarcinoma cells.","method":"Co-IP, ubiquitination assay, ChIP, dual luciferase reporter, siRNA knockdown, xenograft model","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay with ChIP confirmation of downstream transcriptional mechanism, single lab, recently published","pmids":["40696794"],"is_preprint":false},{"year":2021,"finding":"FBXW5 promotes phosphorylation of ASK1 in a TRAF6-dependent manner in hepatic ischemia/reperfusion injury, activating MAPK and IKK pathways. Blockade of TRAF6 abolished FBXW5-driven ASK1 phosphorylation.","method":"FBXW5 overexpression/inhibition in vivo and in vitro, TRAF6 blockade epistasis, pathway phosphorylation assays","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional assays with pharmacological/genetic epistasis but no direct binding or ubiquitination assay between FBXW5 and ASK1/TRAF6, single lab","pmids":["34217994"],"is_preprint":false}],"current_model":"FBXW5 is an F-box/WD40 substrate receptor that operates within at least two distinct E3 ubiquitin ligase complexes—SCF-FBXW5 (SKP1-CUL1-FBXW5) and CRL4-FBXW5 (DDB1-CUL4-ROC1-FBXW5)—to ubiquitinate and destabilize a diverse set of substrates including TSC2, HsSAS-6, DLC1, SEC23B, LATS1/2, kinesin-13 family members (MCAK/Kif2a/Kif2b), AQP3, and KLF13; its activity toward HsSAS-6 is suppressed by PLK4-mediated phosphorylation at Ser151 and its own levels are cell-cycle regulated by APC/C-mediated degradation, while it also enhances sumoylation of c-Myb and negatively regulates TAK1 signaling, collectively placing FBXW5 at the intersection of centrosome duplication, autophagy, Hippo/mTOR signaling, ciliogenesis, and inflammatory kinase cascades."},"narrative":{"mechanistic_narrative":"FBXW5 is an F-box/WD40 substrate receptor that operates within multiple cullin-RING E3 ubiquitin ligase complexes to select substrates for ubiquitin-dependent degradation, placing it at the control point of centrosome duplication, autophagy, growth signaling, and ciliogenesis [PMID:21725316, PMID:30596474]. It functions both as the substrate-targeting subunit of an SCF complex (SKP1-CUL1-FBXW5) and within the DDB1-CUL4-ROC1 (CRL4) complex, depending on the substrate engaged [PMID:18381890, PMID:21725316]. Through the CRL4 pathway it binds and degrades the mTOR-pathway tumor suppressor TSC2, an interaction that is blocked when TSC1 is co-expressed or when Tnfaip8l1/Oxi-β competes for FBXW5 binding to stabilize TSC2 [PMID:18381890, PMID:24444419, PMID:24372178]. As an SCF substrate receptor it limits centrosome duplication by degrading the centriolar protein HsSAS-6; this activity is switched off by PLK4-mediated phosphorylation of FBXW5 at Ser151, while FBXW5 itself is degraded by APC/C during mitosis and G1 so that its levels peak at G1/S [PMID:21725316]. The same SCF-FBXW5 ligase degrades kinesin-13 family members (MCAK/Kif2a/Kif2b) to permit ciliogenesis in quiescent cells, a reaction reconstituted in vitro with neddylated SCF-FBXW5 and Cdc34 [PMID:34368969]. FBXW5 additionally restrains autophagy under nutrient-replete conditions by degrading the COPII component SEC23B, an interaction relieved by ULK1 phosphorylation of SEC23B during starvation [PMID:30596474]. Across cancer contexts FBXW5 degrades the Hippo kinases LATS1/2 to activate YAP1, and degrades DLC1, AQP3, and the transcriptional repressor KLF13 [PMID:24082123, PMID:35210431, PMID:38726865, PMID:40696794]. FBXW5 also acts as a negative regulator of TAK1-driven MAPK and NF-κB signaling in inflammatory and cardiac-hypertrophy settings, and can enhance sumoylation rather than ubiquitination of c-Myb [PMID:19232515, PMID:22910413, PMID:32971071].","teleology":[{"year":2008,"claim":"Established FBXW5 as a substrate receptor that links a specific substrate to a cullin-RING ligase, identifying TSC2 as its first target and connecting it to mTOR-pathway growth control.","evidence":"Reciprocal Co-IP, in vivo ubiquitination, and Drosophila genetic epistasis (Ddb1/Cul4 vs Gigas/Tsc2)","pmids":["18381890"],"confidence":"High","gaps":["Did not resolve whether FBXW5 also functions in SCF (CUL1) complexes","Direct ubiquitination of TSC2 by reconstituted ligase not shown"]},{"year":2009,"claim":"Extended FBXW5 beyond degradation by showing it associates with TAK1 in an IL-1β-dependent manner and negatively regulates inflammatory MAPK/NF-κB signaling.","evidence":"TAP-MS in HeLa, Co-IP, and gain/loss-of-function with kinase and pathway readouts","pmids":["19232515"],"confidence":"Medium","gaps":["Whether regulation is ubiquitin-dependent was not established","Single lab; no in vitro reconstitution"]},{"year":2011,"claim":"Defined FBXW5 as the SCF substrate receptor for HsSAS-6 controlling centrosome copy number, and revealed two layers of regulation: PLK4 phosphorylation inhibiting its activity and APC/C degradation restricting its abundance to G1/S.","evidence":"Co-IP, in vivo ubiquitination, centrosome counting, phospho-site mutagenesis, cell-cycle staging","pmids":["21725316"],"confidence":"High","gaps":["Structural basis of HsSAS-6 recognition not resolved","Interplay between SCF and CRL4 usage not addressed"]},{"year":2012,"claim":"Showed FBXW5 can promote sumoylation rather than ubiquitination of a substrate (c-Myb), broadening its biochemical repertoire and adding a transcriptional output.","evidence":"Co-IP, sumoylation assays, reporter assays, immunofluorescence","pmids":["22910413"],"confidence":"Medium","gaps":["Mechanism by which FBXW5 enhances SUMO conjugation unclear","Single lab"]},{"year":2013,"claim":"Identified DLC1 as a CRL4A-FBXW5 substrate, linking FBXW5 to RhoA-GTP signaling and tumor suppressor turnover in lung cancer.","evidence":"siRNA knockdown, Co-IP, in vivo ubiquitination, RhoA-GTP pulldown in NSCLC cells","pmids":["24082123"],"confidence":"Medium","gaps":["No in vitro reconstitution of DLC1 ubiquitination","Single lab"]},{"year":2014,"claim":"Revealed competitive regulation of FBXW5 substrate selection, with Tnfaip8l1/Oxi-β displacing TSC2 to stabilize it and tune mTOR/autophagy under oxidative stress.","evidence":"Co-IP, competition binding, ubiquitination assay, siRNA, autophagy markers in dopaminergic neurons","pmids":["24444419","24372178"],"confidence":"Medium","gaps":["Binding site on FBXW5 not mapped","Same-lab replication only"]},{"year":2018,"claim":"Connected FBXW5 to autophagy regulation by identifying SEC23B as a degradation target whose stabilization upon ULK1 phosphorylation reroutes COPII to drive autophagosome biogenesis.","evidence":"Co-IP, in vivo ubiquitination, phospho-mapping, ULK1 kinase assay, flux assays, imaging","pmids":["30596474"],"confidence":"High","gaps":["Which cullin scaffold mediates SEC23B degradation not specified","Single rigorous study"]},{"year":2021,"claim":"Provided the most direct biochemical proof of FBXW5 ligase activity by reconstituting SCF-FBXW5-mediated polyubiquitylation of kinesin-13 proteins in vitro, and tied this to ciliogenesis control in G0/G1.","evidence":"Protein microarray, in vitro ubiquitination reconstitution with neddylated SCF and Cdc34, siRNA, ciliogenesis rescue","pmids":["34368969"],"confidence":"High","gaps":["Recognition determinants on MCAK/Kif2a/Kif2b not defined","Single lab"]},{"year":2020,"claim":"Demonstrated in vivo physiological relevance of FBXW5-TAK1 antagonism by showing FBXW5 knockout aggravates and overexpression protects against pressure-overload cardiac hypertrophy.","evidence":"Co-IP, FBXW5 knockout mice, AAV9 overexpression, pressure-overload model, TAK1 inhibitor epistasis","pmids":["32971071"],"confidence":"Medium","gaps":["Whether FBXW5 ubiquitinates TAK1 not shown","Single lab"]},{"year":2022,"claim":"Linked FBXW5 to Hippo pathway control by showing it binds the LATS1/2 PPxY motif and degrades these kinases to activate YAP1, driving gastric cancer invasion and chemoresistance.","evidence":"Co-IP, in vivo ubiquitination, siRNA/overexpression, mouse xenograft, LATS1-YAP1 rescue","pmids":["35210431"],"confidence":"Medium","gaps":["Which ligase scaffold is used not defined","Single lab"]},{"year":2024,"claim":"Added AQP3 as an SCF-FBXW5 substrate and traced a degradation cascade through PDPK1 to AKT-mTOR inactivation and autophagic cell death in hepatocellular carcinoma.","evidence":"Co-IP, in vivo ubiquitination, siRNA, lysosomal inhibition, autophagy assays","pmids":["38726865"],"confidence":"Medium","gaps":["Direct ubiquitination not reconstituted in vitro","Single lab"]},{"year":2025,"claim":"Implicated FBXW5 in EMT by showing it degrades the transcriptional repressor KLF13, relieving repression of TROAP in lung adenocarcinoma.","evidence":"Co-IP, ubiquitination assay, ChIP, dual luciferase, siRNA, xenograft","pmids":["40696794"],"confidence":"Medium","gaps":["Ligase scaffold not defined","Single recent study"]},{"year":null,"claim":"It remains unresolved how FBXW5 selects between SCF (CUL1) and CRL4 (CUL4) scaffolds for different substrates, and whether its non-degradative outputs (sumoylation enhancement, TAK1 inhibition) share a common biochemical basis.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of FBXW5-substrate or FBXW5-cullin assembly","Scaffold choice rules across the substrate set undefined","Mechanism of sumoylation enhancement and TAK1 antagonism not biochemically dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,7,8,9,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[1,7]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,7]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4]}],"complexes":["SCF (SKP1-CUL1-FBXW5)","CRL4 (DDB1-CUL4-ROC1)"],"partners":["TSC2","HSSAS-6","SEC23B","DLC1","LATS1/2","MCAK","TAK1","DDB1"],"other_free_text":[]}},"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":142,"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":128,"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 discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35210431","citation_count":34,"is_preprint":false},{"pmid":"31213005","id":"PMC_31213005","title":"FBXW5 Promotes Tumorigenesis and Metastasis in Gastric Cancer via Activation of the FAK-Src Signaling Pathway.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31213005","citation_count":20,"is_preprint":false},{"pmid":"19232515","id":"PMC_19232515","title":"An F-box protein, FBXW5, negatively regulates TAK1 MAP3K in the IL-1beta signaling pathway.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19232515","citation_count":16,"is_preprint":false},{"pmid":"38726865","id":"PMC_38726865","title":"SCFFBXW5-mediated degradation of AQP3 suppresses autophagic cell death through the PDPK1-AKT-MTOR axis in hepatocellular carcinoma cells.","date":"2024","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/38726865","citation_count":15,"is_preprint":false},{"pmid":"32971071","id":"PMC_32971071","title":"FBXW5 acts as a negative regulator of pathological cardiac hypertrophy by decreasing the TAK1 signaling to pro-hypertrophic members of the MAPK signaling pathway.","date":"2020","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/32971071","citation_count":15,"is_preprint":false},{"pmid":"34368969","id":"PMC_34368969","title":"SCFFbxw5 targets kinesin-13 proteins to facilitate ciliogenesis.","date":"2021","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/34368969","citation_count":13,"is_preprint":false},{"pmid":"31060780","id":"PMC_31060780","title":"FBXW5 reduction alleviates spinal cord injury (SCI) by blocking microglia activity: A mechanism involving p38 and JNK.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31060780","citation_count":12,"is_preprint":false},{"pmid":"22910413","id":"PMC_22910413","title":"Fbxw5 suppresses nuclear c-Myb activity via DDB1-Cul4-Rbx1 ligase-mediated sumoylation.","date":"2012","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/22910413","citation_count":10,"is_preprint":false},{"pmid":"21808243","id":"PMC_21808243","title":"FBXW5 controls centrosome number.","date":"2011","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21808243","citation_count":9,"is_preprint":false},{"pmid":"24372178","id":"PMC_24372178","title":"Tnfaip8l1/Oxi-β binds to FBXW5, increasing autophagy through activation of TSC2 in a Parkinson's disease model.","date":"2013","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24372178","citation_count":5,"is_preprint":false},{"pmid":"40696794","id":"PMC_40696794","title":"FBXW5 Promotes 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":11252,"output_tokens":3686,"usd":0.044523,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11206,"output_tokens":4309,"usd":0.081878,"stage2_stop_reason":"end_turn"},"total_usd":0.126401,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"FBXW5 (FBW5) binds TSC2 and recruits it to the DDB1-CUL4-ROC1 E3 ubiquitin ligase complex, promoting TSC2 ubiquitination and proteasomal degradation. TSC1 co-expression abrogates this degradation. Drosophila Ddb1 or Cul4 mutations cause Gigas/TSC2 accumulation and growth defects rescuable by Gigas/Tsc2 reduction, confirming epistatic relationship.\",\n      \"method\": \"Co-IP, overexpression/depletion assays, in vivo ubiquitination, Drosophila genetic epistasis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic epistasis in Drosophila, and multiple orthogonal loss/gain-of-function experiments across two organisms\",\n      \"pmids\": [\"18381890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FBXW5 acts as the substrate-targeting subunit of the SCF-FBXW5 E3 ubiquitin ligase that ubiquitylates and degrades the centriolar protein HsSAS-6, thereby limiting centrosome duplication. PLK4 phosphorylates FBXW5 at Ser151 to suppress its ubiquitylation activity toward HsSAS-6. APC/C targets FBXW5 for degradation during mitosis and G1, restricting centrosome re-duplication. FBXW5 levels peak at the G1/S transition.\",\n      \"method\": \"Co-IP, in vivo ubiquitination assay, depletion/overexpression with centrosome counting, phosphorylation site mutagenesis, cell-cycle staging\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination assay, phospho-mutagenesis, cell-cycle analysis) in a single focused study with clear mechanistic dissection\",\n      \"pmids\": [\"21725316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FBXW5 targets SEC23B (a COPII component) for proteasomal degradation, limiting autophagic flux under nutrient-replete conditions. ULK1 phosphorylates SEC23B on Ser186 during starvation, blocking the FBXW5–SEC23B interaction and stabilizing SEC23B, which then associates with SEC24A/B (not SEC24C/D) and re-localizes to the ERGIC to promote autophagosome biogenesis.\",\n      \"method\": \"Co-IP, in vivo ubiquitination, phosphorylation site mapping, ULK1 kinase assay, co-localization imaging, autophagy flux assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, kinase assay, phospho-mutagenesis, flux assay, imaging) demonstrating a complete regulatory axis in one rigorous study\",\n      \"pmids\": [\"30596474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FBXW5 is the substrate receptor of the CRL4A (CUL4A-DDB1-ROC1) complex that ubiquitinates and degrades the RhoA-GAP tumor suppressor DLC1. siRNA knockdown of CUL4A, DDB1, or FBXW5 restores DLC1 protein and reduces active RhoA-GTP levels and RhoA effector signaling in NSCLC cells.\",\n      \"method\": \"siRNA knockdown, Co-IP, in vivo ubiquitination assay, RhoA-GTP pulldown, proliferation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assays with functional readout, single lab\",\n      \"pmids\": [\"24082123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FBXW5 associates with endogenous TAK1 in an IL-1β-dependent manner (identified by TAP-MS in HeLa cells). Overexpression of FBXW5 inhibits IL-1β-induced JNK/p38 MAPK and NF-κB activation and blocks TAK1 phosphorylation at Thr187; knockdown prolongs TAK1 activation, establishing FBXW5 as a negative regulator of TAK1 in the IL-1β signaling pathway.\",\n      \"method\": \"Tandem affinity purification / mass spectrometry, Co-IP, overexpression and siRNA knockdown with kinase activity and pathway readouts\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TAP-MS identification followed by Co-IP validation and functional gain/loss-of-function, single lab\",\n      \"pmids\": [\"19232515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FBXW5, via the DDB1-CUL4A-RBX1 complex, enhances sumoylation (rather than ubiquitination) of nuclear c-Myb, causing c-Myb re-localization to nuclear dot-like domains and suppression of c-Myc promoter transactivation. FBXW5 localizes to both nucleus and cytosol.\",\n      \"method\": \"Co-IP, sumoylation assays, reporter gene assays, immunofluorescence localization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sumoylation assay with functional reporter readout and localization, single lab\",\n      \"pmids\": [\"22910413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Tnfaip8l1/Oxi-β binds FBXW5 and competes with TSC2 for FBXW5 binding, thereby preventing TSC2 ubiquitination and degradation by the CUL4 E3 ligase complex. This stabilizes TSC2, reduces mTOR phosphorylation, and increases autophagy in dopaminergic neurons under oxidative stress.\",\n      \"method\": \"Co-IP, competition binding assay, ubiquitination assay, siRNA knockdown, autophagy markers\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and functional assays replicated across two publications from the same lab (PMIDs 24444419 and 24372178)\",\n      \"pmids\": [\"24444419\", \"24372178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SCF-FBXW5 targets kinesin-13 family members MCAK (Kif2c), Kif2a, and Kif2b for proteasomal degradation. In vitro reconstitution with neddylated SCF-FBXW5 and Cdc34 demonstrates efficient polyubiquitylation of MCAK without requiring prior modifications. Loss of Fbxw5 elevates MCAK levels at basal bodies and impairs ciliogenesis in G1/G0; concomitant knockdown of MCAK, Kif2a, or Kif2b rescues ciliogenesis.\",\n      \"method\": \"Protein microarray screening, in vitro ubiquitination reconstitution, siRNA knockdown, ciliogenesis assay, rescue experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution assay demonstrating ubiquitylation without cofactors, combined with genetic rescue experiments, single lab\",\n      \"pmids\": [\"34368969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBXW5 binds the PPxY sequence in the LATS1/2 kinase domain and promotes LATS1/2 ubiquitination and degradation, thereby inactivating the Hippo pathway and increasing YAP1 activity in gastric cancer cells. Blocking LATS1-YAP1 signaling abolishes FBXW5-mediated effects on invasion and chemoresistance.\",\n      \"method\": \"Co-IP, in vivo ubiquitination assay, siRNA/overexpression, mouse xenograft\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay with functional epistasis (LATS1-YAP1 blocking rescue), single lab\",\n      \"pmids\": [\"35210431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXW5 (as part of the SCF complex) directly ubiquitinates AQP3 (aquaporin 3), targeting it for proteasomal degradation. FBXW5 knockdown stabilizes AQP3, which then promotes lysosomal degradation of PDPK1, inactivating the AKT-mTOR pathway and inducing autophagic cell death in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-IP, in vivo ubiquitination assay, siRNA knockdown, lysosomal inhibitor experiments, autophagy assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, and mechanistic pathway dissection with pharmacological inhibitors, single lab\",\n      \"pmids\": [\"38726865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FBXW5 directly interacts with TAK1 and blocks MAPK signaling in cardiomyocytes. FBXW5 knockout mice develop aggravated pressure overload-induced cardiac hypertrophy, while AAV9-mediated FBXW5 overexpression is protective. TAK1 inhibition prevents the hypertrophic effects of FBXW5 loss, placing FBXW5 upstream of TAK1-MAPK in pathological cardiac hypertrophy.\",\n      \"method\": \"Co-IP, FBXW5 knockout mice, AAV9-mediated overexpression, pressure overload model, TAK1 inhibitor epistasis\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss and gain of function in vivo with epistasis via TAK1 inhibition, Co-IP for interaction, single lab\",\n      \"pmids\": [\"32971071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXW5 promotes ubiquitinated degradation of KLF13, a transcriptional repressor. Loss of KLF13 protein relieves transcriptional repression of TROAP, facilitating EMT in lung adenocarcinoma cells.\",\n      \"method\": \"Co-IP, ubiquitination assay, ChIP, dual luciferase reporter, siRNA knockdown, xenograft model\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay with ChIP confirmation of downstream transcriptional mechanism, single lab, recently published\",\n      \"pmids\": [\"40696794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBXW5 promotes phosphorylation of ASK1 in a TRAF6-dependent manner in hepatic ischemia/reperfusion injury, activating MAPK and IKK pathways. Blockade of TRAF6 abolished FBXW5-driven ASK1 phosphorylation.\",\n      \"method\": \"FBXW5 overexpression/inhibition in vivo and in vitro, TRAF6 blockade epistasis, pathway phosphorylation assays\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional assays with pharmacological/genetic epistasis but no direct binding or ubiquitination assay between FBXW5 and ASK1/TRAF6, single lab\",\n      \"pmids\": [\"34217994\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXW5 is an F-box/WD40 substrate receptor that operates within at least two distinct E3 ubiquitin ligase complexes—SCF-FBXW5 (SKP1-CUL1-FBXW5) and CRL4-FBXW5 (DDB1-CUL4-ROC1-FBXW5)—to ubiquitinate and destabilize a diverse set of substrates including TSC2, HsSAS-6, DLC1, SEC23B, LATS1/2, kinesin-13 family members (MCAK/Kif2a/Kif2b), AQP3, and KLF13; its activity toward HsSAS-6 is suppressed by PLK4-mediated phosphorylation at Ser151 and its own levels are cell-cycle regulated by APC/C-mediated degradation, while it also enhances sumoylation of c-Myb and negatively regulates TAK1 signaling, collectively placing FBXW5 at the intersection of centrosome duplication, autophagy, Hippo/mTOR signaling, ciliogenesis, and inflammatory kinase cascades.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBXW5 is an F-box/WD40 substrate receptor that operates within multiple cullin-RING E3 ubiquitin ligase complexes to select substrates for ubiquitin-dependent degradation, placing it at the control point of centrosome duplication, autophagy, growth signaling, and ciliogenesis [#1, #2]. It functions both as the substrate-targeting subunit of an SCF complex (SKP1-CUL1-FBXW5) and within the DDB1-CUL4-ROC1 (CRL4) complex, depending on the substrate engaged [#0, #1]. Through the CRL4 pathway it binds and degrades the mTOR-pathway tumor suppressor TSC2, an interaction that is blocked when TSC1 is co-expressed or when Tnfaip8l1/Oxi-\\u03b2 competes for FBXW5 binding to stabilize TSC2 [#0, #6]. As an SCF substrate receptor it limits centrosome duplication by degrading the centriolar protein HsSAS-6; this activity is switched off by PLK4-mediated phosphorylation of FBXW5 at Ser151, while FBXW5 itself is degraded by APC/C during mitosis and G1 so that its levels peak at G1/S [#1]. The same SCF-FBXW5 ligase degrades kinesin-13 family members (MCAK/Kif2a/Kif2b) to permit ciliogenesis in quiescent cells, a reaction reconstituted in vitro with neddylated SCF-FBXW5 and Cdc34 [#7]. FBXW5 additionally restrains autophagy under nutrient-replete conditions by degrading the COPII component SEC23B, an interaction relieved by ULK1 phosphorylation of SEC23B during starvation [#2]. Across cancer contexts FBXW5 degrades the Hippo kinases LATS1/2 to activate YAP1, and degrades DLC1, AQP3, and the transcriptional repressor KLF13 [#3, #8, #9, #11]. FBXW5 also acts as a negative regulator of TAK1-driven MAPK and NF-\\u03baB signaling in inflammatory and cardiac-hypertrophy settings, and can enhance sumoylation rather than ubiquitination of c-Myb [#4, #5, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established FBXW5 as a substrate receptor that links a specific substrate to a cullin-RING ligase, identifying TSC2 as its first target and connecting it to mTOR-pathway growth control.\",\n      \"evidence\": \"Reciprocal Co-IP, in vivo ubiquitination, and Drosophila genetic epistasis (Ddb1/Cul4 vs Gigas/Tsc2)\",\n      \"pmids\": [\"18381890\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether FBXW5 also functions in SCF (CUL1) complexes\", \"Direct ubiquitination of TSC2 by reconstituted ligase not shown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended FBXW5 beyond degradation by showing it associates with TAK1 in an IL-1\\u03b2-dependent manner and negatively regulates inflammatory MAPK/NF-\\u03baB signaling.\",\n      \"evidence\": \"TAP-MS in HeLa, Co-IP, and gain/loss-of-function with kinase and pathway readouts\",\n      \"pmids\": [\"19232515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether regulation is ubiquitin-dependent was not established\", \"Single lab; no in vitro reconstitution\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined FBXW5 as the SCF substrate receptor for HsSAS-6 controlling centrosome copy number, and revealed two layers of regulation: PLK4 phosphorylation inhibiting its activity and APC/C degradation restricting its abundance to G1/S.\",\n      \"evidence\": \"Co-IP, in vivo ubiquitination, centrosome counting, phospho-site mutagenesis, cell-cycle staging\",\n      \"pmids\": [\"21725316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of HsSAS-6 recognition not resolved\", \"Interplay between SCF and CRL4 usage not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed FBXW5 can promote sumoylation rather than ubiquitination of a substrate (c-Myb), broadening its biochemical repertoire and adding a transcriptional output.\",\n      \"evidence\": \"Co-IP, sumoylation assays, reporter assays, immunofluorescence\",\n      \"pmids\": [\"22910413\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FBXW5 enhances SUMO conjugation unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified DLC1 as a CRL4A-FBXW5 substrate, linking FBXW5 to RhoA-GTP signaling and tumor suppressor turnover in lung cancer.\",\n      \"evidence\": \"siRNA knockdown, Co-IP, in vivo ubiquitination, RhoA-GTP pulldown in NSCLC cells\",\n      \"pmids\": [\"24082123\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of DLC1 ubiquitination\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed competitive regulation of FBXW5 substrate selection, with Tnfaip8l1/Oxi-\\u03b2 displacing TSC2 to stabilize it and tune mTOR/autophagy under oxidative stress.\",\n      \"evidence\": \"Co-IP, competition binding, ubiquitination assay, siRNA, autophagy markers in dopaminergic neurons\",\n      \"pmids\": [\"24444419\", \"24372178\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding site on FBXW5 not mapped\", \"Same-lab replication only\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected FBXW5 to autophagy regulation by identifying SEC23B as a degradation target whose stabilization upon ULK1 phosphorylation reroutes COPII to drive autophagosome biogenesis.\",\n      \"evidence\": \"Co-IP, in vivo ubiquitination, phospho-mapping, ULK1 kinase assay, flux assays, imaging\",\n      \"pmids\": [\"30596474\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which cullin scaffold mediates SEC23B degradation not specified\", \"Single rigorous study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the most direct biochemical proof of FBXW5 ligase activity by reconstituting SCF-FBXW5-mediated polyubiquitylation of kinesin-13 proteins in vitro, and tied this to ciliogenesis control in G0/G1.\",\n      \"evidence\": \"Protein microarray, in vitro ubiquitination reconstitution with neddylated SCF and Cdc34, siRNA, ciliogenesis rescue\",\n      \"pmids\": [\"34368969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recognition determinants on MCAK/Kif2a/Kif2b not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated in vivo physiological relevance of FBXW5-TAK1 antagonism by showing FBXW5 knockout aggravates and overexpression protects against pressure-overload cardiac hypertrophy.\",\n      \"evidence\": \"Co-IP, FBXW5 knockout mice, AAV9 overexpression, pressure-overload model, TAK1 inhibitor epistasis\",\n      \"pmids\": [\"32971071\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FBXW5 ubiquitinates TAK1 not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked FBXW5 to Hippo pathway control by showing it binds the LATS1/2 PPxY motif and degrades these kinases to activate YAP1, driving gastric cancer invasion and chemoresistance.\",\n      \"evidence\": \"Co-IP, in vivo ubiquitination, siRNA/overexpression, mouse xenograft, LATS1-YAP1 rescue\",\n      \"pmids\": [\"35210431\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which ligase scaffold is used not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added AQP3 as an SCF-FBXW5 substrate and traced a degradation cascade through PDPK1 to AKT-mTOR inactivation and autophagic cell death in hepatocellular carcinoma.\",\n      \"evidence\": \"Co-IP, in vivo ubiquitination, siRNA, lysosomal inhibition, autophagy assays\",\n      \"pmids\": [\"38726865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination not reconstituted in vitro\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated FBXW5 in EMT by showing it degrades the transcriptional repressor KLF13, relieving repression of TROAP in lung adenocarcinoma.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, ChIP, dual luciferase, siRNA, xenograft\",\n      \"pmids\": [\"40696794\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligase scaffold not defined\", \"Single recent study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how FBXW5 selects between SCF (CUL1) and CRL4 (CUL4) scaffolds for different substrates, and whether its non-degradative outputs (sumoylation enhancement, TAK1 inhibition) share a common biochemical basis.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of FBXW5-substrate or FBXW5-cullin assembly\", \"Scaffold choice rules across the substrate set undefined\", \"Mechanism of sumoylation enhancement and TAK1 antagonism not biochemically dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 7, 8, 9, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"SCF (SKP1-CUL1-FBXW5)\",\n      \"CRL4 (DDB1-CUL4-ROC1)\"\n    ],\n    \"partners\": [\n      \"TSC2\",\n      \"HsSAS-6\",\n      \"SEC23B\",\n      \"DLC1\",\n      \"LATS1/2\",\n      \"MCAK\",\n      \"TAK1\",\n      \"DDB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}