{"gene":"FBXL7","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2012,"finding":"FBXL7 (as SCFFBXL7 E3 ligase complex) mediates polyubiquitination and proteasomal degradation of Aurora A kinase, causing G2/M arrest, tetraploidy, and monopolar/multipolar spindle formation. FBXL7 co-localizes with Aurora A at the centrosome during mitosis and interacts with Aurora A specifically during mitosis but not interphase.","method":"Co-immunoprecipitation, ectopic overexpression, cell cycle analysis (flow cytometry), immunofluorescence co-localization, ubiquitination assay","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal Co-IP and cell-based ubiquitination assay, single lab, no in vitro reconstitution","pmids":["22306998"],"is_preprint":false},{"year":2015,"finding":"FBXL7 mediates polyubiquitylation and proteasomal degradation of survivin by interacting with Glu-126 within survivin's C-terminal α-helix, with Lys-90 and Lys-91 serving as ubiquitin acceptor sites. This degradation impairs mitochondrial function, and survivin mutants (E126A or KK90RR/KK91RR) that resist FBXL7-mediated ubiquitylation protect mitochondria from FBXL7-induced damage.","method":"Co-immunoprecipitation, ubiquitylation assay, site-directed mutagenesis, mitochondrial function assay (CCCP treatment), ectopic overexpression and depletion","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis identifying specific interaction and ubiquitin acceptor residues, multiple orthogonal methods, functional rescue experiment","pmids":["25778398"],"is_preprint":false},{"year":2015,"finding":"Fbxl18 (another F-box protein) targets FBXL7 for polyubiquitylation and proteasomal degradation, with Lys-109 of FBXL7 as the ubiquitin acceptor site and an FQ motif within FBXL7 as the molecular recognition site for Fbxl18 binding. Fbxl18 thereby limits Fbxl7-induced apoptosis.","method":"Co-immunoprecipitation, ubiquitylation assay, site-directed mutagenesis, apoptosis assay, ectopic overexpression and depletion","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis identifying specific ubiquitin acceptor and interaction motif, functional rescue of apoptosis, multiple orthogonal methods","pmids":["25654763"],"is_preprint":false},{"year":2014,"finding":"Drosophila Fbxl7 binds to a specific region of the intracellular domain (ICD) of the protocadherin Fat, co-localizes with Fat at the proximal edge of cells, and regulates the levels and asymmetric localization of the atypical myosin Dachs at the apical membrane, thereby controlling Hippo signaling and tissue growth. Fbxl7 also regulates trafficking of proteins between the apical membrane and intracellular vesicles.","method":"Genetic loss-of-function (mutations), protein interaction assays, immunofluorescence co-localization, tissue overgrowth phenotype analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis, protein binding, co-localization, and functional phenotype, replicated across two independent labs same year","pmids":["25107277"],"is_preprint":false},{"year":2014,"finding":"Drosophila FbxL7 localizes to the plasma membrane in a Fat-dependent manner and is planar polarized; it controls the level and localization of Dachs (restricting it to the distal side) and also influences Dachsous levels, acting downstream of Fat to regulate tissue size via the Hippo pathway and tissue shape.","method":"GFP-tagging and live imaging, genetic loss-of-function and overexpression, immunofluorescence","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiment with functional consequence, genetic epistasis, corroborated by independent lab (PMID:25107277)","pmids":["25256343"],"is_preprint":false},{"year":2020,"finding":"FBXL7 mediates ubiquitylation and proteasomal degradation of active c-SRC after c-SRC is phosphorylated at Ser-104. Epigenetic silencing of FBXL7 by promoter hypermethylation leads to c-SRC accumulation, promoting epithelial-to-mesenchymal transition and metastasis. Restoration of FBXL7 expression (by decitabine) or c-SRC inhibition (dasatinib) prevents metastasis in vivo.","method":"Co-immunoprecipitation, ubiquitylation assay, promoter methylation analysis, in vivo xenograft metastasis models, pharmacological rescue (decitabine, dasatinib), siRNA knockdown","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including in vivo rescue, phospho-specific substrate requirement identified, strong mechanistic follow-up","pmids":["32839549"],"is_preprint":false},{"year":2023,"finding":"FBXL7 ubiquitinates and promotes proteasomal degradation of PFKFB4, suppressing glucose metabolism in non-small cell lung cancer. Under hypoxia, HIF-1α upregulates EZH2, which epigenetically represses FBXL7 transcription, leading to PFKFB4 stabilization and enhanced glycolysis. EZH2 knockdown impedes tumor growth through the FBXL7/PFKFB4 axis.","method":"Tandem affinity purification/mass spectrometry (substrate identification), ubiquitination assay, siRNA knockdown, EZH2 inhibition, in vivo tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — TAP/MS for substrate identification plus functional validation, single lab","pmids":["37179372"],"is_preprint":false},{"year":2025,"finding":"PSME3 enhances binding between PTEN and FBXL7, promoting FBXL7-mediated ubiquitination and degradation of PTEN, thereby enhancing glycolysis and supporting Treg infiltration in hepatocellular carcinoma.","method":"Co-immunoprecipitation, ubiquitination assay, functional in vivo and in vitro experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and ubiquitination assay, single lab, novel finding with functional consequence","pmids":["41094239"],"is_preprint":false},{"year":2019,"finding":"Biallelic loss-of-function of FBXL7 (homozygous deletion of exon 3, encoding the F-box domain and leucine-rich repeats) is associated with a Hennekam syndrome phenotype, placing FBXL7 in the same pathway as FAT4 (human ortholog of Drosophila Fat) consistent with the Drosophila Fbxl7-Fat interaction.","method":"Genomic sequencing, copy-number analysis, database analysis of control individuals, genetic pathway inference from Drosophila orthologs","journal":"American journal of medical genetics. Part A","confidence":"Low","confidence_rationale":"Tier 3-4 — genetic association with pathway inference from model organism; no direct biochemical validation of mechanism in humans","pmids":["31633297"],"is_preprint":false}],"current_model":"FBXL7 is a substrate-recognition subunit of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex that targets multiple substrates—including Aurora A, survivin, c-SRC (phospho-Ser104), PFKFB4, and PTEN—for polyubiquitylation and proteasomal degradation, thereby regulating mitotic progression, apoptosis, epithelial-to-mesenchymal transition, and glucose metabolism; in Drosophila, the ortholog controls Hippo pathway signaling by acting downstream of the protocadherin Fat to regulate Dachs localization at the apical membrane, and FBXL7 abundance is itself controlled by Fbxl18-mediated ubiquitylation and by epigenetic (promoter methylation) or upstream transcriptional (EZH2) regulation."},"narrative":{"teleology":[{"year":2012,"claim":"Establishing that FBXL7 functions as an SCF-type E3 ligase subunit resolved its molecular activity: it polyubiquitylates Aurora A at centrosomes during mitosis, causing G2/M arrest and spindle defects, thereby linking FBXL7 to cell division control.","evidence":"Co-immunoprecipitation, cell-based ubiquitination assay, flow cytometry, and immunofluorescence in human cell lines","pmids":["22306998"],"confidence":"Medium","gaps":["No in vitro reconstituted ubiquitylation assay for Aurora A","Physiological relevance of FBXL7-Aurora A axis not tested in vivo","Degron or phosphodegron on Aurora A recognized by FBXL7 not mapped"]},{"year":2014,"claim":"Two independent Drosophila studies established that Fbxl7 acts downstream of the protocadherin Fat, localizing to the apical membrane in a Fat-dependent and planar-polarized manner to restrict Dachs levels and asymmetric localization, thus controlling Hippo pathway signaling and tissue growth.","evidence":"Genetic loss-of-function, GFP live imaging, protein interaction assays, immunofluorescence, and tissue overgrowth phenotype analysis in Drosophila wing discs","pmids":["25107277","25256343"],"confidence":"High","gaps":["Whether Fbxl7 directly ubiquitylates Dachs or acts through an intermediate mechanism is unresolved","Conservation of Fat-Fbxl7-Dachs axis in mammalian Hippo signaling not demonstrated biochemically"]},{"year":2015,"claim":"Identification of survivin as an FBXL7 substrate, with specific interaction (Glu-126) and ubiquitin-acceptor (Lys-90/91) residues mapped, established that FBXL7-mediated degradation impairs mitochondrial function and linked FBXL7 to apoptosis regulation beyond its mitotic role.","evidence":"Co-IP, ubiquitylation assay, site-directed mutagenesis with functional rescue using ubiquitylation-resistant survivin mutants","pmids":["25778398"],"confidence":"High","gaps":["In vivo significance of survivin degradation by FBXL7 not tested in animal models","Whether survivin degradation is cell-cycle dependent is not established"]},{"year":2015,"claim":"Discovery that Fbxl18 ubiquitylates FBXL7 at Lys-109 via recognition of an FQ motif revealed a hierarchical regulatory mechanism controlling FBXL7 protein abundance and its pro-apoptotic output.","evidence":"Co-IP, ubiquitylation assay, mutagenesis of degron and acceptor lysine, apoptosis rescue upon depletion of Fbxl18","pmids":["25654763"],"confidence":"High","gaps":["Signals that regulate the Fbxl18-FBXL7 axis (e.g., upstream kinases) are unknown","Whether other E3 ligases also target FBXL7 is unexplored"]},{"year":2019,"claim":"A human genetic finding linked biallelic FBXL7 loss-of-function (exon 3 deletion removing the F-box and LRR domains) to Hennekam syndrome, placing FBXL7 in the FAT4 pathway in humans and providing clinical relevance for the Drosophila Fat-Fbxl7 connection.","evidence":"Genomic sequencing and copy-number analysis in a patient with Hennekam syndrome phenotype, pathway inference from Drosophila ortholog data","pmids":["31633297"],"confidence":"Low","gaps":["Single family report without functional rescue or biochemical validation in human cells","Mechanism linking FBXL7 loss to lymphatic/developmental features of Hennekam syndrome not elucidated","Not independently replicated in additional kindreds"]},{"year":2020,"claim":"Identification of phospho-Ser104 c-SRC as an FBXL7 substrate demonstrated that FBXL7 acts as a tumor suppressor by degrading active c-SRC, and that epigenetic silencing of FBXL7 by promoter hypermethylation drives EMT and metastasis — a mechanism reversible by decitabine in vivo.","evidence":"Co-IP, ubiquitylation assay, promoter methylation analysis, in vivo xenograft metastasis models with pharmacological rescue (decitabine, dasatinib)","pmids":["32839549"],"confidence":"High","gaps":["Structural basis for phospho-Ser104-dependent recognition by FBXL7 is unknown","Whether FBXL7 silencing is a general feature across cancer types beyond those tested is unclear"]},{"year":2023,"claim":"Discovery that FBXL7 ubiquitylates the glycolytic regulator PFKFB4, and that hypoxia-driven EZH2 epigenetically represses FBXL7 to stabilize PFKFB4 and enhance glycolysis, extended FBXL7's tumor-suppressive role to metabolic reprogramming in lung cancer.","evidence":"TAP/mass spectrometry substrate identification, ubiquitination assay, EZH2 knockdown, in vivo tumor models in NSCLC","pmids":["37179372"],"confidence":"Medium","gaps":["Degron on PFKFB4 recognized by FBXL7 not mapped","Single-lab finding; independent confirmation pending","Whether FBXL7-PFKFB4 axis operates in normal metabolism or only in cancer is unknown"]},{"year":2025,"claim":"Identification of PTEN as an FBXL7 substrate whose degradation is enhanced by the proteasome activator PSME3 revealed a mechanism by which FBXL7 promotes glycolysis and Treg infiltration in hepatocellular carcinoma, adding an immunometabolic dimension to FBXL7 function.","evidence":"Co-IP, ubiquitination assay, functional in vivo and in vitro experiments in HCC models","pmids":["41094239"],"confidence":"Medium","gaps":["Single-lab finding without independent replication","How PSME3 mechanistically facilitates the FBXL7-PTEN interaction is unexplained","Apparent contradiction with tumor-suppressive roles of FBXL7 (c-SRC, PFKFB4 degradation) is not reconciled"]},{"year":null,"claim":"It remains unknown how FBXL7 discriminates among its diverse substrates in different cellular contexts, whether there is a unifying degron logic, and how its apparently contradictory pro-tumorigenic (PTEN degradation) and anti-tumorigenic (c-SRC, PFKFB4 degradation) activities are regulated in a tissue- or context-specific manner.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural data for FBXL7 or any FBXL7-substrate complex","No consensus degron motif across substrates","Context-dependent regulation of substrate selectivity is unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,5,6,7]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2,5,6,7]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,2]}],"complexes":["SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase"],"partners":["CUL1","SKP1","AURKA","BIRC5","FBXL18","SRC","PFKFB4","PTEN"],"other_free_text":[]},"mechanistic_narrative":"FBXL7 is the substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase that targets multiple proteins for polyubiquitylation and proteasomal degradation, linking ubiquitin-dependent proteolysis to mitotic control, apoptosis, epithelial integrity, and glucose metabolism. FBXL7 ubiquitylates Aurora A kinase at centrosomes during mitosis and survivin at specific lysine residues (Lys-90/91), impairing mitochondrial function; it also degrades phospho-Ser104 c-SRC to suppress epithelial-to-mesenchymal transition and metastasis, and degrades the glycolytic regulator PFKFB4 [PMID:22306998, PMID:25778398, PMID:32839549, PMID:37179372]. In Drosophila, the ortholog acts downstream of the protocadherin Fat to control planar-polarized localization of the atypical myosin Dachs at the apical membrane, thereby regulating Hippo pathway output and tissue size; biallelic loss-of-function of FBXL7 in humans is associated with Hennekam syndrome, consistent with its placement in the FAT4 signaling pathway [PMID:25107277, PMID:25256343, PMID:31633297]. FBXL7 abundance is itself regulated by Fbxl18-mediated ubiquitylation at Lys-109 and by transcriptional repression through promoter hypermethylation or EZH2-dependent epigenetic silencing under hypoxia [PMID:25654763, PMID:32839549, PMID:37179372]."},"prefetch_data":{"uniprot":{"accession":"Q9UJT9","full_name":"F-box/LRR-repeat protein 7","aliases":["F-box and leucine-rich repeat protein 7","F-box protein FBL6/FBL7"],"length_aa":491,"mass_kda":54.6,"function":"Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex (PubMed:25778398). During mitosis, it mediates the ubiquitination and subsequent proteasomal degradation of AURKA, causing mitotic arrest (By similarity). It also regulates mitochondrial function by mediating the ubiquitination and proteasomal degradation of the apoptosis inhibitor BIRC5 (PubMed:25778398, PubMed:28218735)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q9UJT9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBXL7","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/FBXL7","total_profiled":1310},"omim":[{"mim_id":"605656","title":"F-BOX AND LEUCINE-RICH REPEAT PROTEIN 7; FBXL7","url":"https://www.omim.org/entry/605656"},{"mim_id":"600185","title":"BRCA2 DNA REPAIR-ASSOCIATED PROTEIN; BRCA2","url":"https://www.omim.org/entry/600185"},{"mim_id":"235510","title":"HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME 1; HKLLS1","url":"https://www.omim.org/entry/235510"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FBXL7"},"hgnc":{"alias_symbol":["KIAA0840","FBL7","FBL6"],"prev_symbol":[]},"alphafold":{"accession":"Q9UJT9","domains":[{"cath_id":"1.20.1280","chopping":"116-153","consensus_level":"medium","plddt":94.6574,"start":116,"end":153}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJT9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJT9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJT9-F1-predicted_aligned_error_v6.png","plddt_mean":81.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBXL7","jax_strain_url":"https://www.jax.org/strain/search?query=FBXL7"},"sequence":{"accession":"Q9UJT9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UJT9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UJT9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJT9"}},"corpus_meta":[{"pmid":"25778398","id":"PMC_25778398","title":"The Proapoptotic F-box Protein Fbxl7 Regulates Mitochondrial Function by Mediating the Ubiquitylation and Proteasomal Degradation of Survivin.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25778398","citation_count":61,"is_preprint":false},{"pmid":"22306998","id":"PMC_22306998","title":"Novel E3 ligase component FBXL7 ubiquitinates and degrades Aurora A, causing mitotic arrest.","date":"2012","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/22306998","citation_count":47,"is_preprint":false},{"pmid":"32839549","id":"PMC_32839549","title":"Epigenetic silencing of the ubiquitin ligase subunit FBXL7 impairs c-SRC degradation and promotes epithelial-to-mesenchymal transition and metastasis.","date":"2020","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32839549","citation_count":39,"is_preprint":false},{"pmid":"25654763","id":"PMC_25654763","title":"F-box protein Fbxl18 mediates polyubiquitylation and proteasomal degradation of the pro-apoptotic SCF subunit Fbxl7.","date":"2015","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/25654763","citation_count":39,"is_preprint":false},{"pmid":"25107277","id":"PMC_25107277","title":"The Drosophila F-box protein Fbxl7 binds to the protocadherin fat and regulates Dachs localization and Hippo signaling.","date":"2014","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/25107277","citation_count":38,"is_preprint":false},{"pmid":"25256343","id":"PMC_25256343","title":"The ubiquitin ligase FbxL7 regulates the Dachsous-Fat-Dachs system in Drosophila.","date":"2014","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25256343","citation_count":35,"is_preprint":false},{"pmid":"35069490","id":"PMC_35069490","title":"Complete Genome Sequencing and Comparative Genomics of Three Potential Probiotic Strains, Lacticaseibacillus casei FBL6, Lacticaseibacillus chiayiensis FBL7, and Lacticaseibacillus zeae FBL8.","date":"2022","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/35069490","citation_count":26,"is_preprint":false},{"pmid":"32150671","id":"PMC_32150671","title":"miR-152-5p suppresses glioma progression and tumorigenesis and potentiates temozolomide sensitivity by targeting FBXL7.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32150671","citation_count":19,"is_preprint":false},{"pmid":"37179372","id":"PMC_37179372","title":"Hypoxia-mediated promotion of glucose metabolism in non-small cell lung cancer correlates with activation of the EZH2/FBXL7/PFKFB4 axis.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37179372","citation_count":17,"is_preprint":false},{"pmid":"31633297","id":"PMC_31633297","title":"Biallelic mutation of FBXL7 suggests a novel form of Hennekam syndrome.","date":"2019","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/31633297","citation_count":14,"is_preprint":false},{"pmid":"35906197","id":"PMC_35906197","title":"Functional characterization of FBXL7 as a novel player in human cancers.","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35906197","citation_count":7,"is_preprint":false},{"pmid":"33235922","id":"PMC_33235922","title":"Epigenetic suppression of FBXL7 promotes metastasis.","date":"2020","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33235922","citation_count":4,"is_preprint":false},{"pmid":"34427826","id":"PMC_34427826","title":"7-Ethoxyrosmanol alleviates hyperglycemia-induced vascular endothelial dysfunction by regulating FBXL7 expression.","date":"2021","source":"Journal of bioenergetics and biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/34427826","citation_count":4,"is_preprint":false},{"pmid":"37778649","id":"PMC_37778649","title":"Dexmedetomidine mitigates neuroinflammation in an Alzheimer's disease mouse model via the miR-204-3p/FBXL7 signaling axis.","date":"2023","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/37778649","citation_count":4,"is_preprint":false},{"pmid":"35887149","id":"PMC_35887149","title":"FBXL7 Body Hypomethylation Is Frequent in Tumors from the Digestive and Respiratory Tracts and Is Associated with Risk-Factor Exposure.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35887149","citation_count":2,"is_preprint":false},{"pmid":"41094239","id":"PMC_41094239","title":"PSME3 drives Tregs infiltration and anti-PD1 resistance in hepatocellular carcinoma by regulating FBXL7/PTEN-mediated metabolic reprogramming.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/41094239","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8585,"output_tokens":2477,"usd":0.031455},"stage2":{"model":"claude-opus-4-6","input_tokens":5782,"output_tokens":2867,"usd":0.150877},"total_usd":0.182332,"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\": 2012,\n      \"finding\": \"FBXL7 (as SCFFBXL7 E3 ligase complex) mediates polyubiquitination and proteasomal degradation of Aurora A kinase, causing G2/M arrest, tetraploidy, and monopolar/multipolar spindle formation. FBXL7 co-localizes with Aurora A at the centrosome during mitosis and interacts with Aurora A specifically during mitosis but not interphase.\",\n      \"method\": \"Co-immunoprecipitation, ectopic overexpression, cell cycle analysis (flow cytometry), immunofluorescence co-localization, ubiquitination assay\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal Co-IP and cell-based ubiquitination assay, single lab, no in vitro reconstitution\",\n      \"pmids\": [\"22306998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FBXL7 mediates polyubiquitylation and proteasomal degradation of survivin by interacting with Glu-126 within survivin's C-terminal α-helix, with Lys-90 and Lys-91 serving as ubiquitin acceptor sites. This degradation impairs mitochondrial function, and survivin mutants (E126A or KK90RR/KK91RR) that resist FBXL7-mediated ubiquitylation protect mitochondria from FBXL7-induced damage.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assay, site-directed mutagenesis, mitochondrial function assay (CCCP treatment), ectopic overexpression and depletion\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis identifying specific interaction and ubiquitin acceptor residues, multiple orthogonal methods, functional rescue experiment\",\n      \"pmids\": [\"25778398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Fbxl18 (another F-box protein) targets FBXL7 for polyubiquitylation and proteasomal degradation, with Lys-109 of FBXL7 as the ubiquitin acceptor site and an FQ motif within FBXL7 as the molecular recognition site for Fbxl18 binding. Fbxl18 thereby limits Fbxl7-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assay, site-directed mutagenesis, apoptosis assay, ectopic overexpression and depletion\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis identifying specific ubiquitin acceptor and interaction motif, functional rescue of apoptosis, multiple orthogonal methods\",\n      \"pmids\": [\"25654763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Drosophila Fbxl7 binds to a specific region of the intracellular domain (ICD) of the protocadherin Fat, co-localizes with Fat at the proximal edge of cells, and regulates the levels and asymmetric localization of the atypical myosin Dachs at the apical membrane, thereby controlling Hippo signaling and tissue growth. Fbxl7 also regulates trafficking of proteins between the apical membrane and intracellular vesicles.\",\n      \"method\": \"Genetic loss-of-function (mutations), protein interaction assays, immunofluorescence co-localization, tissue overgrowth phenotype analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis, protein binding, co-localization, and functional phenotype, replicated across two independent labs same year\",\n      \"pmids\": [\"25107277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Drosophila FbxL7 localizes to the plasma membrane in a Fat-dependent manner and is planar polarized; it controls the level and localization of Dachs (restricting it to the distal side) and also influences Dachsous levels, acting downstream of Fat to regulate tissue size via the Hippo pathway and tissue shape.\",\n      \"method\": \"GFP-tagging and live imaging, genetic loss-of-function and overexpression, immunofluorescence\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional consequence, genetic epistasis, corroborated by independent lab (PMID:25107277)\",\n      \"pmids\": [\"25256343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FBXL7 mediates ubiquitylation and proteasomal degradation of active c-SRC after c-SRC is phosphorylated at Ser-104. Epigenetic silencing of FBXL7 by promoter hypermethylation leads to c-SRC accumulation, promoting epithelial-to-mesenchymal transition and metastasis. Restoration of FBXL7 expression (by decitabine) or c-SRC inhibition (dasatinib) prevents metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assay, promoter methylation analysis, in vivo xenograft metastasis models, pharmacological rescue (decitabine, dasatinib), siRNA knockdown\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including in vivo rescue, phospho-specific substrate requirement identified, strong mechanistic follow-up\",\n      \"pmids\": [\"32839549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXL7 ubiquitinates and promotes proteasomal degradation of PFKFB4, suppressing glucose metabolism in non-small cell lung cancer. Under hypoxia, HIF-1α upregulates EZH2, which epigenetically represses FBXL7 transcription, leading to PFKFB4 stabilization and enhanced glycolysis. EZH2 knockdown impedes tumor growth through the FBXL7/PFKFB4 axis.\",\n      \"method\": \"Tandem affinity purification/mass spectrometry (substrate identification), ubiquitination assay, siRNA knockdown, EZH2 inhibition, in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — TAP/MS for substrate identification plus functional validation, single lab\",\n      \"pmids\": [\"37179372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PSME3 enhances binding between PTEN and FBXL7, promoting FBXL7-mediated ubiquitination and degradation of PTEN, thereby enhancing glycolysis and supporting Treg infiltration in hepatocellular carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, functional in vivo and in vitro experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and ubiquitination assay, single lab, novel finding with functional consequence\",\n      \"pmids\": [\"41094239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Biallelic loss-of-function of FBXL7 (homozygous deletion of exon 3, encoding the F-box domain and leucine-rich repeats) is associated with a Hennekam syndrome phenotype, placing FBXL7 in the same pathway as FAT4 (human ortholog of Drosophila Fat) consistent with the Drosophila Fbxl7-Fat interaction.\",\n      \"method\": \"Genomic sequencing, copy-number analysis, database analysis of control individuals, genetic pathway inference from Drosophila orthologs\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3-4 — genetic association with pathway inference from model organism; no direct biochemical validation of mechanism in humans\",\n      \"pmids\": [\"31633297\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXL7 is a substrate-recognition subunit of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex that targets multiple substrates—including Aurora A, survivin, c-SRC (phospho-Ser104), PFKFB4, and PTEN—for polyubiquitylation and proteasomal degradation, thereby regulating mitotic progression, apoptosis, epithelial-to-mesenchymal transition, and glucose metabolism; in Drosophila, the ortholog controls Hippo pathway signaling by acting downstream of the protocadherin Fat to regulate Dachs localization at the apical membrane, and FBXL7 abundance is itself controlled by Fbxl18-mediated ubiquitylation and by epigenetic (promoter methylation) or upstream transcriptional (EZH2) regulation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FBXL7 is the substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase that targets multiple proteins for polyubiquitylation and proteasomal degradation, linking ubiquitin-dependent proteolysis to mitotic control, apoptosis, epithelial integrity, and glucose metabolism. FBXL7 ubiquitylates Aurora A kinase at centrosomes during mitosis and survivin at specific lysine residues (Lys-90/91), impairing mitochondrial function; it also degrades phospho-Ser104 c-SRC to suppress epithelial-to-mesenchymal transition and metastasis, and degrades the glycolytic regulator PFKFB4 [PMID:22306998, PMID:25778398, PMID:32839549, PMID:37179372]. In Drosophila, the ortholog acts downstream of the protocadherin Fat to control planar-polarized localization of the atypical myosin Dachs at the apical membrane, thereby regulating Hippo pathway output and tissue size; biallelic loss-of-function of FBXL7 in humans is associated with Hennekam syndrome, consistent with its placement in the FAT4 signaling pathway [PMID:25107277, PMID:25256343, PMID:31633297]. FBXL7 abundance is itself regulated by Fbxl18-mediated ubiquitylation at Lys-109 and by transcriptional repression through promoter hypermethylation or EZH2-dependent epigenetic silencing under hypoxia [PMID:25654763, PMID:32839549, PMID:37179372].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing that FBXL7 functions as an SCF-type E3 ligase subunit resolved its molecular activity: it polyubiquitylates Aurora A at centrosomes during mitosis, causing G2/M arrest and spindle defects, thereby linking FBXL7 to cell division control.\",\n      \"evidence\": \"Co-immunoprecipitation, cell-based ubiquitination assay, flow cytometry, and immunofluorescence in human cell lines\",\n      \"pmids\": [\"22306998\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro reconstituted ubiquitylation assay for Aurora A\",\n        \"Physiological relevance of FBXL7-Aurora A axis not tested in vivo\",\n        \"Degron or phosphodegron on Aurora A recognized by FBXL7 not mapped\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Two independent Drosophila studies established that Fbxl7 acts downstream of the protocadherin Fat, localizing to the apical membrane in a Fat-dependent and planar-polarized manner to restrict Dachs levels and asymmetric localization, thus controlling Hippo pathway signaling and tissue growth.\",\n      \"evidence\": \"Genetic loss-of-function, GFP live imaging, protein interaction assays, immunofluorescence, and tissue overgrowth phenotype analysis in Drosophila wing discs\",\n      \"pmids\": [\"25107277\", \"25256343\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Fbxl7 directly ubiquitylates Dachs or acts through an intermediate mechanism is unresolved\",\n        \"Conservation of Fat-Fbxl7-Dachs axis in mammalian Hippo signaling not demonstrated biochemically\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of survivin as an FBXL7 substrate, with specific interaction (Glu-126) and ubiquitin-acceptor (Lys-90/91) residues mapped, established that FBXL7-mediated degradation impairs mitochondrial function and linked FBXL7 to apoptosis regulation beyond its mitotic role.\",\n      \"evidence\": \"Co-IP, ubiquitylation assay, site-directed mutagenesis with functional rescue using ubiquitylation-resistant survivin mutants\",\n      \"pmids\": [\"25778398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo significance of survivin degradation by FBXL7 not tested in animal models\",\n        \"Whether survivin degradation is cell-cycle dependent is not established\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that Fbxl18 ubiquitylates FBXL7 at Lys-109 via recognition of an FQ motif revealed a hierarchical regulatory mechanism controlling FBXL7 protein abundance and its pro-apoptotic output.\",\n      \"evidence\": \"Co-IP, ubiquitylation assay, mutagenesis of degron and acceptor lysine, apoptosis rescue upon depletion of Fbxl18\",\n      \"pmids\": [\"25654763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Signals that regulate the Fbxl18-FBXL7 axis (e.g., upstream kinases) are unknown\",\n        \"Whether other E3 ligases also target FBXL7 is unexplored\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A human genetic finding linked biallelic FBXL7 loss-of-function (exon 3 deletion removing the F-box and LRR domains) to Hennekam syndrome, placing FBXL7 in the FAT4 pathway in humans and providing clinical relevance for the Drosophila Fat-Fbxl7 connection.\",\n      \"evidence\": \"Genomic sequencing and copy-number analysis in a patient with Hennekam syndrome phenotype, pathway inference from Drosophila ortholog data\",\n      \"pmids\": [\"31633297\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single family report without functional rescue or biochemical validation in human cells\",\n        \"Mechanism linking FBXL7 loss to lymphatic/developmental features of Hennekam syndrome not elucidated\",\n        \"Not independently replicated in additional kindreds\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of phospho-Ser104 c-SRC as an FBXL7 substrate demonstrated that FBXL7 acts as a tumor suppressor by degrading active c-SRC, and that epigenetic silencing of FBXL7 by promoter hypermethylation drives EMT and metastasis — a mechanism reversible by decitabine in vivo.\",\n      \"evidence\": \"Co-IP, ubiquitylation assay, promoter methylation analysis, in vivo xenograft metastasis models with pharmacological rescue (decitabine, dasatinib)\",\n      \"pmids\": [\"32839549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for phospho-Ser104-dependent recognition by FBXL7 is unknown\",\n        \"Whether FBXL7 silencing is a general feature across cancer types beyond those tested is unclear\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that FBXL7 ubiquitylates the glycolytic regulator PFKFB4, and that hypoxia-driven EZH2 epigenetically represses FBXL7 to stabilize PFKFB4 and enhance glycolysis, extended FBXL7's tumor-suppressive role to metabolic reprogramming in lung cancer.\",\n      \"evidence\": \"TAP/mass spectrometry substrate identification, ubiquitination assay, EZH2 knockdown, in vivo tumor models in NSCLC\",\n      \"pmids\": [\"37179372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Degron on PFKFB4 recognized by FBXL7 not mapped\",\n        \"Single-lab finding; independent confirmation pending\",\n        \"Whether FBXL7-PFKFB4 axis operates in normal metabolism or only in cancer is unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of PTEN as an FBXL7 substrate whose degradation is enhanced by the proteasome activator PSME3 revealed a mechanism by which FBXL7 promotes glycolysis and Treg infiltration in hepatocellular carcinoma, adding an immunometabolic dimension to FBXL7 function.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, functional in vivo and in vitro experiments in HCC models\",\n      \"pmids\": [\"41094239\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding without independent replication\",\n        \"How PSME3 mechanistically facilitates the FBXL7-PTEN interaction is unexplained\",\n        \"Apparent contradiction with tumor-suppressive roles of FBXL7 (c-SRC, PFKFB4 degradation) is not reconciled\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how FBXL7 discriminates among its diverse substrates in different cellular contexts, whether there is a unifying degron logic, and how its apparently contradictory pro-tumorigenic (PTEN degradation) and anti-tumorigenic (c-SRC, PFKFB4 degradation) activities are regulated in a tissue- or context-specific manner.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural data for FBXL7 or any FBXL7-substrate complex\",\n        \"No consensus degron motif across substrates\",\n        \"Context-dependent regulation of substrate selectivity is unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 5, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2, 5, 6, 7]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\n      \"SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase\"\n    ],\n    \"partners\": [\n      \"CUL1\",\n      \"SKP1\",\n      \"AURKA\",\n      \"BIRC5\",\n      \"FBXL18\",\n      \"SRC\",\n      \"PFKFB4\",\n      \"PTEN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}