{"gene":"FBXL3","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2007,"finding":"FBXL3 (F-box protein with leucine-rich repeats) is required for CRY protein degradation in the mammalian circadian clock; the Afh mutation (Cys358Ser substitution) delays CRY protein degradation and results in ~27-hour free-running circadian rhythms in homozygous mice.","method":"ENU mutagenesis screen, in vivo circadian behavioral assays, Per2::Luciferase tissue slices, in vitro degradation assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 — foundational in vivo and in vitro studies with functional mutagenesis, highly cited, replicated across labs","pmids":["17463252"],"is_preprint":false},{"year":2013,"finding":"Crystal structures of CRY2 in apo, FAD-bound, and FBXL3-SKP1-complexed forms reveal that FBXL3 captures CRY2 by inserting its conserved C-terminal tail into the FAD-binding pocket and simultaneously burying the PER-binding interface; FAD and PER proteins can compete with FBXL3 for CRY2 binding, providing a regulatory mechanism for CRY ubiquitination.","method":"X-ray crystallography, in vitro binding assays, structural mutagenesis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — crystal structures with functional validation, multiple orthogonal methods, highly cited","pmids":["23503662"],"is_preprint":false},{"year":2013,"finding":"FBXL3 regulates two circadian feedback loops: it promotes CRY ubiquitination/degradation to control E-box-driven gene expression amplitude, and it regulates Rev-Erbα:HDAC3 corepressor complex activity to control RRE-mediated transcription; deletion of Rev-erbα in Fbxl3-deficient mice rescues the long-period phenotype.","method":"Genetic interaction screen with single and double mutant mice, circadian behavioral assays, transcriptional reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple mutant combinations and multiple molecular readouts","pmids":["23471982"],"is_preprint":false},{"year":2013,"finding":"SCF(FBXL3) complex formation is substrate-dependent in vivo: Fbxl3 does not associate with Skp1 and Cul1 efficiently in cells unless its substrate CRY1 is co-expressed; a mutant Fbxl3 unable to bind CRY1 also fails to form an SCF complex, indicating CRY interaction is required for SCF(FBXL3) assembly.","method":"Co-immunoprecipitation in transfected mammalian cells, in vitro reconstitution with recombinant proteins, domain-swap analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution combined with cellular co-IP and mutant analysis showing mechanism of complex assembly","pmids":["24085301"],"is_preprint":false},{"year":2013,"finding":"Stabilization of endogenous CRY proteins by the Fbxl3(Afh) mutation lengthens circadian period in a CRY-dosage-dependent manner in the SCN; CRY1 is more potent than CRY2 as a transcriptional repressor, and the Afh mutation acts exclusively through CRYs (has no effect in CRY1/CRY2 double-knockout SCN).","method":"Genetic epistasis using Fbxl3(Afh) combined with Cry1 and Cry2 knockout mice, SCN bioluminescence recording, wheel-running behavioral assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — rigorous genetic epistasis with multiple mutant combinations and functional readouts","pmids":["23616524"],"is_preprint":false},{"year":2016,"finding":"CRY2 functions as an essential cofactor in the SCF(FBXL3) E3 ligase complex to recruit T58-phosphorylated c-MYC for ubiquitylation and degradation; CRY1 cannot substitute for CRY2 in this function, revealing substrate-specific cofactor roles for the two CRY paralogs.","method":"Co-immunoprecipitation, ubiquitination assays, protein degradation assays, siRNA knockdown, phosphomimetic mutants","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal biochemical methods establishing mechanism, highly cited","pmids":["27840026"],"is_preprint":false},{"year":2019,"finding":"Both CRY1 and CRY2 recruit the cell cycle kinase TLK2 (in a TLK2 kinase-activity-dependent manner) to SCF(FBXL3) for ubiquitination; CRY overexpression or deletion correspondingly decreases or increases TLK2 protein abundance.","method":"Affinity purification mass spectrometry, co-immunoprecipitation, genetic deletion and overexpression of CRY1/CRY2","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — AP-MS plus genetic validation, single lab","pmids":["30655559"],"is_preprint":false},{"year":2025,"finding":"YAP-TEAD mechanosensing cascade directly transcriptionally upregulates FBXL3, which then promotes CRY protein degradation, attenuating circadian clock gene oscillations in iPSC embryoid bodies under shaking culture conditions.","method":"RNA-seq, ATAC-seq, ChIP-PCR, verteporfin (YAP-TEAD inhibitor) treatment, circadian reporter assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple genomic and functional assays from single lab","pmids":["40413171"],"is_preprint":false},{"year":2025,"finding":"FBXL3 in muscle satellite cells promotes ubiquitination and degradation of TCF12, a transcription factor that activates MEF2C expression; loss of FBXL3 activates TCF12→MEF2C→myogenin axis, augmenting myogenic differentiation and muscle regeneration.","method":"Satellite cell-specific knockout (Pax7-CreER), RNA-seq, GSEA, ChIP-PCR, dual-luciferase reporter assay, co-immunoprecipitation/ubiquitination assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods including ChIP, luciferase, and genetic KO, single lab","pmids":["40755783"],"is_preprint":false},{"year":2025,"finding":"Satellite cell-specific deletion of FBXL3 in mdx mice increases myogenin expression and enhances muscle regeneration, identifying FBXL3 as a negative regulator of muscle repair; AAV-mediated FBXL3 silencing in gastrocnemius muscle also increases myogenin and muscle mass.","method":"Satellite cell-specific conditional knockout in mdx mice, AAV-mediated gene silencing, histological analysis, grip strength/endurance functional tests","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic and AAV silencing approaches with functional and histological readouts, single lab","pmids":["40554051"],"is_preprint":false},{"year":2026,"finding":"EGFR activation triggers SRC-mediated phosphorylation of FBXL3 at Y306, enabling nuclear FBXL3 to interact with GLDC and catalyze K63-linked polyubiquitination at GLDC K636; ubiquitinated GLDC recruits SMARCE1/DMAP1 to inhibit STAT1-driven MHC-I gene transcription, promoting tumor immune evasion.","method":"Co-immunoprecipitation, ubiquitination assays with K63-linkage-specific analysis, site-directed mutagenesis (Y306, K636), ChIP assays, in vivo tumor models with anti-PD-1","journal":"Cell insight","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical methods with mutagenesis and in vivo validation, single lab, not yet replicated","pmids":["41728086"],"is_preprint":false}],"current_model":"FBXL3 is the substrate-recognition subunit of the SCF(FBXL3) E3 ubiquitin ligase complex that binds CRY1/2 via their FAD-binding pocket (competing with FAD and PER proteins) to drive K48-linked ubiquitination and proteasomal degradation of CRYs, thereby controlling circadian period; CRY proteins additionally serve as substrate-recruiting cofactors for FBXL3 to ubiquitinate non-clock targets including c-MYC (via CRY2) and TLK2, and FBXL3 also ubiquitinates TCF12 in muscle satellite cells and GLDC (following SRC-mediated Y306 phosphorylation) in tumor cells to regulate myogenesis and MHC-I-mediated immune evasion, respectively."},"narrative":{"teleology":[{"year":2007,"claim":"The identification of FBXL3 as the F-box protein responsible for CRY degradation established the first molecular link between targeted proteolysis and circadian period determination in mammals.","evidence":"ENU mutagenesis screen yielding Afh (C358S) mice with ~27-h periods, combined with CRY degradation assays in vivo and in vitro","pmids":["17463252"],"confidence":"High","gaps":["Structural basis for FBXL3–CRY recognition unknown","Whether FBXL3 directly binds CRY or acts through intermediaries not resolved","Role of individual CRY paralogs in period determination unclear"]},{"year":2013,"claim":"Crystal structures of the FBXL3–SKP1–CRY2 complex resolved how FBXL3 recognizes CRY via FAD-pocket insertion and PER-interface burial, revealing a competitive regulatory mechanism where FAD and PER antagonize CRY ubiquitination.","evidence":"X-ray crystallography of apo CRY2, FAD-bound CRY2, and FBXL3–SKP1–CRY2 ternary complex with functional mutagenesis","pmids":["23503662"],"confidence":"High","gaps":["Whether FAD/PER competition operates quantitatively in vivo not shown","Structural basis for CRY1 versus CRY2 specificity differences unknown"]},{"year":2013,"claim":"Genetic epistasis studies demonstrated that FBXL3 controls circadian period exclusively through CRY proteins and also regulates a second feedback loop involving Rev-Erbα:HDAC3, while revealing CRY-dosage-dependent and paralog-specific contributions to period setting.","evidence":"Combinatorial Fbxl3(Afh) × Cry1-KO, Cry2-KO, Cry1/2-DKO, and Rev-erbα-KO mice with behavioral and SCN bioluminescence assays","pmids":["23471982","23616524"],"confidence":"High","gaps":["Whether FBXL3 directly targets Rev-Erbα or acts indirectly via CRY not distinguished","Mechanism of CRY1 versus CRY2 differential repressor potency unclear"]},{"year":2013,"claim":"The discovery that SCF(FBXL3) complex assembly requires CRY substrate binding revealed an unusual substrate-dependent activation mechanism for this E3 ligase.","evidence":"Co-immunoprecipitation and in vitro reconstitution showing FBXL3 fails to associate with SKP1/CUL1 without CRY1; CRY-binding-deficient FBXL3 mutant also fails to form SCF complex","pmids":["24085301"],"confidence":"High","gaps":["Whether substrate-dependent assembly is unique to FBXL3 or shared among FBXL family members unknown","Structural mechanism of how CRY binding promotes SKP1/CUL1 recruitment not resolved"]},{"year":2016,"claim":"Showing that CRY2 (but not CRY1) recruits phospho-T58 c-MYC to SCF(FBXL3) for ubiquitination expanded the function of CRY proteins from clock substrates to substrate-recruiting cofactors with paralog-specific target selectivity.","evidence":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, and phosphomimetic mutant analysis in mammalian cells","pmids":["27840026"],"confidence":"High","gaps":["Structural basis for CRY2 specificity in c-MYC recruitment unknown","Full scope of CRY-dependent non-clock substrates not mapped"]},{"year":2019,"claim":"Identification of TLK2 as a second CRY-dependent substrate of SCF(FBXL3) demonstrated that the cofactor-mediated targeting mechanism generalizes beyond c-MYC.","evidence":"Affinity purification mass spectrometry, co-IP, and genetic overexpression/deletion of CRY1/CRY2","pmids":["30655559"],"confidence":"Medium","gaps":["Ubiquitin chain linkage type on TLK2 not characterized","Physiological consequences of TLK2 regulation by FBXL3 not tested in vivo","Single-lab finding awaiting independent replication"]},{"year":2025,"claim":"Discovery that YAP-TEAD signaling transcriptionally upregulates FBXL3 to accelerate CRY degradation provided the first upstream regulatory axis linking mechanotransduction to circadian clock attenuation.","evidence":"RNA-seq, ATAC-seq, ChIP-PCR, and YAP-TEAD inhibitor treatment in iPSC embryoid bodies","pmids":["40413171"],"confidence":"Medium","gaps":["Whether YAP-TEAD regulation of FBXL3 operates in adult SCN or peripheral tissues not tested","Direct versus indirect TEAD binding to FBXL3 promoter not fully resolved"]},{"year":2025,"claim":"Identification of TCF12 as a CRY-independent FBXL3 substrate in muscle satellite cells established FBXL3 as a negative regulator of myogenic differentiation, with in vivo loss-of-function enhancing muscle regeneration in dystrophic mice.","evidence":"Satellite cell-specific Fbxl3 knockout (Pax7-CreER), ubiquitination assays, ChIP-PCR, and AAV-mediated silencing in mdx mice","pmids":["40755783","40554051"],"confidence":"Medium","gaps":["Whether TCF12 ubiquitination is K48-linked and proteasomally degraded not explicitly shown","Contribution of circadian CRY regulation versus TCF12 regulation to muscle phenotype not separated","Single-lab finding in one disease model"]},{"year":2026,"claim":"Demonstration that EGFR/SRC-mediated Y306 phosphorylation of FBXL3 enables K63-linked ubiquitination of nuclear GLDC to suppress MHC-I transcription revealed a non-degradative ubiquitin signaling function for FBXL3 in tumor immune evasion.","evidence":"Co-IP, K63-linkage-specific ubiquitination assays, site-directed mutagenesis, ChIP assays, and in vivo tumor models with anti-PD-1","pmids":["41728086"],"confidence":"Medium","gaps":["Whether CRY proteins are involved in GLDC recruitment not addressed","K63-linked activity represents a new chain-type specificity for SCF(FBXL3) not reconciled with canonical K48-linked activity","Single-lab finding awaiting independent validation"]},{"year":null,"claim":"The full repertoire of FBXL3 substrates, the structural basis for CRY paralog-specific cofactor activity, and how FBXL3 switches between K48- and K63-linked ubiquitination remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["Comprehensive substrate profiling (e.g., ubiquitin-remnant proteomics in FBXL3-depleted cells) not performed","No structural comparison of CRY1 vs CRY2 cofactor complexes with non-clock substrates","Mechanism governing ubiquitin chain-type specificity (K48 vs K63) unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,5,6,8,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,3,5,6,8,10]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[0,2,4,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10]}],"complexes":["SCF(FBXL3)"],"partners":["CRY1","CRY2","SKP1","CUL1","TCF12","GLDC","MYC","TLK2"],"other_free_text":[]},"mechanistic_narrative":"FBXL3 is the substrate-recognition subunit of the SCF(FBXL3) E3 ubiquitin ligase complex and a central regulator of mammalian circadian period, acting primarily through ubiquitin-dependent degradation of CRY1 and CRY2 transcriptional repressors. Structural studies show that FBXL3 captures CRY2 by inserting its C-terminal tail into the FAD-binding pocket while occluding the PER-binding interface, with FAD and PER proteins competing for CRY binding to gate ubiquitination; SCF(FBXL3) complex assembly itself is substrate-dependent, requiring CRY interaction for efficient SKP1–CUL1 recruitment [PMID:23503662, PMID:24085301]. Beyond the clock, CRY proteins serve as substrate-recruiting cofactors that direct FBXL3-mediated ubiquitination toward non-clock targets: CRY2 specifically recruits phospho-T58 c-MYC for degradation, and both CRYs recruit the kinase TLK2 [PMID:27840026, PMID:30655559]. FBXL3 also ubiquitinates CRY-independent substrates including TCF12 in muscle satellite cells to restrain myogenic differentiation, and GLDC in tumor cells—following SRC-mediated Y306 phosphorylation of FBXL3—to promote K63-linked ubiquitination that suppresses MHC-I transcription and facilitates immune evasion [PMID:40755783, PMID:41728086]."},"prefetch_data":{"uniprot":{"accession":"Q9UKT7","full_name":"F-box/LRR-repeat protein 3","aliases":["F-box and leucine-rich repeat protein 3A","F-box/LRR-repeat protein 3A"],"length_aa":428,"mass_kda":48.7,"function":"Substrate-recognition component of the SCF(FBXL3) E3 ubiquitin ligase complex involved in circadian rhythm function. Plays a key role in the maintenance of both the speed and the robustness of the circadian clock oscillation (PubMed:17463251, PubMed:23452855, PubMed:27565346). The SCF(FBXL3) complex mainly acts in the nucleus and mediates ubiquitination and subsequent degradation of CRY1 and CRY2 (PubMed:17463251, PubMed:23452855, PubMed:27565346). Activity of the SCF(FBXL3) complex is counteracted by the SCF(FBXL21) complex (PubMed:23452855)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9UKT7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBXL3","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FBXL3","total_profiled":1310},"omim":[{"mim_id":"609087","title":"F-BOX AND LEUCINE-RICH REPEAT PROTEIN 21; FBXL21","url":"https://www.omim.org/entry/609087"},{"mim_id":"606220","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH SHORT STATURE, FACIAL ANOMALIES, AND SPEECH DEFECTS; IDDSFAS","url":"https://www.omim.org/entry/606220"},{"mim_id":"605653","title":"F-BOX AND LEUCINE-RICH REPEAT PROTEIN 3; FBXL3","url":"https://www.omim.org/entry/605653"},{"mim_id":"603732","title":"CRYPTOCHROME 2; CRY2","url":"https://www.omim.org/entry/603732"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nuclear bodies","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FBXL3"},"hgnc":{"alias_symbol":["FBL3","FBL3A"],"prev_symbol":["FBXL3A"]},"alphafold":{"accession":"Q9UKT7","domains":[{"cath_id":"1.20.1280.50","chopping":"40-75","consensus_level":"medium","plddt":92.1947,"start":40,"end":75},{"cath_id":"3.80.10.10","chopping":"83-415","consensus_level":"medium","plddt":95.0652,"start":83,"end":415}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKT7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKT7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKT7-F1-predicted_aligned_error_v6.png","plddt_mean":90.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBXL3","jax_strain_url":"https://www.jax.org/strain/search?query=FBXL3"},"sequence":{"accession":"Q9UKT7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKT7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKT7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKT7"}},"corpus_meta":[{"pmid":"17463252","id":"PMC_17463252","title":"The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period.","date":"2007","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/17463252","citation_count":387,"is_preprint":false},{"pmid":"23503662","id":"PMC_23503662","title":"SCF(FBXL3) ubiquitin ligase targets cryptochromes at their cofactor pocket.","date":"2013","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23503662","citation_count":192,"is_preprint":false},{"pmid":"27840026","id":"PMC_27840026","title":"CRY2 and FBXL3 Cooperatively Degrade c-MYC.","date":"2016","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/27840026","citation_count":168,"is_preprint":false},{"pmid":"8892898","id":"PMC_8892898","title":"Identification of a gag-encoded cytotoxic T-lymphocyte epitope from FBL-3 leukemia shared by Friend, Moloney, and Rauscher murine leukemia virus-induced tumors.","date":"1996","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/8892898","citation_count":112,"is_preprint":false},{"pmid":"28749470","id":"PMC_28749470","title":"miR-181d and c-myc-mediated inhibition of CRY2 and FBXL3 reprograms metabolism in colorectal cancer.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/28749470","citation_count":63,"is_preprint":false},{"pmid":"7687300","id":"PMC_7687300","title":"Multiplicity of virus-encoded helper T-cell epitopes expressed on FBL-3 tumor cells.","date":"1993","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/7687300","citation_count":56,"is_preprint":false},{"pmid":"23616524","id":"PMC_23616524","title":"Distinct and separable roles for endogenous CRY1 and CRY2 within the circadian molecular clockwork of the suprachiasmatic nucleus, as revealed by the Fbxl3(Afh) mutation.","date":"2013","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23616524","citation_count":51,"is_preprint":false},{"pmid":"23471982","id":"PMC_23471982","title":"Dual roles of FBXL3 in the mammalian circadian feedback loops are important for period determination and robustness of the clock.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23471982","citation_count":41,"is_preprint":false},{"pmid":"24085301","id":"PMC_24085301","title":"Substrate binding promotes formation of the Skp1-Cul1-Fbxl3 (SCF(Fbxl3)) protein complex.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24085301","citation_count":27,"is_preprint":false},{"pmid":"8496592","id":"PMC_8496592","title":"Rejection of an IA+ variant line of FBL-3 leukemia by cytotoxic T lymphocytes with CD4+ and CD4-CD8- T cell receptor-alpha beta phenotypes generated in CD8-depleted C57BL/6 mice.","date":"1993","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8496592","citation_count":27,"is_preprint":false},{"pmid":"7525983","id":"PMC_7525983","title":"Fine structure of a virus-encoded helper T-cell epitope expressed on FBL-3 tumor cells.","date":"1994","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/7525983","citation_count":26,"is_preprint":false},{"pmid":"30655559","id":"PMC_30655559","title":"The circadian E3 ligase complex SCFFBXL3+CRY targets TLK2.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30655559","citation_count":25,"is_preprint":false},{"pmid":"30481285","id":"PMC_30481285","title":"Biallelic variants in FBXL3 cause intellectual disability, delayed motor development and short stature.","date":"2019","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30481285","citation_count":18,"is_preprint":false},{"pmid":"30594330","id":"PMC_30594330","title":"FBXL3 is regulated by miRNA-4735-3p and suppresses cell proliferation and migration in non-small cell lung cancer.","date":"2018","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/30594330","citation_count":15,"is_preprint":false},{"pmid":"2483152","id":"PMC_2483152","title":"Characterization of a CD4(L3T4)-positive cytotoxic T cell clone that is restricted by class I major histocompatibility complex antigen on FBL-3 tumor cell.","date":"1989","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/2483152","citation_count":13,"is_preprint":false},{"pmid":"7474084","id":"PMC_7474084","title":"A single retroviral gag precursor signal peptide recognized by FBL-3 tumor-specific cytotoxic T lymphocytes.","date":"1995","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/7474084","citation_count":13,"is_preprint":false},{"pmid":"35216494","id":"PMC_35216494","title":"A Zebrafish Model for a Rare Genetic Disease Reveals a Conserved Role for FBXL3 in the Circadian Clock System.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35216494","citation_count":8,"is_preprint":false},{"pmid":"32138500","id":"PMC_32138500","title":"lncRNA CASC2 suppresses the growth of hemangioma cells by regulating miR-18a-5p/FBXL3 axis.","date":"2020","source":"Journal of biological regulators and homeostatic agents","url":"https://pubmed.ncbi.nlm.nih.gov/32138500","citation_count":7,"is_preprint":false},{"pmid":"9719100","id":"PMC_9719100","title":"Induction of cross-reactivity in an endogenous viral peptide non-reactive to FBL-3 tumor-specific helper T-cell clones.","date":"1998","source":"Microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9719100","citation_count":4,"is_preprint":false},{"pmid":"7916205","id":"PMC_7916205","title":"Effects of non-MHC background genes on the induction of CD4+ T cells that prevent rejection of a highly immunogenic tumor, FBL-3.","date":"1994","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7916205","citation_count":3,"is_preprint":false},{"pmid":"40413171","id":"PMC_40413171","title":"Shaking culture attenuates circadian rhythms in induced pluripotent stem cells during osteogenic differentiation through the TEAD-Fbxl3-CRY axis.","date":"2025","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/40413171","citation_count":1,"is_preprint":false},{"pmid":"39051074","id":"PMC_39051074","title":"[Tumor-associated fibroblasts promotes proliferation and migration of prostate cancer cells by suppressing FBXL3 via upregulating hsa-miR-18b-5p].","date":"2024","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/39051074","citation_count":1,"is_preprint":false},{"pmid":"41728086","id":"PMC_41728086","title":"Phosphorylation of FBXL3 mediates GLDC polyubiquitination to suppress MHC-I expression and promote cancer immune evasion.","date":"2026","source":"Cell insight","url":"https://pubmed.ncbi.nlm.nih.gov/41728086","citation_count":0,"is_preprint":false},{"pmid":"40554051","id":"PMC_40554051","title":"Fbxl3 deletion mitigates myopathy in mdx mice through upregulation of myogenin.","date":"2025","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/40554051","citation_count":0,"is_preprint":false},{"pmid":"40755783","id":"PMC_40755783","title":"FBXL3 serves as a suppressor of regenerative myogenesis.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40755783","citation_count":0,"is_preprint":false},{"pmid":"21129245","id":"PMC_21129245","title":"[Establishment of an erythroleukemia model in CB6F1 mice by transplant with haploidentical mouse leukemic cell line FBL-3].","date":"2010","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/21129245","citation_count":0,"is_preprint":false},{"pmid":"6968022","id":"PMC_6968022","title":"Regulation of the in vitro secondary cell-mediated cytotoxic response against syngeneic FBL-3 leukemia by macrophages.","date":"1980","source":"Microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/6968022","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.17.633578","title":"Evolution of circadian clock and light-input pathway genes in Hemiptera","date":"2025-01-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.17.633578","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15434,"output_tokens":2694,"usd":0.043356},"stage2":{"model":"claude-opus-4-6","input_tokens":6033,"output_tokens":2855,"usd":0.15231},"total_usd":0.195666,"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\": 2007,\n      \"finding\": \"FBXL3 (F-box protein with leucine-rich repeats) is required for CRY protein degradation in the mammalian circadian clock; the Afh mutation (Cys358Ser substitution) delays CRY protein degradation and results in ~27-hour free-running circadian rhythms in homozygous mice.\",\n      \"method\": \"ENU mutagenesis screen, in vivo circadian behavioral assays, Per2::Luciferase tissue slices, in vitro degradation assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — foundational in vivo and in vitro studies with functional mutagenesis, highly cited, replicated across labs\",\n      \"pmids\": [\"17463252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structures of CRY2 in apo, FAD-bound, and FBXL3-SKP1-complexed forms reveal that FBXL3 captures CRY2 by inserting its conserved C-terminal tail into the FAD-binding pocket and simultaneously burying the PER-binding interface; FAD and PER proteins can compete with FBXL3 for CRY2 binding, providing a regulatory mechanism for CRY ubiquitination.\",\n      \"method\": \"X-ray crystallography, in vitro binding assays, structural mutagenesis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with functional validation, multiple orthogonal methods, highly cited\",\n      \"pmids\": [\"23503662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FBXL3 regulates two circadian feedback loops: it promotes CRY ubiquitination/degradation to control E-box-driven gene expression amplitude, and it regulates Rev-Erbα:HDAC3 corepressor complex activity to control RRE-mediated transcription; deletion of Rev-erbα in Fbxl3-deficient mice rescues the long-period phenotype.\",\n      \"method\": \"Genetic interaction screen with single and double mutant mice, circadian behavioral assays, transcriptional reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple mutant combinations and multiple molecular readouts\",\n      \"pmids\": [\"23471982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SCF(FBXL3) complex formation is substrate-dependent in vivo: Fbxl3 does not associate with Skp1 and Cul1 efficiently in cells unless its substrate CRY1 is co-expressed; a mutant Fbxl3 unable to bind CRY1 also fails to form an SCF complex, indicating CRY interaction is required for SCF(FBXL3) assembly.\",\n      \"method\": \"Co-immunoprecipitation in transfected mammalian cells, in vitro reconstitution with recombinant proteins, domain-swap analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution combined with cellular co-IP and mutant analysis showing mechanism of complex assembly\",\n      \"pmids\": [\"24085301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Stabilization of endogenous CRY proteins by the Fbxl3(Afh) mutation lengthens circadian period in a CRY-dosage-dependent manner in the SCN; CRY1 is more potent than CRY2 as a transcriptional repressor, and the Afh mutation acts exclusively through CRYs (has no effect in CRY1/CRY2 double-knockout SCN).\",\n      \"method\": \"Genetic epistasis using Fbxl3(Afh) combined with Cry1 and Cry2 knockout mice, SCN bioluminescence recording, wheel-running behavioral assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — rigorous genetic epistasis with multiple mutant combinations and functional readouts\",\n      \"pmids\": [\"23616524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CRY2 functions as an essential cofactor in the SCF(FBXL3) E3 ligase complex to recruit T58-phosphorylated c-MYC for ubiquitylation and degradation; CRY1 cannot substitute for CRY2 in this function, revealing substrate-specific cofactor roles for the two CRY paralogs.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, protein degradation assays, siRNA knockdown, phosphomimetic mutants\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical methods establishing mechanism, highly cited\",\n      \"pmids\": [\"27840026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Both CRY1 and CRY2 recruit the cell cycle kinase TLK2 (in a TLK2 kinase-activity-dependent manner) to SCF(FBXL3) for ubiquitination; CRY overexpression or deletion correspondingly decreases or increases TLK2 protein abundance.\",\n      \"method\": \"Affinity purification mass spectrometry, co-immunoprecipitation, genetic deletion and overexpression of CRY1/CRY2\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — AP-MS plus genetic validation, single lab\",\n      \"pmids\": [\"30655559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YAP-TEAD mechanosensing cascade directly transcriptionally upregulates FBXL3, which then promotes CRY protein degradation, attenuating circadian clock gene oscillations in iPSC embryoid bodies under shaking culture conditions.\",\n      \"method\": \"RNA-seq, ATAC-seq, ChIP-PCR, verteporfin (YAP-TEAD inhibitor) treatment, circadian reporter assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple genomic and functional assays from single lab\",\n      \"pmids\": [\"40413171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXL3 in muscle satellite cells promotes ubiquitination and degradation of TCF12, a transcription factor that activates MEF2C expression; loss of FBXL3 activates TCF12→MEF2C→myogenin axis, augmenting myogenic differentiation and muscle regeneration.\",\n      \"method\": \"Satellite cell-specific knockout (Pax7-CreER), RNA-seq, GSEA, ChIP-PCR, dual-luciferase reporter assay, co-immunoprecipitation/ubiquitination assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including ChIP, luciferase, and genetic KO, single lab\",\n      \"pmids\": [\"40755783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Satellite cell-specific deletion of FBXL3 in mdx mice increases myogenin expression and enhances muscle regeneration, identifying FBXL3 as a negative regulator of muscle repair; AAV-mediated FBXL3 silencing in gastrocnemius muscle also increases myogenin and muscle mass.\",\n      \"method\": \"Satellite cell-specific conditional knockout in mdx mice, AAV-mediated gene silencing, histological analysis, grip strength/endurance functional tests\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic and AAV silencing approaches with functional and histological readouts, single lab\",\n      \"pmids\": [\"40554051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"EGFR activation triggers SRC-mediated phosphorylation of FBXL3 at Y306, enabling nuclear FBXL3 to interact with GLDC and catalyze K63-linked polyubiquitination at GLDC K636; ubiquitinated GLDC recruits SMARCE1/DMAP1 to inhibit STAT1-driven MHC-I gene transcription, promoting tumor immune evasion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays with K63-linkage-specific analysis, site-directed mutagenesis (Y306, K636), ChIP assays, in vivo tumor models with anti-PD-1\",\n      \"journal\": \"Cell insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods with mutagenesis and in vivo validation, single lab, not yet replicated\",\n      \"pmids\": [\"41728086\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXL3 is the substrate-recognition subunit of the SCF(FBXL3) E3 ubiquitin ligase complex that binds CRY1/2 via their FAD-binding pocket (competing with FAD and PER proteins) to drive K48-linked ubiquitination and proteasomal degradation of CRYs, thereby controlling circadian period; CRY proteins additionally serve as substrate-recruiting cofactors for FBXL3 to ubiquitinate non-clock targets including c-MYC (via CRY2) and TLK2, and FBXL3 also ubiquitinates TCF12 in muscle satellite cells and GLDC (following SRC-mediated Y306 phosphorylation) in tumor cells to regulate myogenesis and MHC-I-mediated immune evasion, respectively.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FBXL3 is the substrate-recognition subunit of the SCF(FBXL3) E3 ubiquitin ligase complex and a central regulator of mammalian circadian period, acting primarily through ubiquitin-dependent degradation of CRY1 and CRY2 transcriptional repressors. Structural studies show that FBXL3 captures CRY2 by inserting its C-terminal tail into the FAD-binding pocket while occluding the PER-binding interface, with FAD and PER proteins competing for CRY binding to gate ubiquitination; SCF(FBXL3) complex assembly itself is substrate-dependent, requiring CRY interaction for efficient SKP1–CUL1 recruitment [PMID:23503662, PMID:24085301]. Beyond the clock, CRY proteins serve as substrate-recruiting cofactors that direct FBXL3-mediated ubiquitination toward non-clock targets: CRY2 specifically recruits phospho-T58 c-MYC for degradation, and both CRYs recruit the kinase TLK2 [PMID:27840026, PMID:30655559]. FBXL3 also ubiquitinates CRY-independent substrates including TCF12 in muscle satellite cells to restrain myogenic differentiation, and GLDC in tumor cells—following SRC-mediated Y306 phosphorylation of FBXL3—to promote K63-linked ubiquitination that suppresses MHC-I transcription and facilitates immune evasion [PMID:40755783, PMID:41728086].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"The identification of FBXL3 as the F-box protein responsible for CRY degradation established the first molecular link between targeted proteolysis and circadian period determination in mammals.\",\n      \"evidence\": \"ENU mutagenesis screen yielding Afh (C358S) mice with ~27-h periods, combined with CRY degradation assays in vivo and in vitro\",\n      \"pmids\": [\"17463252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for FBXL3–CRY recognition unknown\",\n        \"Whether FBXL3 directly binds CRY or acts through intermediaries not resolved\",\n        \"Role of individual CRY paralogs in period determination unclear\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Crystal structures of the FBXL3–SKP1–CRY2 complex resolved how FBXL3 recognizes CRY via FAD-pocket insertion and PER-interface burial, revealing a competitive regulatory mechanism where FAD and PER antagonize CRY ubiquitination.\",\n      \"evidence\": \"X-ray crystallography of apo CRY2, FAD-bound CRY2, and FBXL3–SKP1–CRY2 ternary complex with functional mutagenesis\",\n      \"pmids\": [\"23503662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether FAD/PER competition operates quantitatively in vivo not shown\",\n        \"Structural basis for CRY1 versus CRY2 specificity differences unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genetic epistasis studies demonstrated that FBXL3 controls circadian period exclusively through CRY proteins and also regulates a second feedback loop involving Rev-Erbα:HDAC3, while revealing CRY-dosage-dependent and paralog-specific contributions to period setting.\",\n      \"evidence\": \"Combinatorial Fbxl3(Afh) × Cry1-KO, Cry2-KO, Cry1/2-DKO, and Rev-erbα-KO mice with behavioral and SCN bioluminescence assays\",\n      \"pmids\": [\"23471982\", \"23616524\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether FBXL3 directly targets Rev-Erbα or acts indirectly via CRY not distinguished\",\n        \"Mechanism of CRY1 versus CRY2 differential repressor potency unclear\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The discovery that SCF(FBXL3) complex assembly requires CRY substrate binding revealed an unusual substrate-dependent activation mechanism for this E3 ligase.\",\n      \"evidence\": \"Co-immunoprecipitation and in vitro reconstitution showing FBXL3 fails to associate with SKP1/CUL1 without CRY1; CRY-binding-deficient FBXL3 mutant also fails to form SCF complex\",\n      \"pmids\": [\"24085301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether substrate-dependent assembly is unique to FBXL3 or shared among FBXL family members unknown\",\n        \"Structural mechanism of how CRY binding promotes SKP1/CUL1 recruitment not resolved\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing that CRY2 (but not CRY1) recruits phospho-T58 c-MYC to SCF(FBXL3) for ubiquitination expanded the function of CRY proteins from clock substrates to substrate-recruiting cofactors with paralog-specific target selectivity.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, and phosphomimetic mutant analysis in mammalian cells\",\n      \"pmids\": [\"27840026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for CRY2 specificity in c-MYC recruitment unknown\",\n        \"Full scope of CRY-dependent non-clock substrates not mapped\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of TLK2 as a second CRY-dependent substrate of SCF(FBXL3) demonstrated that the cofactor-mediated targeting mechanism generalizes beyond c-MYC.\",\n      \"evidence\": \"Affinity purification mass spectrometry, co-IP, and genetic overexpression/deletion of CRY1/CRY2\",\n      \"pmids\": [\"30655559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ubiquitin chain linkage type on TLK2 not characterized\",\n        \"Physiological consequences of TLK2 regulation by FBXL3 not tested in vivo\",\n        \"Single-lab finding awaiting independent replication\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that YAP-TEAD signaling transcriptionally upregulates FBXL3 to accelerate CRY degradation provided the first upstream regulatory axis linking mechanotransduction to circadian clock attenuation.\",\n      \"evidence\": \"RNA-seq, ATAC-seq, ChIP-PCR, and YAP-TEAD inhibitor treatment in iPSC embryoid bodies\",\n      \"pmids\": [\"40413171\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether YAP-TEAD regulation of FBXL3 operates in adult SCN or peripheral tissues not tested\",\n        \"Direct versus indirect TEAD binding to FBXL3 promoter not fully resolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of TCF12 as a CRY-independent FBXL3 substrate in muscle satellite cells established FBXL3 as a negative regulator of myogenic differentiation, with in vivo loss-of-function enhancing muscle regeneration in dystrophic mice.\",\n      \"evidence\": \"Satellite cell-specific Fbxl3 knockout (Pax7-CreER), ubiquitination assays, ChIP-PCR, and AAV-mediated silencing in mdx mice\",\n      \"pmids\": [\"40755783\", \"40554051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether TCF12 ubiquitination is K48-linked and proteasomally degraded not explicitly shown\",\n        \"Contribution of circadian CRY regulation versus TCF12 regulation to muscle phenotype not separated\",\n        \"Single-lab finding in one disease model\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstration that EGFR/SRC-mediated Y306 phosphorylation of FBXL3 enables K63-linked ubiquitination of nuclear GLDC to suppress MHC-I transcription revealed a non-degradative ubiquitin signaling function for FBXL3 in tumor immune evasion.\",\n      \"evidence\": \"Co-IP, K63-linkage-specific ubiquitination assays, site-directed mutagenesis, ChIP assays, and in vivo tumor models with anti-PD-1\",\n      \"pmids\": [\"41728086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether CRY proteins are involved in GLDC recruitment not addressed\",\n        \"K63-linked activity represents a new chain-type specificity for SCF(FBXL3) not reconciled with canonical K48-linked activity\",\n        \"Single-lab finding awaiting independent validation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The full repertoire of FBXL3 substrates, the structural basis for CRY paralog-specific cofactor activity, and how FBXL3 switches between K48- and K63-linked ubiquitination remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Comprehensive substrate profiling (e.g., ubiquitin-remnant proteomics in FBXL3-depleted cells) not performed\",\n        \"No structural comparison of CRY1 vs CRY2 cofactor complexes with non-clock substrates\",\n        \"Mechanism governing ubiquitin chain-type specificity (K48 vs K63) unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 5, 6, 8, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 3, 5, 6, 8, 10]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [0, 2, 4, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\n      \"SCF(FBXL3)\"\n    ],\n    \"partners\": [\n      \"CRY1\",\n      \"CRY2\",\n      \"SKP1\",\n      \"CUL1\",\n      \"TCF12\",\n      \"GLDC\",\n      \"MYC\",\n      \"TLK2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}