{"gene":"FBXL2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2017,"finding":"FBXL2 (as the substrate-recognition subunit of SCF-FBXL2 ubiquitin ligase) binds IP3R3 and targets it for ubiquitin-, p97- and proteasome-mediated degradation, limiting Ca2+ release from the ER into mitochondria. PTEN competes with FBXL2 for IP3R3 binding, counteracting this degradation to promote Ca2+-dependent apoptosis. Loss of PTEN accelerates FBXL2-dependent IP3R3 degradation, and FBXL2 localization (and thus activity) requires geranylgeranylation.","method":"Co-immunoprecipitation, knock-in FBXL2-insensitive IP3R3 mutant clones, FBXL2 knockdown, Ca2+ flux assays, xenograft models, GGTi-2418 (geranylgeranyl transferase inhibitor) treatment","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, CRISPR knock-in mutants, in vivo xenografts, pharmacological inhibition), replicated across cell and mouse models in one rigorous study","pmids":["28614300"],"is_preprint":false},{"year":2013,"finding":"FBXL2 interacts specifically with the pool of p85β PI(3)K regulatory subunit that is free of p110 catalytic subunits and targets it for ubiquitylation and proteasomal degradation, dependent on p85β's CaaX motif. Phosphorylation of p85β on Tyr655 inhibits its binding to FBXL2, while dephosphorylation by PTPL1 stimulates binding and degradation. FBXL2-mediated p85β degradation promotes p110 association with IRS1 and sustains PI(3)K signaling; loss of this degradation inhibits PI(3)K and promotes autophagy.","method":"Affinity purification/mass spectrometry of FBXL2 interactors, Co-IP, in vitro ubiquitylation assay, phospho-mutant analysis, IRS1 binding assays, autophagy readouts","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstitution-level biochemistry (in vitro ubiquitylation, purification of complex), phospho-site mutagenesis, multiple orthogonal functional readouts, single rigorous study","pmids":["23604317"],"is_preprint":false},{"year":2012,"finding":"SCF-FBXL2 ubiquitinates and destabilizes cyclin D2, leading to G0 phase arrest and apoptosis. FBXL2 recognizes a calmodulin-binding motif within cyclin D2 (not a phosphodegron). Calmodulin competes with FBXL2 for occupancy of this motif, protecting cyclin D2 from degradation.","method":"Ectopic FBXL2 expression, RNAi knockdown, ubiquitination assay, cell cycle analysis, calmodulin competition assay, leukemia patient sample analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro ubiquitination, calmodulin competition biochemistry, and multiple cellular readouts in one study with patient validation","pmids":["22323446"],"is_preprint":false},{"year":2011,"finding":"SCF-FBXL2 mediates polyubiquitination and proteasomal degradation of cyclin D3, causing G2/M-phase arrest, supernumerary centrosomes, and apoptosis in lung cancer cells. FBXL2 recognizes a calmodulin-binding motif in cyclin D3 (not a phosphodegron); calmodulin competes with FBXL2 for this site, protecting cyclin D3. Both cyclin D3 and FBXL2 colocalize within the centrosome.","method":"Ectopic expression and RNAi, ubiquitination assay, cell cycle and centrosome analysis, co-localization imaging, calmodulin competition assay, xenograft tumor assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro ubiquitination, calmodulin competition biochemistry, subcellular localization, in vivo xenograft, multiple orthogonal methods","pmids":["22020328"],"is_preprint":false},{"year":2011,"finding":"During Pseudomonas aeruginosa infection, FBXL2 is activated by calcium influx and localizes to the Golgi complex, where it monoubiquitinates and degrades CCTα (the rate-limiting enzyme for phosphatidylcholine synthesis) via binding to the IQ motif of CCTα through its C-terminus. Calmodulin traffics to the Golgi, binds FBXL2 (residues 80–90) via its C-terminus, and competes with FBXL2 for occupancy of the CCTα IQ motif, antagonizing FBXL2 activity.","method":"Co-IP, domain-mapping mutagenesis, calcium influx assays, Golgi fractionation/localization, RNAi knockdown, calmodulin gene transfer in murine pneumonia model","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic domain mapping, subcellular localization with functional consequence, in vivo murine model, multiple orthogonal approaches","pmids":["21343341"],"is_preprint":false},{"year":2013,"finding":"SCF-FBXL2 mediates ubiquitination and proteasomal degradation of Aurora B kinase within the midbody during cytokinesis. Key ubiquitin acceptor lysines K102, K103, and K207 on Aurora B were identified; a triple K→R mutant resists SCF-FBXL2-directed polyubiquitination and causes anaphase delay and apoptosis when overexpressed.","method":"Ubiquitination assay, lysine-to-arginine mutagenesis of Aurora B, overexpression and knockdown, mitotic arrest/apoptosis assays, xenograft tumor model with small-molecule FBXL2 activator BC-1258","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro ubiquitination with site-directed mutagenesis, in vivo tumor model, multiple cellular readouts in one study","pmids":["23928698"],"is_preprint":false},{"year":2011,"finding":"SCF-FBXL2 impairs cell proliferation by mediating cyclin D3 polyubiquitination and degradation; cyclin D3 and FBXL2 colocalize at the centrosome. FBXL2 overexpression disrupts cyclin D3 association with centrosomal assembly proteins Aurora A, Plk4, and CDK11.","method":"Ectopic expression and RNAi, ubiquitination assay, co-localization imaging, co-immunoprecipitation of cyclin D3 with centrosomal proteins","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, co-localization, and functional readouts but overlaps heavily with PMID:22020328; centrosomal protein interaction data adds new specificity","pmids":["22024926"],"is_preprint":false},{"year":2015,"finding":"Fbxo3 promotes Fbxl2 ubiquitination and degradation; this relieves Fbxl2-mediated ubiquitination of TRAF2, leading to TRAF2 accumulation, TNIK activation, GluR1 phosphorylation, and trafficking of GluR1-containing AMPA receptors to the plasma membrane in dorsal horn neurons, contributing to neuropathic allodynia.","method":"Spinal nerve ligation rat model, intrathecal siRNA/inhibitor (BC-1215) injection, co-immunoprecipitation, GluR1 trafficking assays, behavioral allodynia measurement","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — epistasis established by in vivo knockdown and pharmacological inhibition, Co-IP for interactions, but in vivo complexity limits mechanistic precision","pmids":["26674878"],"is_preprint":false},{"year":2016,"finding":"Fbxo3 inhibits Fbxl2-mediated ubiquitination and degradation of the active zone protein RIM1α in the spinal dorsal horn. Deubiquitinated RIM1α accumulates in synaptic plasma membranes, directly binds CaV2.2, and increases presynaptic CaV2.2 expression, driving neuropathic allodynia.","method":"Spinal nerve ligation rat model, intrathecal BC-1215 (Fbxo3 inhibitor), siRNA knockdown of Fbxl2 and RIM1α, co-immunoprecipitation, subcellular fractionation, electrophysiology (sEPSC)","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — epistasis via pharmacological and genetic tools, Co-IP for RIM1α-FBXL2 and RIM1α-CaV2.2, in vivo behavioral and electrophysiological readouts","pmids":["27629721"],"is_preprint":false},{"year":2016,"finding":"FBXL2 interacts with the transcription factor FoxM1 and promotes its ubiquitination and proteasomal degradation in gastric cancer cells, thereby reducing expression of FoxM1 downstream targets Cdc25B and p27 and inhibiting cell proliferation and invasion.","method":"Tandem mass spectrometry, co-immunoprecipitation, ubiquitination assay, ectopic expression and knockdown, cell proliferation/invasion assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — MS identification plus Co-IP plus ubiquitination assay, single lab with multiple orthogonal methods","pmids":["26790640"],"is_preprint":false},{"year":2019,"finding":"O-GlcNAcylation promotes FBXL2 ubiquitination and degradation (FBXL2 is itself a target of ubiquitin-mediated degradation), leading to stabilization of FOXM1 (an FBXL2 ubiquitination substrate) and cancer cell proliferation. The O-GlcNAcase inhibitor Thiamet G reduces FBXL2-FOXM1 interaction and FOXM1 ubiquitination.","method":"Co-immunoprecipitation, ubiquitination assay, pharmacological O-GlcNAcylation manipulation, western blot, cell proliferation assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ubiquitination assays replicated across cell lines, but single lab and no direct identification of O-GlcNAc site on FBXL2","pmids":["31679690"],"is_preprint":false},{"year":2020,"finding":"FUNDC1 interacts with FBXL2 via FBXL2's F-box domain; loss of FUNDC1 accelerates FBXL2 degradation and decelerates IP3R3 degradation, leading to mitochondrial Ca2+ overload. The FUNDC1-FBXL2 interaction thus functions as a gatekeeper for IP3R3 protein levels and mitochondrial Ca2+ homeostasis in the heart.","method":"Mass spectrometry, co-immunoprecipitation, FUNDC1-/- mouse model on high-fat diet, truncated F-box deletion mutants, FBXL2 overexpression/transfection, IP3R3 inhibition","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — MS-confirmed interaction, Co-IP with domain mapping, genetic KO mouse model with cardiac phenotype, multiple orthogonal approaches in one study","pmids":["32938669"],"is_preprint":false},{"year":2021,"finding":"FBXL2 targets EGFR (and TKI-resistant EGFR mutants) for proteasomal degradation. Grp94 (glucose-regulated protein 94) protects EGFR from this degradation by blocking FBXL2 binding to EGFR. Disruption of FBXL2 membrane localization (by GGTi-2418) or upregulation of FBXL2 expression (by nebivolol) reduces EGFR levels and inhibits NSCLC growth.","method":"Co-IP, proteasome inhibitor experiments, FBXL2 knockdown/overexpression, Grp94 manipulation, nebivolol treatment, xenograft models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, multiple EGFR mutants tested, in vivo xenograft validation, identification of competitive Grp94 mechanism, multiple orthogonal approaches","pmids":["34635651"],"is_preprint":false},{"year":2021,"finding":"Smurf1 ubiquitinates and degrades FBXL2; loss of FBXL2 leads to activation of Wnt/β-catenin signaling, promoting colorectal cancer progression. FOSL1 drives this pathway by upregulating Smurf1.","method":"Co-IP, ubiquitination assay, FBXL2 and Smurf1 knockdown/overexpression, Wnt/β-catenin reporter, xenograft metastasis assay","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ubiquitination assay for Smurf1-FBXL2 interaction, in vivo xenograft, but single lab","pmids":["33450386"],"is_preprint":false},{"year":2022,"finding":"FBXL2 polyubiquitinates the transcription factor T-bet and co-immunoprecipitates with T-bet; ectopic FBXL2 expression reduces T-bet protein in a dose-dependent manner. TNF-α negatively regulates both FBXL2 mRNA and protein levels, providing cross-regulation of FBXL2 and T-bet during lung allograft rejection.","method":"Co-immunoprecipitation/pulldown, ubiquitination assay, FBXL2 transfection with dose-response, orthotopic lung transplant mouse model, immunohistochemistry, costimulation blockade treatment","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and ubiquitination assay supported by in vivo transplant model, single lab but multiple contexts tested","pmids":["36113884"],"is_preprint":false},{"year":2022,"finding":"FBXL2 targets transcription factor E47 for polyubiquitin- and proteasome-mediated degradation, inhibiting breast cancer stem cell stemness (CD44high/CD24low subpopulation, mammosphere formation) and overcoming paclitaxel resistance. Nebivolol (a β1 receptor inhibitor) activates FBXL2 expression to achieve this effect.","method":"Co-IP, ubiquitination assay, ectopic expression and knockdown, flow cytometry, mammosphere assay, in vivo xenograft, nebivolol treatment","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP plus ubiquitination assay plus in vivo model, single lab","pmids":["36460773"],"is_preprint":false},{"year":2023,"finding":"FBXL2 binds to and ubiquitinates both NLRP3 and pro-IL-1β (but not pro-caspase-1), targeting them for proteasome-mediated degradation. BC-1215 (an FBXO3 inhibitor that prevents FBXL2 ubiquitination/degradation) upregulates FBXL2 levels and thereby reduces NLRP3 and pro-IL-1β protein levels, suppressing ATP-induced IL-1β secretion.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor (MG-132) rescue, FBXL2 overexpression, BC-1215 pharmacological treatment, western blot and ELISA","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and ubiquitination assays with proteasome rescue, single lab but multiple substrates tested with appropriate controls","pmids":["37004285"],"is_preprint":false},{"year":2020,"finding":"TNF-α suppresses Fbxl2 mRNA expression in skeletal myoblasts by activating JNK-mediated phosphorylation of SP1, which impairs SP1 binding to the Fbxl2 core promoter (localized to bp -160 to +42). SP1 transcriptional activation of Fbxl2 is required for myogenic differentiation; FBXL2 knockdown in myoblasts activates MAP kinases and NF-κB, promotes proliferation, and impairs myotube formation.","method":"Chromatin immunoprecipitation, gel shift (EMSA), promoter reporter assays, SP1 phospho-site analysis, RNAi knockdown, myogenic differentiation assays, mRNA stability measurement","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and EMSA establish direct SP1-promoter interaction, functional knockdown phenotype, mechanistic link to JNK, single lab","pmids":["32205409"],"is_preprint":false},{"year":2017,"finding":"FBXL2-mediated ubiquitination and degradation of TRAF6 is implicated in LIPUS-mediated protection against polyethylene debris-induced periprosthetic inflammatory loosening; LIPUS strengthens this FBXL2-TRAF6 ubiquitination pathway.","method":"Gene overexpression and siRNA in RAW264.7 macrophages, western blot for FBXL2 and TRAF6 levels, inflammatory cytokine measurement, LIPUS treatment","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, no direct ubiquitination assay or Co-IP reported for FBXL2-TRAF6 in this paper; inferred from protein level changes","pmids":["28378753"],"is_preprint":false},{"year":2026,"finding":"FBXL2 promotes HER2 polyubiquitination at lysine K747 and proteasomal degradation, reducing HER2 surface expression. Blocking FBXL2 membrane localization with GGTi-2418 or ketoconazole elevates HER2 expression on the plasma membrane of HER2-IHC 0 TNBC cells, sensitizing them to trastuzumab deruxtecan.","method":"Co-IP, site-directed mutagenesis (K747 ubiquitination site), proteasomal degradation assays, FBXL2 membrane localization inhibition, lipid nanoparticle delivery, xenograft models","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — site-specific ubiquitination mutagenesis, proteasomal degradation assays, membrane localization experiments with functional consequence, in vivo xenograft validation, single rigorous study","pmids":["41612000"],"is_preprint":false},{"year":2025,"finding":"Nrf2 transcriptionally upregulates FBXL2 expression; FBXL2 promotes NLRP3 ubiquitination-mediated degradation and suppresses pyroptosis. High glucose treatment decreases Nrf2 and FBXL2 and enhances NLRP3-mediated pyroptosis; scutellarin reverses this by increasing Nrf2/FBXL2.","method":"Dual-luciferase reporter assay (Nrf2 binding to FBXL2 promoter), immunoprecipitation for ubiquitination, western blotting, Nrf2 knockdown, FBXL2 knockdown, NLRP3 activation rescue","journal":"Endocrine journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Weak — luciferase reporter and Co-IP/ubiquitination assays, but single lab and limited mechanistic depth","pmids":["40010729"],"is_preprint":false}],"current_model":"FBXL2 is the substrate-recognition subunit of an SCF-type E3 ubiquitin ligase (SCF-FBXL2) that requires membrane localization via geranylgeranylation and is negatively regulated by FBXO3-mediated ubiquitination and calmodulin competition; it ubiquitinates and targets for proteasomal degradation a broad range of substrates including IP3R3 (limiting ER-to-mitochondria Ca2+ transfer), the free p85β subunit of PI(3)K (sustaining PI(3)K signaling), cyclin D2/D3 (inducing cell cycle arrest), Aurora B (regulating cytokinesis), TRAF2/TRAF6, NLRP3, pro-IL-1β, FoxM1/FOXM1, E47, T-bet, CCTα, EGFR, HER2, and RIM1α, recognizing substrates often via calmodulin-binding (IQ) motifs rather than classical phosphodegrons, and its activity is regulated by calcium, PTEN competition (for IP3R3), Grp94 competition (for EGFR), FUNDC1 interaction (via the F-box domain), O-GlcNAcylation, and SP1-mediated transcription that is suppressed by TNF-α/JNK signaling."},"narrative":{"mechanistic_narrative":"FBXL2 is the substrate-recognition subunit of an SCF-type E3 ubiquitin ligase (SCF-FBXL2) that controls the abundance of a broad set of cell-cycle, signaling, and inflammatory proteins by directing them to proteasomal degradation [PMID:28614300, PMID:22323446]. A defining mechanistic feature is that FBXL2 frequently engages substrates through their calmodulin-binding (IQ) motifs rather than classical phosphodegrons, and calmodulin competes for these motifs to protect substrates from degradation, as shown for cyclin D2, cyclin D3, and CCTα [PMID:22323446, PMID:22020328, PMID:21343341]. FBXL2 activity additionally requires geranylgeranylation-dependent membrane localization, and disrupting this localization pharmacologically (e.g. GGTi-2418) blocks degradation of membrane-associated substrates including IP3R3, EGFR, and HER2 [PMID:28614300, PMID:34635651, PMID:41612000]. Through these activities FBXL2 limits ER-to-mitochondria Ca2+ transfer by degrading IP3R3 [PMID:28614300], restrains proliferation by destabilizing cyclins D2/D3 and the transcription factors FoxM1, E47, and T-bet [PMID:22323446, PMID:22020328, PMID:26790640, PMID:36113884, PMID:36460773], regulates cytokinesis via Aurora B turnover [PMID:23928698], and dampens inflammation by degrading NLRP3, pro-IL-1β, TRAF2, and TRAF6 [PMID:26674878, PMID:37004285, PMID:28378753]. FBXL2 itself is a tightly regulated target: it is destabilized by FBXO3- and Smurf1-mediated ubiquitination and by O-GlcNAcylation, while substrate access is gated by competing partners such as PTEN (for IP3R3), Grp94 (for EGFR), and FUNDC1 (via the F-box domain) [PMID:26674878, PMID:31679690, PMID:32938669, PMID:34635651, PMID:33450386]. Its expression is transcriptionally driven by SP1 and Nrf2 and suppressed by TNF-α/JNK signaling [PMID:32205409, PMID:40010729].","teleology":[{"year":2011,"claim":"Established that FBXL2 acts as an SCF substrate receptor using a non-canonical recognition mode — binding calmodulin-binding IQ motifs rather than phosphodegrons — by showing it degrades cyclin D3 and the lipid-synthesis enzyme CCTα with calmodulin acting as a competitive protector.","evidence":"Ectopic expression/RNAi, in vitro ubiquitination, calmodulin competition assays, domain mapping, Golgi fractionation, and xenograft/murine models","pmids":["22020328","21343341","22024926"],"confidence":"High","gaps":["Structural basis of IQ-motif recognition by the FBXL2 LRR domain not resolved","Generality of calmodulin competition across all substrates untested"]},{"year":2012,"claim":"Extended the calmodulin-competition model to cyclin D2, demonstrating FBXL2 controls G0 arrest and apoptosis and linking its activity to leukemia biology.","evidence":"Ectopic FBXL2, RNAi, ubiquitination and calmodulin competition assays, cell-cycle analysis, patient sample analysis","pmids":["22323446"],"confidence":"High","gaps":["In vivo requirement for cyclin D2 turnover not established","Relative contribution of D2 vs D3 to arrest unclear"]},{"year":2013,"claim":"Resolved how FBXL2 sustains growth-factor signaling and how it regulates mitosis: it selectively degrades the free p85β pool of PI(3)K to promote p110-IRS1 coupling, and it degrades Aurora B at the midbody during cytokinesis.","evidence":"Affinity-MS, in vitro ubiquitylation, phospho-mutant analysis, lysine-to-arginine mutagenesis of Aurora B, IRS1 binding and autophagy readouts, xenograft with activator BC-1258","pmids":["23604317","23928698"],"confidence":"High","gaps":["How Tyr655 phosphorylation gates p85β binding structurally not defined","Coordination of Aurora B degradation timing with mitotic exit unresolved"]},{"year":2015,"claim":"Defined upstream control of FBXL2 itself by showing FBXO3 ubiquitinates and degrades FBXL2, with epistatic consequences for TRAF2 stability and AMPA receptor trafficking in neuropathic pain.","evidence":"Spinal nerve ligation model, intrathecal siRNA/BC-1215, Co-IP, GluR1 trafficking and behavioral assays","pmids":["26674878"],"confidence":"Medium","gaps":["Direct TRAF2 ubiquitination by FBXL2 inferred from epistasis, not reconstituted","In vivo complexity limits assignment of effects to FBXL2 alone"]},{"year":2016,"claim":"Broadened the FBXL2 substrate repertoire to transcription factors and active-zone proteins, identifying FoxM1 and RIM1α as targets controlling proliferation and presynaptic CaV2.2 signaling respectively.","evidence":"Tandem MS, Co-IP, ubiquitination assays, subcellular fractionation, electrophysiology, in vivo nerve ligation model","pmids":["26790640","27629721"],"confidence":"Medium","gaps":["Recognition motifs on FoxM1 and RIM1α not mapped","Single-lab findings without reciprocal validation"]},{"year":2020,"claim":"Identified additional layers of FBXL2 regulation: FUNDC1 binds the F-box domain to gate IP3R3 turnover and cardiac mitochondrial Ca2+ homeostasis, and SP1 transcription (suppressed by TNF-α/JNK) drives FBXL2 expression required for myogenic differentiation.","evidence":"MS, Co-IP with F-box deletion mutants, FUNDC1-/- mouse on high-fat diet; ChIP, EMSA, promoter reporters, SP1 phospho-analysis, differentiation assays","pmids":["32938669","32205409"],"confidence":"High","gaps":["How FUNDC1 binding stabilizes FBXL2 mechanistically unclear","JNK target site on SP1 not definitively mapped"]},{"year":2021,"claim":"Established competitive substrate shielding and proteostatic control as recurring themes by showing Grp94 blocks EGFR degradation by FBXL2, and Smurf1 (driven by FOSL1) degrades FBXL2 to activate Wnt/β-catenin signaling.","evidence":"Reciprocal Co-IP, proteasome inhibition, knockdown/overexpression, Wnt reporter, nebivolol treatment, xenograft models","pmids":["34635651","33450386"],"confidence":"High","gaps":["Structural basis of Grp94-EGFR-FBXL2 competition not resolved","Smurf1-FBXL2 link is single-lab"]},{"year":2022,"claim":"Connected FBXL2 to immune and stemness regulation by demonstrating degradation of T-bet (modulated by TNF-α) in lung allograft rejection and of E47 to suppress breast cancer stem-cell traits.","evidence":"Co-IP, ubiquitination assays, dose-response transfection, orthotopic lung transplant and xenograft models, mammosphere and flow assays, nebivolol treatment","pmids":["36113884","36460773"],"confidence":"Medium","gaps":["Degron determinants on T-bet and E47 not defined","Specificity over related bHLH/T-box factors untested"]},{"year":2023,"claim":"Demonstrated FBXL2 directly restrains inflammasome output by ubiquitinating and degrading NLRP3 and pro-IL-1β (but not pro-caspase-1), positioning FBXL2 stabilization (via FBXO3 inhibition) as a brake on IL-1β secretion.","evidence":"Co-IP, ubiquitination assays, MG-132 rescue, FBXL2 overexpression, BC-1215 treatment, ELISA","pmids":["37004285"],"confidence":"Medium","gaps":["Substrate selectivity between NLRP3 and pro-IL-1β not dissected","Single-lab study"]},{"year":2026,"claim":"Resolved a clinically actionable substrate by mapping FBXL2-driven HER2 polyubiquitination at K747, showing that blocking FBXL2 membrane localization elevates surface HER2 and sensitizes HER2-low TNBC to antibody-drug conjugates.","evidence":"Co-IP, K747 site-directed mutagenesis, proteasomal degradation assays, membrane-localization inhibition, lipid nanoparticle delivery, xenograft models","pmids":["41612000"],"confidence":"High","gaps":["Whether HER2 is recognized via an IQ-like motif unknown","Endogenous physiological context of HER2 regulation by FBXL2 untested"]},{"year":null,"claim":"It remains unresolved how FBXL2 achieves selectivity across its unusually broad substrate range and how its membrane localization, calmodulin/calcium status, and competing partners are integrated to license degradation of specific substrates in a given cell.","evidence":"No structural or systems-level study in the timeline addresses combined substrate-selection logic","pmids":[],"confidence":"Low","gaps":["No structure of FBXL2 bound to any substrate","No global rules distinguishing IQ-motif from non-IQ substrates","Quantitative interplay of calcium, calmodulin, and membrane targeting unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,3,5,9,12,14,15,16,19]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,2,3,5,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,11,12]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[4]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[3,6]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,12,19]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,3,5,9]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,12,19]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,16,18,20]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,13]}],"complexes":["SCF-FBXL2 (SCF-type E3 ubiquitin ligase)"],"partners":["FBXO3","FUNDC1","PTEN","GRP94","SMURF1","CALMODULIN","IP3R3","EGFR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UKC9","full_name":"F-box/LRR-repeat protein 2","aliases":["F-box and leucine-rich repeat protein 2","F-box protein FBL2/FBL3"],"length_aa":423,"mass_kda":47.1,"function":"Calcium-activated substrate recognition component of the SCF (SKP1-cullin-F-box protein) E3 ubiquitin-protein ligase complex, SCF(FBXL2), which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:22020328, PubMed:22323446, PubMed:31209342). Unlike many F-box proteins, FBXL2 does not seem to target phosphodegron within its substrates but rather calmodulin-binding motifs and is thereby antagonized by calmodulin (PubMed:22020328, PubMed:22323446). This is the case for the cyclins CCND2 and CCND3 which polyubiquitination and subsequent degradation are inhibited by calmodulin (PubMed:22020328, PubMed:22323446). Through CCND2 and CCND3 degradation induces cell-cycle arrest in G(0) (PubMed:22020328, PubMed:22323446). SCF(FBXL2) also mediates PIK3R2 ubiquitination and proteasomal degradation thereby regulating phosphatidylinositol 3-kinase signaling and autophagy (PubMed:23604317). PCYT1A monoubiquitination by SCF(FBXL2) and subsequent degradation regulates synthesis of phosphatidylcholine, which is utilized for formation of membranes and of pulmonary surfactant (By similarity). The SCF(FBXL2) complex acts as a regulator of inflammation by mediating ubiquitination and degradation of TRAF proteins (TRAF1, TRAF2, TRAF3, TRAF4, TRAF5 and TRAF6) (By similarity). The SCF(FBXL2) complex acts as a negative regulator of the NLRP3 inflammasome by mediating ubiquitination and degradation of NLRP3 (PubMed:26037928). The GGTase-3 complex, composed of PTAR1 and RABGGTB, geranylgeranylates and targets FBXL2 to the cellular membranes, where FBXL2 forms part of the SCF(FBXL2) complex that mediates the degradation of membrane-anchored proteins (PubMed:31209342, PubMed:32128853)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9UKC9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBXL2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FBXL2","total_profiled":1310},"omim":[{"mim_id":"621024","title":"PROTEIN PRENYLTRANSFERASE ALPHA SUBUNIT REPEAT-CONTAINING PROTEIN 1; PTAR1","url":"https://www.omim.org/entry/621024"},{"mim_id":"605652","title":"F-BOX AND LEUCINE-RICH REPEAT PROTEIN 2; FBXL2","url":"https://www.omim.org/entry/605652"},{"mim_id":"601728","title":"PHOSPHATASE AND TENSIN HOMOLOG; PTEN","url":"https://www.omim.org/entry/601728"},{"mim_id":"179080","title":"RAB GERANYLGERANYL TRANSFERASE, BETA SUBUNIT; RABGGTB","url":"https://www.omim.org/entry/179080"},{"mim_id":"147267","title":"INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR, TYPE 3; ITPR3","url":"https://www.omim.org/entry/147267"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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counteracts FBXL2 to promote IP3R3- and Ca2+-mediated apoptosis limiting tumour growth.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28614300","citation_count":208,"is_preprint":false},{"pmid":"32938669","id":"PMC_32938669","title":"FUNDC1 interacts with FBXL2 to govern mitochondrial integrity and cardiac function through an IP3R3-dependent manner in obesity.","date":"2020","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/32938669","citation_count":118,"is_preprint":false},{"pmid":"23604317","id":"PMC_23604317","title":"FBXL2- and PTPL1-mediated degradation of p110-free p85β regulatory subunit controls the PI(3)K signalling cascade.","date":"2013","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23604317","citation_count":109,"is_preprint":false},{"pmid":"22323446","id":"PMC_22323446","title":"F-box protein FBXL2 targets cyclin D2 for ubiquitination and degradation to inhibit leukemic cell proliferation.","date":"2012","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/22323446","citation_count":85,"is_preprint":false},{"pmid":"22020328","id":"PMC_22020328","title":"F-box protein FBXL2 exerts human lung tumor suppressor-like activity by ubiquitin-mediated degradation of cyclin D3 resulting in cell cycle arrest.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/22020328","citation_count":66,"is_preprint":false},{"pmid":"23928698","id":"PMC_23928698","title":"Skp-cullin-F box E3 ligase component FBXL2 ubiquitinates Aurora B to inhibit tumorigenesis.","date":"2013","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/23928698","citation_count":56,"is_preprint":false},{"pmid":"34635651","id":"PMC_34635651","title":"FBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth.","date":"2021","source":"Nature 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Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/22024926","citation_count":33,"is_preprint":false},{"pmid":"33450386","id":"PMC_33450386","title":"FOSL1 promotes tumorigenesis in colorectal carcinoma by mediating the FBXL2/Wnt/β-catenin axis via Smurf1.","date":"2021","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/33450386","citation_count":32,"is_preprint":false},{"pmid":"27629721","id":"PMC_27629721","title":"Spinal Fbxo3-Dependent Fbxl2 Ubiquitination of Active Zone Protein RIM1α Mediates Neuropathic Allodynia through CaV2.2 Activation.","date":"2016","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/27629721","citation_count":30,"is_preprint":false},{"pmid":"26790640","id":"PMC_26790640","title":"F-box protein FBXL2 inhibits gastric cancer proliferation by ubiquitin-mediated degradation of forkhead box M1.","date":"2016","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/26790640","citation_count":28,"is_preprint":false},{"pmid":"31953162","id":"PMC_31953162","title":"MiR-346-5p promotes colorectal cancer cell proliferation in vitro and in vivo by targeting FBXL2 and activating the β-catenin signaling pathway.","date":"2020","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31953162","citation_count":21,"is_preprint":false},{"pmid":"28378753","id":"PMC_28378753","title":"Low-intensity pulsed ultrasound (LIPUS) prevents periprosthetic inflammatory loosening through FBXL2-TRAF6 ubiquitination pathway.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28378753","citation_count":20,"is_preprint":false},{"pmid":"36460773","id":"PMC_36460773","title":"FBXL2 promotes E47 protein instability to inhibit breast cancer stemness and paclitaxel resistance.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/36460773","citation_count":16,"is_preprint":false},{"pmid":"35515212","id":"PMC_35515212","title":"Circular RNA SMARCA5 inhibits gastric cancer progression through targeting the miR-346/ FBXL2 axis.","date":"2019","source":"RSC advances","url":"https://pubmed.ncbi.nlm.nih.gov/35515212","citation_count":16,"is_preprint":false},{"pmid":"32205409","id":"PMC_32205409","title":"Tumor Necrosis Factor Alpha Regulates Skeletal Myogenesis by Inhibiting SP1 Interaction with cis-Acting Regulatory Elements within the Fbxl2 Gene Promoter.","date":"2020","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/32205409","citation_count":15,"is_preprint":false},{"pmid":"24994500","id":"PMC_24994500","title":"A lack of association between polymorphisms of three positional candidate genes (CLASP2 , UBP1, and FBXL2) and canine disorder of sexual development (78,XX; SRY -negative).","date":"2014","source":"Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/24994500","citation_count":7,"is_preprint":false},{"pmid":"31679690","id":"PMC_31679690","title":"O-GlcNAcylation-mediated degradation of FBXL2 stabilizes FOXM1 to induce cancer progression.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31679690","citation_count":6,"is_preprint":false},{"pmid":"37004285","id":"PMC_37004285","title":"BC-1215 inhibits ATP-induced IL-1β secretion via the FBXL2-mediated ubiquitination and degradation of not only NLRP3, but also pro-IL-1β in LPS-primed THP-1 cells.","date":"2023","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/37004285","citation_count":6,"is_preprint":false},{"pmid":"36113884","id":"PMC_36113884","title":"Cross-Regulation of F-Box Protein FBXL2 with T-bet and TNF-α during Acute and Chronic Lung Allograft Rejection.","date":"2022","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/36113884","citation_count":3,"is_preprint":false},{"pmid":"38947217","id":"PMC_38947217","title":"Methylation regulation for FUNDC1 stability in childhood leukemia was up-regulated and facilitates metastasis and reduces ferroptosis of leukemia through mitochondrial damage by FBXL2.","date":"2024","source":"Open medicine (Warsaw, Poland)","url":"https://pubmed.ncbi.nlm.nih.gov/38947217","citation_count":3,"is_preprint":false},{"pmid":"40010729","id":"PMC_40010729","title":"Scutellarin mitigates high glucose-induced pyroptosis in diabetic atherosclerosis: Role of Nrf2-FBXL2-mediated NLRP3 degradation.","date":"2025","source":"Endocrine journal","url":"https://pubmed.ncbi.nlm.nih.gov/40010729","citation_count":2,"is_preprint":false},{"pmid":"39323222","id":"PMC_39323222","title":"FUNDC1 mediated mitochondria-dependent ferroptosis of epithelial cells in model of asthma by FBXL2/ar/GPX4 signaling pathway of SUMO1 at K136.","date":"2024","source":"International reviews of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39323222","citation_count":2,"is_preprint":false},{"pmid":"41612000","id":"PMC_41612000","title":"Targeted inhibition of FBXL2 confers susceptibility of HER2-negative breast cancer to trastuzumab deruxtecan.","date":"2026","source":"Nature cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41612000","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16696,"output_tokens":6253,"usd":0.071942,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14845,"output_tokens":4277,"usd":0.090575,"stage2_stop_reason":"end_turn"},"total_usd":0.162517,"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\": 2017,\n      \"finding\": \"FBXL2 (as the substrate-recognition subunit of SCF-FBXL2 ubiquitin ligase) binds IP3R3 and targets it for ubiquitin-, p97- and proteasome-mediated degradation, limiting Ca2+ release from the ER into mitochondria. PTEN competes with FBXL2 for IP3R3 binding, counteracting this degradation to promote Ca2+-dependent apoptosis. Loss of PTEN accelerates FBXL2-dependent IP3R3 degradation, and FBXL2 localization (and thus activity) requires geranylgeranylation.\",\n      \"method\": \"Co-immunoprecipitation, knock-in FBXL2-insensitive IP3R3 mutant clones, FBXL2 knockdown, Ca2+ flux assays, xenograft models, GGTi-2418 (geranylgeranyl transferase inhibitor) treatment\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, CRISPR knock-in mutants, in vivo xenografts, pharmacological inhibition), replicated across cell and mouse models in one rigorous study\",\n      \"pmids\": [\"28614300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FBXL2 interacts specifically with the pool of p85β PI(3)K regulatory subunit that is free of p110 catalytic subunits and targets it for ubiquitylation and proteasomal degradation, dependent on p85β's CaaX motif. Phosphorylation of p85β on Tyr655 inhibits its binding to FBXL2, while dephosphorylation by PTPL1 stimulates binding and degradation. FBXL2-mediated p85β degradation promotes p110 association with IRS1 and sustains PI(3)K signaling; loss of this degradation inhibits PI(3)K and promotes autophagy.\",\n      \"method\": \"Affinity purification/mass spectrometry of FBXL2 interactors, Co-IP, in vitro ubiquitylation assay, phospho-mutant analysis, IRS1 binding assays, autophagy readouts\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstitution-level biochemistry (in vitro ubiquitylation, purification of complex), phospho-site mutagenesis, multiple orthogonal functional readouts, single rigorous study\",\n      \"pmids\": [\"23604317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SCF-FBXL2 ubiquitinates and destabilizes cyclin D2, leading to G0 phase arrest and apoptosis. FBXL2 recognizes a calmodulin-binding motif within cyclin D2 (not a phosphodegron). Calmodulin competes with FBXL2 for occupancy of this motif, protecting cyclin D2 from degradation.\",\n      \"method\": \"Ectopic FBXL2 expression, RNAi knockdown, ubiquitination assay, cell cycle analysis, calmodulin competition assay, leukemia patient sample analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro ubiquitination, calmodulin competition biochemistry, and multiple cellular readouts in one study with patient validation\",\n      \"pmids\": [\"22323446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SCF-FBXL2 mediates polyubiquitination and proteasomal degradation of cyclin D3, causing G2/M-phase arrest, supernumerary centrosomes, and apoptosis in lung cancer cells. FBXL2 recognizes a calmodulin-binding motif in cyclin D3 (not a phosphodegron); calmodulin competes with FBXL2 for this site, protecting cyclin D3. Both cyclin D3 and FBXL2 colocalize within the centrosome.\",\n      \"method\": \"Ectopic expression and RNAi, ubiquitination assay, cell cycle and centrosome analysis, co-localization imaging, calmodulin competition assay, xenograft tumor assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro ubiquitination, calmodulin competition biochemistry, subcellular localization, in vivo xenograft, multiple orthogonal methods\",\n      \"pmids\": [\"22020328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"During Pseudomonas aeruginosa infection, FBXL2 is activated by calcium influx and localizes to the Golgi complex, where it monoubiquitinates and degrades CCTα (the rate-limiting enzyme for phosphatidylcholine synthesis) via binding to the IQ motif of CCTα through its C-terminus. Calmodulin traffics to the Golgi, binds FBXL2 (residues 80–90) via its C-terminus, and competes with FBXL2 for occupancy of the CCTα IQ motif, antagonizing FBXL2 activity.\",\n      \"method\": \"Co-IP, domain-mapping mutagenesis, calcium influx assays, Golgi fractionation/localization, RNAi knockdown, calmodulin gene transfer in murine pneumonia model\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic domain mapping, subcellular localization with functional consequence, in vivo murine model, multiple orthogonal approaches\",\n      \"pmids\": [\"21343341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SCF-FBXL2 mediates ubiquitination and proteasomal degradation of Aurora B kinase within the midbody during cytokinesis. Key ubiquitin acceptor lysines K102, K103, and K207 on Aurora B were identified; a triple K→R mutant resists SCF-FBXL2-directed polyubiquitination and causes anaphase delay and apoptosis when overexpressed.\",\n      \"method\": \"Ubiquitination assay, lysine-to-arginine mutagenesis of Aurora B, overexpression and knockdown, mitotic arrest/apoptosis assays, xenograft tumor model with small-molecule FBXL2 activator BC-1258\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro ubiquitination with site-directed mutagenesis, in vivo tumor model, multiple cellular readouts in one study\",\n      \"pmids\": [\"23928698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SCF-FBXL2 impairs cell proliferation by mediating cyclin D3 polyubiquitination and degradation; cyclin D3 and FBXL2 colocalize at the centrosome. FBXL2 overexpression disrupts cyclin D3 association with centrosomal assembly proteins Aurora A, Plk4, and CDK11.\",\n      \"method\": \"Ectopic expression and RNAi, ubiquitination assay, co-localization imaging, co-immunoprecipitation of cyclin D3 with centrosomal proteins\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, co-localization, and functional readouts but overlaps heavily with PMID:22020328; centrosomal protein interaction data adds new specificity\",\n      \"pmids\": [\"22024926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Fbxo3 promotes Fbxl2 ubiquitination and degradation; this relieves Fbxl2-mediated ubiquitination of TRAF2, leading to TRAF2 accumulation, TNIK activation, GluR1 phosphorylation, and trafficking of GluR1-containing AMPA receptors to the plasma membrane in dorsal horn neurons, contributing to neuropathic allodynia.\",\n      \"method\": \"Spinal nerve ligation rat model, intrathecal siRNA/inhibitor (BC-1215) injection, co-immunoprecipitation, GluR1 trafficking assays, behavioral allodynia measurement\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — epistasis established by in vivo knockdown and pharmacological inhibition, Co-IP for interactions, but in vivo complexity limits mechanistic precision\",\n      \"pmids\": [\"26674878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fbxo3 inhibits Fbxl2-mediated ubiquitination and degradation of the active zone protein RIM1α in the spinal dorsal horn. Deubiquitinated RIM1α accumulates in synaptic plasma membranes, directly binds CaV2.2, and increases presynaptic CaV2.2 expression, driving neuropathic allodynia.\",\n      \"method\": \"Spinal nerve ligation rat model, intrathecal BC-1215 (Fbxo3 inhibitor), siRNA knockdown of Fbxl2 and RIM1α, co-immunoprecipitation, subcellular fractionation, electrophysiology (sEPSC)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — epistasis via pharmacological and genetic tools, Co-IP for RIM1α-FBXL2 and RIM1α-CaV2.2, in vivo behavioral and electrophysiological readouts\",\n      \"pmids\": [\"27629721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FBXL2 interacts with the transcription factor FoxM1 and promotes its ubiquitination and proteasomal degradation in gastric cancer cells, thereby reducing expression of FoxM1 downstream targets Cdc25B and p27 and inhibiting cell proliferation and invasion.\",\n      \"method\": \"Tandem mass spectrometry, co-immunoprecipitation, ubiquitination assay, ectopic expression and knockdown, cell proliferation/invasion assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — MS identification plus Co-IP plus ubiquitination assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26790640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"O-GlcNAcylation promotes FBXL2 ubiquitination and degradation (FBXL2 is itself a target of ubiquitin-mediated degradation), leading to stabilization of FOXM1 (an FBXL2 ubiquitination substrate) and cancer cell proliferation. The O-GlcNAcase inhibitor Thiamet G reduces FBXL2-FOXM1 interaction and FOXM1 ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, pharmacological O-GlcNAcylation manipulation, western blot, cell proliferation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ubiquitination assays replicated across cell lines, but single lab and no direct identification of O-GlcNAc site on FBXL2\",\n      \"pmids\": [\"31679690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FUNDC1 interacts with FBXL2 via FBXL2's F-box domain; loss of FUNDC1 accelerates FBXL2 degradation and decelerates IP3R3 degradation, leading to mitochondrial Ca2+ overload. The FUNDC1-FBXL2 interaction thus functions as a gatekeeper for IP3R3 protein levels and mitochondrial Ca2+ homeostasis in the heart.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, FUNDC1-/- mouse model on high-fat diet, truncated F-box deletion mutants, FBXL2 overexpression/transfection, IP3R3 inhibition\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-confirmed interaction, Co-IP with domain mapping, genetic KO mouse model with cardiac phenotype, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"32938669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBXL2 targets EGFR (and TKI-resistant EGFR mutants) for proteasomal degradation. Grp94 (glucose-regulated protein 94) protects EGFR from this degradation by blocking FBXL2 binding to EGFR. Disruption of FBXL2 membrane localization (by GGTi-2418) or upregulation of FBXL2 expression (by nebivolol) reduces EGFR levels and inhibits NSCLC growth.\",\n      \"method\": \"Co-IP, proteasome inhibitor experiments, FBXL2 knockdown/overexpression, Grp94 manipulation, nebivolol treatment, xenograft models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, multiple EGFR mutants tested, in vivo xenograft validation, identification of competitive Grp94 mechanism, multiple orthogonal approaches\",\n      \"pmids\": [\"34635651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Smurf1 ubiquitinates and degrades FBXL2; loss of FBXL2 leads to activation of Wnt/β-catenin signaling, promoting colorectal cancer progression. FOSL1 drives this pathway by upregulating Smurf1.\",\n      \"method\": \"Co-IP, ubiquitination assay, FBXL2 and Smurf1 knockdown/overexpression, Wnt/β-catenin reporter, xenograft metastasis assay\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ubiquitination assay for Smurf1-FBXL2 interaction, in vivo xenograft, but single lab\",\n      \"pmids\": [\"33450386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBXL2 polyubiquitinates the transcription factor T-bet and co-immunoprecipitates with T-bet; ectopic FBXL2 expression reduces T-bet protein in a dose-dependent manner. TNF-α negatively regulates both FBXL2 mRNA and protein levels, providing cross-regulation of FBXL2 and T-bet during lung allograft rejection.\",\n      \"method\": \"Co-immunoprecipitation/pulldown, ubiquitination assay, FBXL2 transfection with dose-response, orthotopic lung transplant mouse model, immunohistochemistry, costimulation blockade treatment\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and ubiquitination assay supported by in vivo transplant model, single lab but multiple contexts tested\",\n      \"pmids\": [\"36113884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBXL2 targets transcription factor E47 for polyubiquitin- and proteasome-mediated degradation, inhibiting breast cancer stem cell stemness (CD44high/CD24low subpopulation, mammosphere formation) and overcoming paclitaxel resistance. Nebivolol (a β1 receptor inhibitor) activates FBXL2 expression to achieve this effect.\",\n      \"method\": \"Co-IP, ubiquitination assay, ectopic expression and knockdown, flow cytometry, mammosphere assay, in vivo xenograft, nebivolol treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP plus ubiquitination assay plus in vivo model, single lab\",\n      \"pmids\": [\"36460773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXL2 binds to and ubiquitinates both NLRP3 and pro-IL-1β (but not pro-caspase-1), targeting them for proteasome-mediated degradation. BC-1215 (an FBXO3 inhibitor that prevents FBXL2 ubiquitination/degradation) upregulates FBXL2 levels and thereby reduces NLRP3 and pro-IL-1β protein levels, suppressing ATP-induced IL-1β secretion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor (MG-132) rescue, FBXL2 overexpression, BC-1215 pharmacological treatment, western blot and ELISA\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and ubiquitination assays with proteasome rescue, single lab but multiple substrates tested with appropriate controls\",\n      \"pmids\": [\"37004285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TNF-α suppresses Fbxl2 mRNA expression in skeletal myoblasts by activating JNK-mediated phosphorylation of SP1, which impairs SP1 binding to the Fbxl2 core promoter (localized to bp -160 to +42). SP1 transcriptional activation of Fbxl2 is required for myogenic differentiation; FBXL2 knockdown in myoblasts activates MAP kinases and NF-κB, promotes proliferation, and impairs myotube formation.\",\n      \"method\": \"Chromatin immunoprecipitation, gel shift (EMSA), promoter reporter assays, SP1 phospho-site analysis, RNAi knockdown, myogenic differentiation assays, mRNA stability measurement\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and EMSA establish direct SP1-promoter interaction, functional knockdown phenotype, mechanistic link to JNK, single lab\",\n      \"pmids\": [\"32205409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FBXL2-mediated ubiquitination and degradation of TRAF6 is implicated in LIPUS-mediated protection against polyethylene debris-induced periprosthetic inflammatory loosening; LIPUS strengthens this FBXL2-TRAF6 ubiquitination pathway.\",\n      \"method\": \"Gene overexpression and siRNA in RAW264.7 macrophages, western blot for FBXL2 and TRAF6 levels, inflammatory cytokine measurement, LIPUS treatment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, no direct ubiquitination assay or Co-IP reported for FBXL2-TRAF6 in this paper; inferred from protein level changes\",\n      \"pmids\": [\"28378753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FBXL2 promotes HER2 polyubiquitination at lysine K747 and proteasomal degradation, reducing HER2 surface expression. Blocking FBXL2 membrane localization with GGTi-2418 or ketoconazole elevates HER2 expression on the plasma membrane of HER2-IHC 0 TNBC cells, sensitizing them to trastuzumab deruxtecan.\",\n      \"method\": \"Co-IP, site-directed mutagenesis (K747 ubiquitination site), proteasomal degradation assays, FBXL2 membrane localization inhibition, lipid nanoparticle delivery, xenograft models\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — site-specific ubiquitination mutagenesis, proteasomal degradation assays, membrane localization experiments with functional consequence, in vivo xenograft validation, single rigorous study\",\n      \"pmids\": [\"41612000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nrf2 transcriptionally upregulates FBXL2 expression; FBXL2 promotes NLRP3 ubiquitination-mediated degradation and suppresses pyroptosis. High glucose treatment decreases Nrf2 and FBXL2 and enhances NLRP3-mediated pyroptosis; scutellarin reverses this by increasing Nrf2/FBXL2.\",\n      \"method\": \"Dual-luciferase reporter assay (Nrf2 binding to FBXL2 promoter), immunoprecipitation for ubiquitination, western blotting, Nrf2 knockdown, FBXL2 knockdown, NLRP3 activation rescue\",\n      \"journal\": \"Endocrine journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Weak — luciferase reporter and Co-IP/ubiquitination assays, but single lab and limited mechanistic depth\",\n      \"pmids\": [\"40010729\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXL2 is the substrate-recognition subunit of an SCF-type E3 ubiquitin ligase (SCF-FBXL2) that requires membrane localization via geranylgeranylation and is negatively regulated by FBXO3-mediated ubiquitination and calmodulin competition; it ubiquitinates and targets for proteasomal degradation a broad range of substrates including IP3R3 (limiting ER-to-mitochondria Ca2+ transfer), the free p85β subunit of PI(3)K (sustaining PI(3)K signaling), cyclin D2/D3 (inducing cell cycle arrest), Aurora B (regulating cytokinesis), TRAF2/TRAF6, NLRP3, pro-IL-1β, FoxM1/FOXM1, E47, T-bet, CCTα, EGFR, HER2, and RIM1α, recognizing substrates often via calmodulin-binding (IQ) motifs rather than classical phosphodegrons, and its activity is regulated by calcium, PTEN competition (for IP3R3), Grp94 competition (for EGFR), FUNDC1 interaction (via the F-box domain), O-GlcNAcylation, and SP1-mediated transcription that is suppressed by TNF-α/JNK signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBXL2 is the substrate-recognition subunit of an SCF-type E3 ubiquitin ligase (SCF-FBXL2) that controls the abundance of a broad set of cell-cycle, signaling, and inflammatory proteins by directing them to proteasomal degradation [#0, #2]. A defining mechanistic feature is that FBXL2 frequently engages substrates through their calmodulin-binding (IQ) motifs rather than classical phosphodegrons, and calmodulin competes for these motifs to protect substrates from degradation, as shown for cyclin D2, cyclin D3, and CCT\\u03b1 [#2, #3, #4]. FBXL2 activity additionally requires geranylgeranylation-dependent membrane localization, and disrupting this localization pharmacologically (e.g. GGTi-2418) blocks degradation of membrane-associated substrates including IP3R3, EGFR, and HER2 [#0, #12, #19]. Through these activities FBXL2 limits ER-to-mitochondria Ca2+ transfer by degrading IP3R3 [#0], restrains proliferation by destabilizing cyclins D2/D3 and the transcription factors FoxM1, E47, and T-bet [#2, #3, #9, #14, #15], regulates cytokinesis via Aurora B turnover [#5], and dampens inflammation by degrading NLRP3, pro-IL-1\\u03b2, TRAF2, and TRAF6 [#7, #16, #18]. FBXL2 itself is a tightly regulated target: it is destabilized by FBXO3- and Smurf1-mediated ubiquitination and by O-GlcNAcylation, while substrate access is gated by competing partners such as PTEN (for IP3R3), Grp94 (for EGFR), and FUNDC1 (via the F-box domain) [#7, #10, #11, #12, #13]. Its expression is transcriptionally driven by SP1 and Nrf2 and suppressed by TNF-\\u03b1/JNK signaling [#17, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that FBXL2 acts as an SCF substrate receptor using a non-canonical recognition mode \\u2014 binding calmodulin-binding IQ motifs rather than phosphodegrons \\u2014 by showing it degrades cyclin D3 and the lipid-synthesis enzyme CCT\\u03b1 with calmodulin acting as a competitive protector.\",\n      \"evidence\": \"Ectopic expression/RNAi, in vitro ubiquitination, calmodulin competition assays, domain mapping, Golgi fractionation, and xenograft/murine models\",\n      \"pmids\": [\"22020328\", \"21343341\", \"22024926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of IQ-motif recognition by the FBXL2 LRR domain not resolved\", \"Generality of calmodulin competition across all substrates untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended the calmodulin-competition model to cyclin D2, demonstrating FBXL2 controls G0 arrest and apoptosis and linking its activity to leukemia biology.\",\n      \"evidence\": \"Ectopic FBXL2, RNAi, ubiquitination and calmodulin competition assays, cell-cycle analysis, patient sample analysis\",\n      \"pmids\": [\"22323446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo requirement for cyclin D2 turnover not established\", \"Relative contribution of D2 vs D3 to arrest unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved how FBXL2 sustains growth-factor signaling and how it regulates mitosis: it selectively degrades the free p85\\u03b2 pool of PI(3)K to promote p110-IRS1 coupling, and it degrades Aurora B at the midbody during cytokinesis.\",\n      \"evidence\": \"Affinity-MS, in vitro ubiquitylation, phospho-mutant analysis, lysine-to-arginine mutagenesis of Aurora B, IRS1 binding and autophagy readouts, xenograft with activator BC-1258\",\n      \"pmids\": [\"23604317\", \"23928698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Tyr655 phosphorylation gates p85\\u03b2 binding structurally not defined\", \"Coordination of Aurora B degradation timing with mitotic exit unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined upstream control of FBXL2 itself by showing FBXO3 ubiquitinates and degrades FBXL2, with epistatic consequences for TRAF2 stability and AMPA receptor trafficking in neuropathic pain.\",\n      \"evidence\": \"Spinal nerve ligation model, intrathecal siRNA/BC-1215, Co-IP, GluR1 trafficking and behavioral assays\",\n      \"pmids\": [\"26674878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct TRAF2 ubiquitination by FBXL2 inferred from epistasis, not reconstituted\", \"In vivo complexity limits assignment of effects to FBXL2 alone\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Broadened the FBXL2 substrate repertoire to transcription factors and active-zone proteins, identifying FoxM1 and RIM1\\u03b1 as targets controlling proliferation and presynaptic CaV2.2 signaling respectively.\",\n      \"evidence\": \"Tandem MS, Co-IP, ubiquitination assays, subcellular fractionation, electrophysiology, in vivo nerve ligation model\",\n      \"pmids\": [\"26790640\", \"27629721\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Recognition motifs on FoxM1 and RIM1\\u03b1 not mapped\", \"Single-lab findings without reciprocal validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified additional layers of FBXL2 regulation: FUNDC1 binds the F-box domain to gate IP3R3 turnover and cardiac mitochondrial Ca2+ homeostasis, and SP1 transcription (suppressed by TNF-\\u03b1/JNK) drives FBXL2 expression required for myogenic differentiation.\",\n      \"evidence\": \"MS, Co-IP with F-box deletion mutants, FUNDC1-/- mouse on high-fat diet; ChIP, EMSA, promoter reporters, SP1 phospho-analysis, differentiation assays\",\n      \"pmids\": [\"32938669\", \"32205409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FUNDC1 binding stabilizes FBXL2 mechanistically unclear\", \"JNK target site on SP1 not definitively mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established competitive substrate shielding and proteostatic control as recurring themes by showing Grp94 blocks EGFR degradation by FBXL2, and Smurf1 (driven by FOSL1) degrades FBXL2 to activate Wnt/\\u03b2-catenin signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, proteasome inhibition, knockdown/overexpression, Wnt reporter, nebivolol treatment, xenograft models\",\n      \"pmids\": [\"34635651\", \"33450386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Grp94-EGFR-FBXL2 competition not resolved\", \"Smurf1-FBXL2 link is single-lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected FBXL2 to immune and stemness regulation by demonstrating degradation of T-bet (modulated by TNF-\\u03b1) in lung allograft rejection and of E47 to suppress breast cancer stem-cell traits.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, dose-response transfection, orthotopic lung transplant and xenograft models, mammosphere and flow assays, nebivolol treatment\",\n      \"pmids\": [\"36113884\", \"36460773\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degron determinants on T-bet and E47 not defined\", \"Specificity over related bHLH/T-box factors untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated FBXL2 directly restrains inflammasome output by ubiquitinating and degrading NLRP3 and pro-IL-1\\u03b2 (but not pro-caspase-1), positioning FBXL2 stabilization (via FBXO3 inhibition) as a brake on IL-1\\u03b2 secretion.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, MG-132 rescue, FBXL2 overexpression, BC-1215 treatment, ELISA\",\n      \"pmids\": [\"37004285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate selectivity between NLRP3 and pro-IL-1\\u03b2 not dissected\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved a clinically actionable substrate by mapping FBXL2-driven HER2 polyubiquitination at K747, showing that blocking FBXL2 membrane localization elevates surface HER2 and sensitizes HER2-low TNBC to antibody-drug conjugates.\",\n      \"evidence\": \"Co-IP, K747 site-directed mutagenesis, proteasomal degradation assays, membrane-localization inhibition, lipid nanoparticle delivery, xenograft models\",\n      \"pmids\": [\"41612000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HER2 is recognized via an IQ-like motif unknown\", \"Endogenous physiological context of HER2 regulation by FBXL2 untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how FBXL2 achieves selectivity across its unusually broad substrate range and how its membrane localization, calmodulin/calcium status, and competing partners are integrated to license degradation of specific substrates in a given cell.\",\n      \"evidence\": \"No structural or systems-level study in the timeline addresses combined substrate-selection logic\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of FBXL2 bound to any substrate\", \"No global rules distinguishing IQ-motif from non-IQ substrates\", \"Quantitative interplay of calcium, calmodulin, and membrane targeting unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 9, 12, 14, 15, 16, 19]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 2, 3, 5, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 11, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 12, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 3, 5, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 12, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 16, 18, 20]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 13]}\n    ],\n    \"complexes\": [\"SCF-FBXL2 (SCF-type E3 ubiquitin ligase)\"],\n    \"partners\": [\"FBXO3\", \"FUNDC1\", \"PTEN\", \"Grp94\", \"Smurf1\", \"calmodulin\", \"IP3R3\", \"EGFR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}