{"gene":"FBXW10","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2010,"finding":"FBXW10, an F-box protein involved in E3 ubiquitin ligase activity, is transcriptionally induced by mislocalized lamin A rod domain mutants (G232E, Q294P, R386K) and mediates proteasomal degradation of HP1alpha and HP1beta (but not HP1gamma) via ubiquitin-mediated pathway; ectopic expression of FBXW10 in HeLa cells depleted HP1alpha and HP1beta without altering HP1gamma levels.","method":"Ectopic overexpression of FBXW10 in HeLa cells, transcript analysis, proteasomal inhibitor (MG132) rescue experiments","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, ectopic expression plus inhibitor rescue; two orthogonal approaches but no direct ubiquitination assay or binding confirmation","pmids":["20498703"],"is_preprint":false},{"year":2012,"finding":"FBXW10 (along with RNF123 and HECW2) is transcriptionally upregulated by lamin A mutant expression or lamin A shRNA knockdown, and ectopic expression of FBXW10 directly causes proteasomal degradation of ATR kinase within the nucleus; this degradation was reversed by MG132 but not by the nuclear export inhibitor leptomycin B, indicating nuclear degradation of ATR.","method":"Ectopic FBXW10 overexpression, proteasomal inhibitor (MG132) rescue, nuclear export inhibitor (leptomycin B) experiments, transcript analysis","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, two orthogonal methods (overexpression + chemical inhibitors), no direct ubiquitination assay for FBXW10-ATR interaction","pmids":["22382637"],"is_preprint":false},{"year":2017,"finding":"Belinostat transcriptionally upregulates FBXW10 (and FBXO3), which directly targets SOS (son of sevenless), an upstream regulator of the MAPK pathway, for proteasome-mediated degradation; siRNA knockdown of FBXW10 abrogated the suppression of the SOS/ERK pathway by belinostat in lung squamous cell carcinoma cells.","method":"siRNA knockdown of FBXW10, belinostat drug treatment, phosphoproteomic analysis, bortezomib proteasomal inhibition","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined pathway phenotype plus pharmacological validation, single lab","pmids":["28397399"],"is_preprint":false},{"year":2020,"finding":"FBXW10, as a component of SCF E3 ubiquitin ligases, promotes hepatocellular carcinoma cell proliferation and migration in HCC cell lines, and male FBXW10-transgenic mice showed increased susceptibility to tumorigenesis, liver injury, and inflammation, establishing a functional role for FBXW10 in hepatocarcinogenesis with a male-biased effect.","method":"FBXW10 transgenic (Tg) mouse model, HCC cell line overexpression/knockdown, proliferation and migration assays","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model plus in vitro functional assays, single lab, no direct substrate identified","pmids":["31400758"],"is_preprint":false},{"year":2023,"finding":"FBXW10, as part of the SCF E3 ubiquitin ligase complex, promotes K63-linked polyubiquitination and activation of ANXA2 (Annexin A2) in male HCC tissues; this process requires S6K1-mediated phosphorylation of ANXA2, and the activated ANXA2 translocates from cytoplasm to cell membrane to bind KRAS, activating the MEK/ERK pathway to drive HCC proliferation and lung metastasis.","method":"Co-immunoprecipitation, ubiquitination assays, in vitro and in vivo knockdown/overexpression experiments, phosphorylation site mapping, subcellular fractionation/localization","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assays, phosphorylation analysis, in vivo mouse models, multiple orthogonal methods in single study","pmids":["37277019"],"is_preprint":false},{"year":2023,"finding":"FBXW10 promotes K48- or K63-linked polyubiquitination and activation of GAPDH; VRK2-dependent phosphorylation of GAPDH at Ser151 is required for FBXW10-mediated GAPDH ubiquitination and activation; activated GAPDH interacts with TRAF2 to upregulate canonical and noncanonical NF-κB pathways, increasing PD-L1 and AR-VRK2 expression, leading to immune evasion and HCC tumorigenesis in males; and this axis is driven by androgen receptor (AR)-mediated VRK2 upregulation.","method":"In vitro ubiquitination assays, phosphorylation site mutagenesis (Ser151), Co-IP, transgenic mouse models, GAPDH inhibitor (koningic acid) treatment in vivo","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ubiquitination assays with mutagenesis, in vivo transgenic models, pharmacological validation, multiple orthogonal methods in a single study","pmids":["37450367"],"is_preprint":false},{"year":2023,"finding":"FBXW10 (as SCF E3 ubiquitin ligase) ubiquitinates LATS2 (large tumor suppressor kinase 2) and promotes its proteasomal degradation, requiring the F-box region of FBXW10; this leads to upregulation of angiogenesis and liver metastasis in colorectal cancer.","method":"Ubiquitination assays, FBXW10 overexpression/knockdown in vitro and in vivo (xenograft/knockout models), F-box domain mutant analysis","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assays plus in vivo knockout, F-box domain mutagenesis; single lab","pmids":["36990424"],"is_preprint":false},{"year":2025,"finding":"ZNF169 transcription factor promotes FBXW10 expression by binding to the FBXW10 promoter (demonstrated by luciferase reporter assay and ChIP-PCR), placing FBXW10 downstream of ZNF169 in a regulatory axis driving thyroid cancer proliferation and tumor growth.","method":"Luciferase reporter assay, ChIP-PCR, FBXW10 knockdown rescue experiments in vitro and in vivo","journal":"Cell division","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding (ChIP-PCR + luciferase), rescue experiments; single lab","pmids":["39875985"],"is_preprint":false},{"year":2025,"finding":"VSIG2 competes with FBXW10 for binding to ANXA2 at the cell membrane; when VSIG2 levels are high, it blocks FBXW10-mediated K63-linked polyubiquitination of ANXA2, preventing ANXA2 membrane localization and NF-κB activation, thereby suppressing gastric cancer progression.","method":"Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assays, in vitro and in vivo (nude mouse) models","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assays, in vivo model; single lab, single study","pmids":["41185558"],"is_preprint":false}],"current_model":"FBXW10 is an F-box protein component of SCF-type E3 ubiquitin ligase complexes that mediates polyubiquitination (K63- and/or K48-linked) and proteasomal degradation or activation of multiple substrates including HP1alpha/beta, ATR kinase, SOS, ANXA2, GAPDH, and LATS2; in hepatocellular carcinoma, FBXW10 drives male-biased tumorigenesis through two parallel axes—S6K1-phosphorylation-dependent K63-ubiquitination of ANXA2 leading to KRAS/MEK/ERK activation, and VRK2-phosphorylation-dependent GAPDH ubiquitination leading to TRAF2/NF-κB/PD-L1/AR signaling—while in other cancers it promotes oncogenesis by degrading tumor suppressors such as LATS2 or activating the MAPK pathway via SOS degradation."},"narrative":{"mechanistic_narrative":"FBXW10 is an F-box protein that functions as the substrate-recognition subunit of SCF-type E3 ubiquitin ligase complexes, directing the polyubiquitination of diverse substrates to either destabilize or activate them and thereby controlling chromatin regulators, DNA-damage signaling, and pro-oncogenic pathways [PMID:20498703, PMID:37277019, PMID:36990424]. In its degradative mode it targets the heterochromatin proteins HP1alpha and HP1beta but not HP1gamma for proteasomal turnover [PMID:20498703], drives intranuclear proteasomal degradation of the ATR kinase [PMID:22382637], and eliminates the MAPK regulator SOS and the tumor suppressor kinase LATS2, the latter requiring its intact F-box region [PMID:28397399, PMID:36990424]. A distinct, non-degradative branch of FBXW10 activity operates in hepatocellular carcinoma, where it catalyzes K63-linked polyubiquitination that activates rather than destroys its substrates: S6K1-phosphorylated ANXA2 is K63-ubiquitinated, driving its membrane translocation, KRAS binding, and MEK/ERK activation [PMID:37277019], while VRK2-phosphorylated GAPDH (Ser151) is ubiquitinated to engage TRAF2 and amplify NF-kappaB signaling that elevates PD-L1 and androgen-receptor output, producing a male-biased, immune-evasive tumorigenic program [PMID:31400758, PMID:37450367]. FBXW10 expression is itself controlled at the promoter level, being induced by mislocalized lamin A mutants, by HDAC inhibition, and by the transcription factor ZNF169 [PMID:20498703, PMID:28397399, PMID:39875985], and its ANXA2 axis is antagonized by VSIG2, which competes for ANXA2 binding to block its K63-ubiquitination [PMID:41185558].","teleology":[{"year":2010,"claim":"Established that FBXW10 acts as an E3 ligase substrate-recognition factor by linking its transcriptional induction to selective proteasomal turnover of heterochromatin proteins.","evidence":"Ectopic FBXW10 overexpression in HeLa cells with MG132 rescue and transcript analysis","pmids":["20498703"],"confidence":"Medium","gaps":["No direct ubiquitination assay or FBXW10–HP1 binding demonstrated","Basis for HP1alpha/beta vs HP1gamma selectivity unknown","SCF complex composition not defined"]},{"year":2012,"claim":"Extended FBXW10 substrate repertoire to DNA-damage signaling by showing it triggers intranuclear proteasomal degradation of ATR kinase.","evidence":"Ectopic FBXW10 overexpression with MG132 and leptomycin B rescue, transcript analysis","pmids":["22382637"],"confidence":"Medium","gaps":["No direct ubiquitination or binding assay for FBXW10–ATR","Phenotypic consequence for DNA-damage response untested","Physiological context of induction unclear"]},{"year":2017,"claim":"Connected FBXW10 to MAPK pathway control by identifying SOS as a degradation target downstream of HDAC inhibition.","evidence":"siRNA knockdown plus belinostat treatment and bortezomib inhibition with phosphoproteomics in lung squamous carcinoma cells","pmids":["28397399"],"confidence":"Medium","gaps":["Direct FBXW10–SOS ubiquitination not shown","Whether FBXW10 binds SOS directly unresolved"]},{"year":2020,"claim":"Demonstrated an in vivo oncogenic role with male bias, framing FBXW10 as a driver of hepatocarcinogenesis rather than a passive ubiquitin component.","evidence":"FBXW10 transgenic mouse model and HCC cell line proliferation/migration assays","pmids":["31400758"],"confidence":"Medium","gaps":["No substrate identified in this study","Mechanism of male-biased effect undefined"]},{"year":2023,"claim":"Revealed a non-degradative, activating mode of FBXW10 ubiquitination, mechanistically explaining the HCC phenotype via two parallel substrate axes.","evidence":"Reciprocal Co-IP, ubiquitination assays, phosphosite mapping, subcellular fractionation, and transgenic mouse models for ANXA2 (S6K1/K63/KRAS-MEK-ERK) and GAPDH (VRK2/Ser151/TRAF2-NF-kappaB/PD-L1/AR)","pmids":["37277019","37450367"],"confidence":"High","gaps":["How FBXW10 discriminates activating K63 vs degradative K48 linkage is unresolved","Direct contribution of SCF core subunits to these reactions not dissected","Generality of activating ubiquitination beyond HCC unknown"]},{"year":2023,"claim":"Showed FBXW10 also degrades a bona fide tumor suppressor in a different cancer, supporting a broad pro-oncogenic function dependent on its F-box.","evidence":"Ubiquitination assays, in vivo xenograft/knockout models, and F-box domain mutagenesis for LATS2 in colorectal cancer","pmids":["36990424"],"confidence":"Medium","gaps":["Phosphodegron or recognition motif on LATS2 not mapped","Single lab"]},{"year":2025,"claim":"Placed FBXW10 within transcriptional and competitive regulatory circuits, defining how its levels and substrate access are controlled.","evidence":"ZNF169 promoter binding by luciferase/ChIP-PCR in thyroid cancer; VSIG2 competition for ANXA2 binding by Co-IP, immunofluorescence, and in vivo gastric cancer models","pmids":["39875985","41185558"],"confidence":"Medium","gaps":["Whether ZNF169 control of FBXW10 operates outside thyroid cancer untested","Structural basis of VSIG2/FBXW10 competition for ANXA2 undefined"]},{"year":null,"claim":"The molecular determinants by which FBXW10 chooses degradative versus activating ubiquitin linkage and recognizes its varied substrates remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of FBXW10 substrate-binding interface","No defined degron/recognition motif shared across substrates","Determinant of K48 vs K63 linkage choice unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,4,6]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[4,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,8]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,4,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,4,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,5,6]}],"complexes":["SCF E3 ubiquitin ligase"],"partners":["ANXA2","GAPDH","LATS2","ATR","SOS","VSIG2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5XX13","full_name":"F-box/WD repeat-containing protein 10","aliases":["F-box and WD-40 domain-containing protein 10","Ubiquitin ligase-specificity factor"],"length_aa":1052,"mass_kda":119.8,"function":"Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Overexpression is leading to degradation of CBX5 and CBX1","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q5XX13/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBXW10","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1165,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FBXW10","total_profiled":1310},"omim":[{"mim_id":"618952","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 46; COXPD46","url":"https://www.omim.org/entry/618952"},{"mim_id":"611985","title":"MITOCHONDRIAL RIBOSOMAL PROTEIN S23; MRPS23","url":"https://www.omim.org/entry/611985"},{"mim_id":"611679","title":"F-BOX AND WD40 DOMAIN PROTEIN 10; FBXW10","url":"https://www.omim.org/entry/611679"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"testis","ntpm":9.1}],"url":"https://www.proteinatlas.org/search/FBXW10"},"hgnc":{"alias_symbol":["SM2SH2","HREP","Fbw10"],"prev_symbol":["C17orf1","C17orf1A"]},"alphafold":{"accession":"Q5XX13","domains":[{"cath_id":"-","chopping":"24-89_108-166_257-272","consensus_level":"medium","plddt":76.0073,"start":24,"end":272},{"cath_id":"-","chopping":"282-334","consensus_level":"high","plddt":81.8489,"start":282,"end":334}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5XX13","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5XX13-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5XX13-F1-predicted_aligned_error_v6.png","plddt_mean":61.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBXW10","jax_strain_url":"https://www.jax.org/strain/search?query=FBXW10"},"sequence":{"accession":"Q5XX13","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5XX13.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5XX13/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5XX13"}},"corpus_meta":[{"pmid":"24825865","id":"PMC_24825865","title":"Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia.","date":"2014","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/24825865","citation_count":218,"is_preprint":false},{"pmid":"20498703","id":"PMC_20498703","title":"Lamin A rod domain mutants target heterochromatin protein 1alpha and beta for proteasomal degradation by activation of F-box protein, FBXW10.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20498703","citation_count":42,"is_preprint":false},{"pmid":"22382637","id":"PMC_22382637","title":"Lamin misexpression upregulates three distinct ubiquitin ligase systems that degrade ATR kinase in HeLa cells.","date":"2012","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22382637","citation_count":26,"is_preprint":false},{"pmid":"26722292","id":"PMC_26722292","title":"Abnormal methylation status of FBXW10 and SMPD3, and associations with clinical characteristics in clear cell renal cell carcinoma.","date":"2015","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/26722292","citation_count":25,"is_preprint":false},{"pmid":"28397399","id":"PMC_28397399","title":"Belinostat exerts antitumor cytotoxicity through the ubiquitin-proteasome pathway in lung squamous cell carcinoma.","date":"2017","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28397399","citation_count":25,"is_preprint":false},{"pmid":"37277019","id":"PMC_37277019","title":"FBXW10-S6K1 promotes ANXA2 polyubiquitination and KRAS activation to drive hepatocellular carcinoma development in males.","date":"2023","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/37277019","citation_count":21,"is_preprint":false},{"pmid":"31712638","id":"PMC_31712638","title":"KMT2C, a histone methyltransferase, is mutated in a family segregating non-syndromic primary failure of tooth eruption.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31712638","citation_count":21,"is_preprint":false},{"pmid":"37450367","id":"PMC_37450367","title":"Elevated FBXW10 drives hepatocellular carcinoma tumorigenesis via AR-VRK2 phosphorylation-dependent GAPDH ubiquitination in male transgenic mice.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37450367","citation_count":19,"is_preprint":false},{"pmid":"31400758","id":"PMC_31400758","title":"FBXW10 promotes hepatocarcinogenesis in male patients and mice.","date":"2020","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/31400758","citation_count":14,"is_preprint":false},{"pmid":"35909123","id":"PMC_35909123","title":"Identification of immune-related and autophagy-related genes for the prediction of survival in bladder cancer.","date":"2022","source":"BMC genomic 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cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37775405","citation_count":2,"is_preprint":false},{"pmid":"39875985","id":"PMC_39875985","title":"ZNF169 promotes thyroid cancer progression via upregulating FBXW10.","date":"2025","source":"Cell division","url":"https://pubmed.ncbi.nlm.nih.gov/39875985","citation_count":1,"is_preprint":false},{"pmid":"41185558","id":"PMC_41185558","title":"VSIG2 hinders gastric cancer progression by suppressing ANXA2-mediated NF-κB pathway activation.","date":"2025","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/41185558","citation_count":0,"is_preprint":false},{"pmid":"41749864","id":"PMC_41749864","title":"Pimozide Reprograms the Ran GTPase-SCF Axis and Matrix Remodeling Pathways in Breast, Colorectal, and Pancreatic Cancer Models.","date":"2026","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/41749864","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10356,"output_tokens":2577,"usd":0.034861,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9712,"output_tokens":2893,"usd":0.060443,"stage2_stop_reason":"end_turn"},"total_usd":0.095304,"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\": 2010,\n      \"finding\": \"FBXW10, an F-box protein involved in E3 ubiquitin ligase activity, is transcriptionally induced by mislocalized lamin A rod domain mutants (G232E, Q294P, R386K) and mediates proteasomal degradation of HP1alpha and HP1beta (but not HP1gamma) via ubiquitin-mediated pathway; ectopic expression of FBXW10 in HeLa cells depleted HP1alpha and HP1beta without altering HP1gamma levels.\",\n      \"method\": \"Ectopic overexpression of FBXW10 in HeLa cells, transcript analysis, proteasomal inhibitor (MG132) rescue experiments\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, ectopic expression plus inhibitor rescue; two orthogonal approaches but no direct ubiquitination assay or binding confirmation\",\n      \"pmids\": [\"20498703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FBXW10 (along with RNF123 and HECW2) is transcriptionally upregulated by lamin A mutant expression or lamin A shRNA knockdown, and ectopic expression of FBXW10 directly causes proteasomal degradation of ATR kinase within the nucleus; this degradation was reversed by MG132 but not by the nuclear export inhibitor leptomycin B, indicating nuclear degradation of ATR.\",\n      \"method\": \"Ectopic FBXW10 overexpression, proteasomal inhibitor (MG132) rescue, nuclear export inhibitor (leptomycin B) experiments, transcript analysis\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, two orthogonal methods (overexpression + chemical inhibitors), no direct ubiquitination assay for FBXW10-ATR interaction\",\n      \"pmids\": [\"22382637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Belinostat transcriptionally upregulates FBXW10 (and FBXO3), which directly targets SOS (son of sevenless), an upstream regulator of the MAPK pathway, for proteasome-mediated degradation; siRNA knockdown of FBXW10 abrogated the suppression of the SOS/ERK pathway by belinostat in lung squamous cell carcinoma cells.\",\n      \"method\": \"siRNA knockdown of FBXW10, belinostat drug treatment, phosphoproteomic analysis, bortezomib proteasomal inhibition\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined pathway phenotype plus pharmacological validation, single lab\",\n      \"pmids\": [\"28397399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FBXW10, as a component of SCF E3 ubiquitin ligases, promotes hepatocellular carcinoma cell proliferation and migration in HCC cell lines, and male FBXW10-transgenic mice showed increased susceptibility to tumorigenesis, liver injury, and inflammation, establishing a functional role for FBXW10 in hepatocarcinogenesis with a male-biased effect.\",\n      \"method\": \"FBXW10 transgenic (Tg) mouse model, HCC cell line overexpression/knockdown, proliferation and migration assays\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model plus in vitro functional assays, single lab, no direct substrate identified\",\n      \"pmids\": [\"31400758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXW10, as part of the SCF E3 ubiquitin ligase complex, promotes K63-linked polyubiquitination and activation of ANXA2 (Annexin A2) in male HCC tissues; this process requires S6K1-mediated phosphorylation of ANXA2, and the activated ANXA2 translocates from cytoplasm to cell membrane to bind KRAS, activating the MEK/ERK pathway to drive HCC proliferation and lung metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, in vitro and in vivo knockdown/overexpression experiments, phosphorylation site mapping, subcellular fractionation/localization\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assays, phosphorylation analysis, in vivo mouse models, multiple orthogonal methods in single study\",\n      \"pmids\": [\"37277019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXW10 promotes K48- or K63-linked polyubiquitination and activation of GAPDH; VRK2-dependent phosphorylation of GAPDH at Ser151 is required for FBXW10-mediated GAPDH ubiquitination and activation; activated GAPDH interacts with TRAF2 to upregulate canonical and noncanonical NF-κB pathways, increasing PD-L1 and AR-VRK2 expression, leading to immune evasion and HCC tumorigenesis in males; and this axis is driven by androgen receptor (AR)-mediated VRK2 upregulation.\",\n      \"method\": \"In vitro ubiquitination assays, phosphorylation site mutagenesis (Ser151), Co-IP, transgenic mouse models, GAPDH inhibitor (koningic acid) treatment in vivo\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ubiquitination assays with mutagenesis, in vivo transgenic models, pharmacological validation, multiple orthogonal methods in a single study\",\n      \"pmids\": [\"37450367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXW10 (as SCF E3 ubiquitin ligase) ubiquitinates LATS2 (large tumor suppressor kinase 2) and promotes its proteasomal degradation, requiring the F-box region of FBXW10; this leads to upregulation of angiogenesis and liver metastasis in colorectal cancer.\",\n      \"method\": \"Ubiquitination assays, FBXW10 overexpression/knockdown in vitro and in vivo (xenograft/knockout models), F-box domain mutant analysis\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assays plus in vivo knockout, F-box domain mutagenesis; single lab\",\n      \"pmids\": [\"36990424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZNF169 transcription factor promotes FBXW10 expression by binding to the FBXW10 promoter (demonstrated by luciferase reporter assay and ChIP-PCR), placing FBXW10 downstream of ZNF169 in a regulatory axis driving thyroid cancer proliferation and tumor growth.\",\n      \"method\": \"Luciferase reporter assay, ChIP-PCR, FBXW10 knockdown rescue experiments in vitro and in vivo\",\n      \"journal\": \"Cell division\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding (ChIP-PCR + luciferase), rescue experiments; single lab\",\n      \"pmids\": [\"39875985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VSIG2 competes with FBXW10 for binding to ANXA2 at the cell membrane; when VSIG2 levels are high, it blocks FBXW10-mediated K63-linked polyubiquitination of ANXA2, preventing ANXA2 membrane localization and NF-κB activation, thereby suppressing gastric cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assays, in vitro and in vivo (nude mouse) models\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assays, in vivo model; single lab, single study\",\n      \"pmids\": [\"41185558\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXW10 is an F-box protein component of SCF-type E3 ubiquitin ligase complexes that mediates polyubiquitination (K63- and/or K48-linked) and proteasomal degradation or activation of multiple substrates including HP1alpha/beta, ATR kinase, SOS, ANXA2, GAPDH, and LATS2; in hepatocellular carcinoma, FBXW10 drives male-biased tumorigenesis through two parallel axes—S6K1-phosphorylation-dependent K63-ubiquitination of ANXA2 leading to KRAS/MEK/ERK activation, and VRK2-phosphorylation-dependent GAPDH ubiquitination leading to TRAF2/NF-κB/PD-L1/AR signaling—while in other cancers it promotes oncogenesis by degrading tumor suppressors such as LATS2 or activating the MAPK pathway via SOS degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBXW10 is an F-box protein that functions as the substrate-recognition subunit of SCF-type E3 ubiquitin ligase complexes, directing the polyubiquitination of diverse substrates to either destabilize or activate them and thereby controlling chromatin regulators, DNA-damage signaling, and pro-oncogenic pathways [#0, #4, #6]. In its degradative mode it targets the heterochromatin proteins HP1alpha and HP1beta but not HP1gamma for proteasomal turnover [#0], drives intranuclear proteasomal degradation of the ATR kinase [#1], and eliminates the MAPK regulator SOS and the tumor suppressor kinase LATS2, the latter requiring its intact F-box region [#2, #6]. A distinct, non-degradative branch of FBXW10 activity operates in hepatocellular carcinoma, where it catalyzes K63-linked polyubiquitination that activates rather than destroys its substrates: S6K1-phosphorylated ANXA2 is K63-ubiquitinated, driving its membrane translocation, KRAS binding, and MEK/ERK activation [#4], while VRK2-phosphorylated GAPDH (Ser151) is ubiquitinated to engage TRAF2 and amplify NF-kappaB signaling that elevates PD-L1 and androgen-receptor output, producing a male-biased, immune-evasive tumorigenic program [#3, #5]. FBXW10 expression is itself controlled at the promoter level, being induced by mislocalized lamin A mutants, by HDAC inhibition, and by the transcription factor ZNF169 [#0, #2, #7], and its ANXA2 axis is antagonized by VSIG2, which competes for ANXA2 binding to block its K63-ubiquitination [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that FBXW10 acts as an E3 ligase substrate-recognition factor by linking its transcriptional induction to selective proteasomal turnover of heterochromatin proteins.\",\n      \"evidence\": \"Ectopic FBXW10 overexpression in HeLa cells with MG132 rescue and transcript analysis\",\n      \"pmids\": [\"20498703\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct ubiquitination assay or FBXW10\\u2013HP1 binding demonstrated\", \"Basis for HP1alpha/beta vs HP1gamma selectivity unknown\", \"SCF complex composition not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended FBXW10 substrate repertoire to DNA-damage signaling by showing it triggers intranuclear proteasomal degradation of ATR kinase.\",\n      \"evidence\": \"Ectopic FBXW10 overexpression with MG132 and leptomycin B rescue, transcript analysis\",\n      \"pmids\": [\"22382637\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct ubiquitination or binding assay for FBXW10\\u2013ATR\", \"Phenotypic consequence for DNA-damage response untested\", \"Physiological context of induction unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected FBXW10 to MAPK pathway control by identifying SOS as a degradation target downstream of HDAC inhibition.\",\n      \"evidence\": \"siRNA knockdown plus belinostat treatment and bortezomib inhibition with phosphoproteomics in lung squamous carcinoma cells\",\n      \"pmids\": [\"28397399\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct FBXW10\\u2013SOS ubiquitination not shown\", \"Whether FBXW10 binds SOS directly unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated an in vivo oncogenic role with male bias, framing FBXW10 as a driver of hepatocarcinogenesis rather than a passive ubiquitin component.\",\n      \"evidence\": \"FBXW10 transgenic mouse model and HCC cell line proliferation/migration assays\",\n      \"pmids\": [\"31400758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No substrate identified in this study\", \"Mechanism of male-biased effect undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a non-degradative, activating mode of FBXW10 ubiquitination, mechanistically explaining the HCC phenotype via two parallel substrate axes.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assays, phosphosite mapping, subcellular fractionation, and transgenic mouse models for ANXA2 (S6K1/K63/KRAS-MEK-ERK) and GAPDH (VRK2/Ser151/TRAF2-NF-kappaB/PD-L1/AR)\",\n      \"pmids\": [\"37277019\", \"37450367\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FBXW10 discriminates activating K63 vs degradative K48 linkage is unresolved\", \"Direct contribution of SCF core subunits to these reactions not dissected\", \"Generality of activating ubiquitination beyond HCC unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed FBXW10 also degrades a bona fide tumor suppressor in a different cancer, supporting a broad pro-oncogenic function dependent on its F-box.\",\n      \"evidence\": \"Ubiquitination assays, in vivo xenograft/knockout models, and F-box domain mutagenesis for LATS2 in colorectal cancer\",\n      \"pmids\": [\"36990424\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphodegron or recognition motif on LATS2 not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed FBXW10 within transcriptional and competitive regulatory circuits, defining how its levels and substrate access are controlled.\",\n      \"evidence\": \"ZNF169 promoter binding by luciferase/ChIP-PCR in thyroid cancer; VSIG2 competition for ANXA2 binding by Co-IP, immunofluorescence, and in vivo gastric cancer models\",\n      \"pmids\": [\"39875985\", \"41185558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ZNF169 control of FBXW10 operates outside thyroid cancer untested\", \"Structural basis of VSIG2/FBXW10 competition for ANXA2 undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular determinants by which FBXW10 chooses degradative versus activating ubiquitin linkage and recognizes its varied substrates remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of FBXW10 substrate-binding interface\", \"No defined degron/recognition motif shared across substrates\", \"Determinant of K48 vs K63 linkage choice unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 4, 6]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 4, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 5, 6]}\n    ],\n    \"complexes\": [\"SCF E3 ubiquitin ligase\"],\n    \"partners\": [\"ANXA2\", \"GAPDH\", \"LATS2\", \"ATR\", \"SOS\", \"VSIG2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}