{"gene":"FBXW10","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2010,"finding":"FBXW10, an F-box protein component of E3 ubiquitin ligase complexes, is induced by mislocalized lamin A rod domain mutants (G232E, Q294P, R386K) and promotes ubiquitin-mediated proteasomal degradation of HP1alpha and HP1beta (but not HP1gamma). Ectopic expression of FBXW10 in HeLa cells depleted HP1alpha and HP1beta, and proteasomal inhibitors restored HP1 levels.","method":"Ectopic overexpression of FBXW10 in HeLa cells, proteasomal inhibitor rescue, transcript analysis, ubiquitination assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, overexpression + proteasomal inhibitor rescue, no in vitro reconstitution of ubiquitination","pmids":["20498703"],"is_preprint":false},{"year":2023,"finding":"FBXW10 promotes K63-linked polyubiquitination and activation of ANXA2 in HCC, a process requiring S6K1-mediated phosphorylation of ANXA2. Activated ANXA2 translocates from cytoplasm to cell membrane, binds KRAS, and activates the MEK/ERK pathway, driving HCC proliferation and lung metastasis.","method":"Co-immunoprecipitation, ubiquitination assays (K63-linkage-specific), phosphorylation assays, subcellular fractionation/localization, in vitro and in vivo knockdown/overexpression with proliferation and metastasis readouts","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, ubiquitination assay, localization, in vivo), single lab","pmids":["37277019"],"is_preprint":false},{"year":2023,"finding":"FBXW10 promotes polyubiquitination and activation of GAPDH; VRK2-dependent phosphorylation of GAPDH Ser151 is required for FBXW10-mediated GAPDH ubiquitination and activation. Activated GAPDH interacts with TRAF2, upregulating canonical and noncanonical NF-κB pathways and increasing PD-L1 and AR-VRK2 expression, driving HCC tumorigenesis and immune evasion in males.","method":"Ubiquitination assays, phosphorylation site mutagenesis (Ser151), Co-immunoprecipitation (GAPDH-TRAF2 interaction), transgenic mouse model, GAPDH inhibitor (koningic acid) rescue in vivo","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis of phosphorylation site, multiple orthogonal biochemical assays, in vivo transgenic model, single lab with strong mechanistic resolution","pmids":["37450367"],"is_preprint":false},{"year":2023,"finding":"FBXW10 (as part of the SCF E3 ubiquitin ligase complex) ubiquitinates LATS2 and promotes its proteasomal degradation; the F-box region of FBXW10 is essential for this activity. LATS2 degradation promotes angiogenesis and liver metastasis in colorectal cancer.","method":"Co-immunoprecipitation, ubiquitination assays, F-box domain deletion/mutation, in vitro and in vivo knockdown/overexpression with angiogenesis and metastasis readouts","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct ubiquitination assay with domain mapping, supported by in vivo data, single lab","pmids":["36990424"],"is_preprint":false},{"year":2025,"finding":"ZNF169 directly binds the FBXW10 promoter and enhances FBXW10 transcription, placing FBXW10 downstream of ZNF169 in thyroid cancer; FBXW10 knockdown reverses the pro-proliferative effects of ZNF169 overexpression in vitro and in vivo.","method":"Luciferase reporter assay, ChIP-PCR, knockdown/overexpression rescue assays in cells and animal models","journal":"Cell division","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-PCR and luciferase assay establish direct transcriptional regulation; rescue experiments confirm epistasis; single lab","pmids":["39875985"],"is_preprint":false}],"current_model":"FBXW10 is an F-box protein subunit of SCF-type E3 ubiquitin ligase complexes that polyubiquitinates multiple substrates (HP1alpha/beta, ANXA2, GAPDH, LATS2) to promote their activation or proteasomal degradation, with substrate selection regulated by upstream kinases (S6K1, VRK2) that phosphorylate target proteins, and its own transcription controlled by transcription factors such as ZNF169, collectively driving oncogenic signaling (MEK/ERK, NF-κB) and tumor progression, particularly in male HCC."},"narrative":{"teleology":[{"year":2010,"claim":"Establishing FBXW10 as an F-box E3 ligase component capable of targeting specific chromatin-associated substrates for proteasomal degradation answered the initial question of whether FBXW10 has ubiquitin ligase activity and identified HP1α/β as its first substrates.","evidence":"Ectopic overexpression in HeLa cells with proteasomal inhibitor rescue and ubiquitination assays","pmids":["20498703"],"confidence":"Medium","gaps":["No in vitro reconstitution of FBXW10-dependent ubiquitination of HP1α/β","Physiological conditions triggering FBXW10-mediated HP1 degradation beyond lamin A mutant context are unknown","Whether SCF complex assembly is required was not directly tested"]},{"year":2023,"claim":"Demonstrating that FBXW10 can catalyze non-degradative K63-linked polyubiquitination (of ANXA2 and GAPDH) expanded its functional repertoire beyond proteasomal targeting and linked it to activation of MEK/ERK and NF-κB oncogenic pathways in HCC, while revealing that upstream kinases (S6K1 for ANXA2, VRK2 for GAPDH) gate substrate recognition.","evidence":"K63-linkage-specific ubiquitination assays, phosphorylation site mutagenesis (GAPDH S151), Co-IP of substrate–effector interactions (ANXA2–KRAS, GAPDH–TRAF2), subcellular fractionation, and in vivo HCC/metastasis models including transgenic mice","pmids":["37277019","37450367"],"confidence":"High","gaps":["Direct biochemical reconstitution of FBXW10 SCF complex with purified substrates has not been performed","How FBXW10 selects between K48 and K63 ubiquitin chain linkages on different substrates is unknown","Male-specific HCC phenotype linked to GAPDH–NF-κB–AR axis has not been validated in independent cohorts"]},{"year":2023,"claim":"Identifying LATS2 as a degradative substrate of FBXW10 and mapping the requirement for the F-box domain established that FBXW10 promotes angiogenesis and colorectal cancer metastasis through Hippo pathway inactivation, broadening its oncogenic substrate repertoire beyond HCC.","evidence":"Co-IP, ubiquitination assays, F-box domain deletion mutants, in vivo knockdown/overexpression with angiogenesis and liver metastasis readouts","pmids":["36990424"],"confidence":"Medium","gaps":["Degron motif on LATS2 recognized by FBXW10 WD40 repeats has not been mapped","Whether LATS2 ubiquitination requires prior phosphorylation (analogous to ANXA2/GAPDH) is untested","Single-lab finding without independent replication"]},{"year":2025,"claim":"Showing that ZNF169 directly binds the FBXW10 promoter to drive its transcription answered how FBXW10 expression is regulated and placed it within a defined transcriptional–oncogenic axis in thyroid cancer.","evidence":"ChIP-PCR, luciferase reporter assay, knockdown/overexpression epistasis rescue in cells and xenograft models","pmids":["39875985"],"confidence":"Medium","gaps":["Other transcription factors regulating FBXW10 in different tumor contexts are unknown","Whether ZNF169-driven FBXW10 expression engages the same downstream substrates (ANXA2, GAPDH, LATS2) in thyroid cancer has not been tested","Single-lab finding in one cancer type"]},{"year":null,"claim":"The structural basis for FBXW10 substrate recognition by its WD40 repeats, the mechanism determining K48 versus K63 ubiquitin chain specificity, and the full spectrum of physiological substrates remain uncharacterized.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of FBXW10 or its SCF complex exists","No unbiased proteomics screen for FBXW10 substrates has been reported","Mechanism of ubiquitin chain-type selection is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,3]}],"complexes":["SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex"],"partners":["ANXA2","GAPDH","LATS2","CBX5","CBX1","ZNF169"],"other_free_text":[]},"mechanistic_narrative":"FBXW10 is an F-box protein that functions as the substrate-recognition subunit of SCF-type E3 ubiquitin ligase complexes, directing both K48-linked degradative and K63-linked activating polyubiquitination of distinct substrates. FBXW10 promotes proteasomal degradation of the heterochromatin proteins HP1α and HP1β and of the Hippo pathway kinase LATS2, the latter requiring an intact F-box domain [PMID:20498703, PMID:36990424]. FBXW10 also catalyzes K63-linked polyubiquitination and activation of ANXA2 (dependent on S6K1-mediated phosphorylation) and of GAPDH (dependent on VRK2-mediated Ser151 phosphorylation), thereby engaging MEK/ERK and NF-κB oncogenic signaling, respectively, and driving hepatocellular carcinoma proliferation, metastasis, and immune evasion [PMID:37277019, PMID:37450367]. FBXW10 transcription is directly activated by ZNF169 binding its promoter, and FBXW10 is required for ZNF169-driven proliferation in thyroid cancer [PMID:39875985]."},"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":"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":"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":"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":20,"is_preprint":false},{"pmid":"11371518","id":"PMC_11371518","title":"HreP, an in vivo-expressed protease of Yersinia enterocolitica, is a new member of the family of subtilisin/kexin-like proteases.","date":"2001","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/11371518","citation_count":20,"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":17,"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":"9799091","id":"PMC_9799091","title":"The NIK protein kinase and C17orf1 genes: chromosomal mapping, gene structures and mutational screening in frontotemporal dementia and parkinsonism linked to chromosome 17.","date":"1998","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9799091","citation_count":12,"is_preprint":false},{"pmid":"19114497","id":"PMC_19114497","title":"A regulatory network controls expression of the in vivo-expressed HreP protease of Yersinia enterocolitica.","date":"2008","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/19114497","citation_count":8,"is_preprint":false},{"pmid":"9787083","id":"PMC_9787083","title":"Genomic structure and physical mapping of C17orf1: a gene associated with the proximal element of the CMT1A-REP binary repeat.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9787083","citation_count":7,"is_preprint":false},{"pmid":"36990424","id":"PMC_36990424","title":"The E3 ubiquitin ligase SCF (FBXW10)-mediated LATS2 degradation regulates angiogenesis and liver metastasis in colorectal cancer.","date":"2023","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/36990424","citation_count":4,"is_preprint":false},{"pmid":"37775405","id":"PMC_37775405","title":"FBXW10: a male-biased E3 ligase in liver cancer.","date":"2023","source":"Trends in 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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6933,"output_tokens":1469,"usd":0.021417},"stage2":{"model":"claude-opus-4-6","input_tokens":4695,"output_tokens":1884,"usd":0.105862},"total_usd":0.127279,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"FBXW10, an F-box protein component of E3 ubiquitin ligase complexes, is induced by mislocalized lamin A rod domain mutants (G232E, Q294P, R386K) and promotes ubiquitin-mediated proteasomal degradation of HP1alpha and HP1beta (but not HP1gamma). Ectopic expression of FBXW10 in HeLa cells depleted HP1alpha and HP1beta, and proteasomal inhibitors restored HP1 levels.\",\n      \"method\": \"Ectopic overexpression of FBXW10 in HeLa cells, proteasomal inhibitor rescue, transcript analysis, ubiquitination assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, overexpression + proteasomal inhibitor rescue, no in vitro reconstitution of ubiquitination\",\n      \"pmids\": [\"20498703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXW10 promotes K63-linked polyubiquitination and activation of ANXA2 in HCC, a process requiring S6K1-mediated phosphorylation of ANXA2. Activated ANXA2 translocates from cytoplasm to cell membrane, binds KRAS, and activates the MEK/ERK pathway, driving HCC proliferation and lung metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays (K63-linkage-specific), phosphorylation assays, subcellular fractionation/localization, in vitro and in vivo knockdown/overexpression with proliferation and metastasis readouts\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, ubiquitination assay, localization, in vivo), single lab\",\n      \"pmids\": [\"37277019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXW10 promotes polyubiquitination and activation of GAPDH; VRK2-dependent phosphorylation of GAPDH Ser151 is required for FBXW10-mediated GAPDH ubiquitination and activation. Activated GAPDH interacts with TRAF2, upregulating canonical and noncanonical NF-κB pathways and increasing PD-L1 and AR-VRK2 expression, driving HCC tumorigenesis and immune evasion in males.\",\n      \"method\": \"Ubiquitination assays, phosphorylation site mutagenesis (Ser151), Co-immunoprecipitation (GAPDH-TRAF2 interaction), transgenic mouse model, GAPDH inhibitor (koningic acid) rescue in vivo\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis of phosphorylation site, multiple orthogonal biochemical assays, in vivo transgenic model, single lab with strong mechanistic resolution\",\n      \"pmids\": [\"37450367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXW10 (as part of the SCF E3 ubiquitin ligase complex) ubiquitinates LATS2 and promotes its proteasomal degradation; the F-box region of FBXW10 is essential for this activity. LATS2 degradation promotes angiogenesis and liver metastasis in colorectal cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, F-box domain deletion/mutation, in vitro and in vivo knockdown/overexpression with angiogenesis and metastasis readouts\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct ubiquitination assay with domain mapping, supported by in vivo data, single lab\",\n      \"pmids\": [\"36990424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZNF169 directly binds the FBXW10 promoter and enhances FBXW10 transcription, placing FBXW10 downstream of ZNF169 in thyroid cancer; FBXW10 knockdown reverses the pro-proliferative effects of ZNF169 overexpression in vitro and in vivo.\",\n      \"method\": \"Luciferase reporter assay, ChIP-PCR, knockdown/overexpression rescue assays in cells and animal models\",\n      \"journal\": \"Cell division\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-PCR and luciferase assay establish direct transcriptional regulation; rescue experiments confirm epistasis; single lab\",\n      \"pmids\": [\"39875985\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXW10 is an F-box protein subunit of SCF-type E3 ubiquitin ligase complexes that polyubiquitinates multiple substrates (HP1alpha/beta, ANXA2, GAPDH, LATS2) to promote their activation or proteasomal degradation, with substrate selection regulated by upstream kinases (S6K1, VRK2) that phosphorylate target proteins, and its own transcription controlled by transcription factors such as ZNF169, collectively driving oncogenic signaling (MEK/ERK, NF-κB) and tumor progression, particularly in male HCC.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FBXW10 is an F-box protein that functions as the substrate-recognition subunit of SCF-type E3 ubiquitin ligase complexes, directing both K48-linked degradative and K63-linked activating polyubiquitination of distinct substrates. FBXW10 promotes proteasomal degradation of the heterochromatin proteins HP1α and HP1β and of the Hippo pathway kinase LATS2, the latter requiring an intact F-box domain [PMID:20498703, PMID:36990424]. FBXW10 also catalyzes K63-linked polyubiquitination and activation of ANXA2 (dependent on S6K1-mediated phosphorylation) and of GAPDH (dependent on VRK2-mediated Ser151 phosphorylation), thereby engaging MEK/ERK and NF-κB oncogenic signaling, respectively, and driving hepatocellular carcinoma proliferation, metastasis, and immune evasion [PMID:37277019, PMID:37450367]. FBXW10 transcription is directly activated by ZNF169 binding its promoter, and FBXW10 is required for ZNF169-driven proliferation in thyroid cancer [PMID:39875985].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing FBXW10 as an F-box E3 ligase component capable of targeting specific chromatin-associated substrates for proteasomal degradation answered the initial question of whether FBXW10 has ubiquitin ligase activity and identified HP1α/β as its first substrates.\",\n      \"evidence\": \"Ectopic overexpression in HeLa cells with proteasomal inhibitor rescue and ubiquitination assays\",\n      \"pmids\": [\"20498703\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro reconstitution of FBXW10-dependent ubiquitination of HP1α/β\",\n        \"Physiological conditions triggering FBXW10-mediated HP1 degradation beyond lamin A mutant context are unknown\",\n        \"Whether SCF complex assembly is required was not directly tested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that FBXW10 can catalyze non-degradative K63-linked polyubiquitination (of ANXA2 and GAPDH) expanded its functional repertoire beyond proteasomal targeting and linked it to activation of MEK/ERK and NF-κB oncogenic pathways in HCC, while revealing that upstream kinases (S6K1 for ANXA2, VRK2 for GAPDH) gate substrate recognition.\",\n      \"evidence\": \"K63-linkage-specific ubiquitination assays, phosphorylation site mutagenesis (GAPDH S151), Co-IP of substrate–effector interactions (ANXA2–KRAS, GAPDH–TRAF2), subcellular fractionation, and in vivo HCC/metastasis models including transgenic mice\",\n      \"pmids\": [\"37277019\", \"37450367\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct biochemical reconstitution of FBXW10 SCF complex with purified substrates has not been performed\",\n        \"How FBXW10 selects between K48 and K63 ubiquitin chain linkages on different substrates is unknown\",\n        \"Male-specific HCC phenotype linked to GAPDH–NF-κB–AR axis has not been validated in independent cohorts\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying LATS2 as a degradative substrate of FBXW10 and mapping the requirement for the F-box domain established that FBXW10 promotes angiogenesis and colorectal cancer metastasis through Hippo pathway inactivation, broadening its oncogenic substrate repertoire beyond HCC.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, F-box domain deletion mutants, in vivo knockdown/overexpression with angiogenesis and liver metastasis readouts\",\n      \"pmids\": [\"36990424\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Degron motif on LATS2 recognized by FBXW10 WD40 repeats has not been mapped\",\n        \"Whether LATS2 ubiquitination requires prior phosphorylation (analogous to ANXA2/GAPDH) is untested\",\n        \"Single-lab finding without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing that ZNF169 directly binds the FBXW10 promoter to drive its transcription answered how FBXW10 expression is regulated and placed it within a defined transcriptional–oncogenic axis in thyroid cancer.\",\n      \"evidence\": \"ChIP-PCR, luciferase reporter assay, knockdown/overexpression epistasis rescue in cells and xenograft models\",\n      \"pmids\": [\"39875985\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Other transcription factors regulating FBXW10 in different tumor contexts are unknown\",\n        \"Whether ZNF169-driven FBXW10 expression engages the same downstream substrates (ANXA2, GAPDH, LATS2) in thyroid cancer has not been tested\",\n        \"Single-lab finding in one cancer type\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for FBXW10 substrate recognition by its WD40 repeats, the mechanism determining K48 versus K63 ubiquitin chain specificity, and the full spectrum of physiological substrates remain uncharacterized.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of FBXW10 or its SCF complex exists\",\n        \"No unbiased proteomics screen for FBXW10 substrates has been reported\",\n        \"Mechanism of ubiquitin chain-type selection is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"complexes\": [\n      \"SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex\"\n    ],\n    \"partners\": [\n      \"ANXA2\",\n      \"GAPDH\",\n      \"LATS2\",\n      \"CBX5\",\n      \"CBX1\",\n      \"ZNF169\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}