{"gene":"UGT2B28","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2001,"finding":"UGT2B28 type I catalyzes the glucuronidation (transfer of glucuronic acid) of endogenous steroids and exogenous compounds; the cofactor-binding domain and substrate-binding domain are both required for glucuronidation activity, but neither is required for subcellular localization to the endoplasmic reticulum and perinuclear membrane.","method":"Glucuronidation assays in heterologous expression system; sequence analysis of deletion isoforms; subcellular localization studies of all three isoforms","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct enzymatic activity assay plus domain-deletion isoforms and subcellular localization, single lab but multiple orthogonal methods","pmids":["11300766"],"is_preprint":false},{"year":2015,"finding":"UGT2B28 acts as a regulator of steroidogenesis: tumor overexpression of UGT2B28 correlates with ~30% higher circulating testosterone and DHT levels, while patients with zero genomic copies of UGT2B28 have lower levels of testosterone (19%), DHT (17%), their glucuronide metabolites (18–38%), and elevated androstenedione (36%), demonstrating that UGT2B28 enzymatic activity modulates systemic androgen bioavailability.","method":"Mass spectrometry measurement of circulating steroid hormones in prostate cancer patients stratified by UGT2B28 gene copy number; tumor tissue microarray expression analysis","journal":"European urology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative mass spectrometry of hormone levels in genotyped human cohort, single lab, two complementary approaches (copy number and expression)","pmids":["26215610"],"is_preprint":false},{"year":2022,"finding":"UGT2B28 physically interacts with the endocytic adaptor protein HIP1 (huntingtin-interacting protein 1), stabilizing HIP1 protein and thereby activating AR and EGFR signaling pathways, leading to ERK1/2 activation, cell proliferation, and epithelial-to-mesenchymal transition (EMT) in prostate cancer cells; HIP1 knockdown or dual pharmacological targeting of AR and EGFR abolished the proliferative advantage conferred by UGT2B28.","method":"Co-immunoprecipitation/protein interaction assays; HIP1 knockdown; pharmacological inhibition of AR and EGFR; cell proliferation and EMT assays; functional rescue experiments","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal protein interaction plus genetic (siRNA) and pharmacological epistasis, single lab, multiple orthogonal functional readouts","pmids":["36343786"],"is_preprint":false},{"year":2022,"finding":"UGT2B28 expression is transcriptionally regulated by full-length androgen receptor (AR) and the splice variant AR-v7; genetic knockdown of UGT2B28 in multiple PCa cell lines impairs 3D organoid formation and delays xenograft tumor growth, both rescued by re-expression of UGT2B28, establishing a cell-autonomous tumor-promoting role.","method":"AR/ARv7 modulation with expression readout; siRNA knockdown in LNCaP, LAPC-4, VCaP cell lines; 3D organoid formation assay; xenograft tumor growth assay with rescue by re-expression","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotype plus rescue experiment, multiple cell lines, single lab","pmids":["35954173"],"is_preprint":false},{"year":2011,"finding":"UGT2B28 mRNA is specifically expressed in breast and adipose tissue among human tissues examined; quantitative RT-PCR confirmed that UGT2B28 expression is distinct from the closely related UGT2B11 (97% cDNA identity), with UGT2B11 expressed in liver, breast, and kidney while UGT2B28 is not detected in liver.","method":"Quantitative real-time RT-PCR with isoform-specific primers across human tissue panel","journal":"Drug metabolism letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — specific and validated quantitative localization method, single lab, single method","pmids":["21679149"],"is_preprint":false}],"current_model":"UGT2B28 is an endoplasmic reticulum-resident UDP-glucuronosyltransferase that glucuronidates androgens (testosterone, DHT) and other steroids to regulate systemic androgen bioavailability; beyond its conjugating enzyme role, UGT2B28 acts as a non-canonical signaling scaffold by binding and stabilizing the endocytic adaptor HIP1, thereby activating AR and EGFR/ERK1/2 pathways to drive prostate cancer cell proliferation and EMT, with its own expression regulated by AR and AR-v7."},"narrative":{"mechanistic_narrative":"UGT2B28 is an endoplasmic reticulum-resident UDP-glucuronosyltransferase that conjugates glucuronic acid onto endogenous steroids and exogenous compounds, with both its cofactor-binding and substrate-binding domains required for catalysis but dispensable for ER and perinuclear membrane localization [PMID:11300766]. Functionally, its enzymatic activity sets systemic androgen tone: tumor overexpression correlates with elevated circulating testosterone and DHT, while loss of UGT2B28 gene copies lowers androgen and androgen-glucuronide levels and raises androstenedione, establishing UGT2B28 as a modulator of androgen bioavailability [PMID:26215610]. Beyond conjugation, UGT2B28 functions as a tumor-promoting factor in prostate cancer: it physically binds and stabilizes the endocytic adaptor HIP1 to activate AR and EGFR/ERK1/2 signaling, driving proliferation and epithelial-to-mesenchymal transition, with HIP1 knockdown or combined AR/EGFR inhibition abolishing this advantage [PMID:36343786]. UGT2B28 expression is itself controlled transcriptionally by full-length AR and the AR-v7 splice variant, and its knockdown impairs organoid formation and xenograft growth in a manner rescued by re-expression, defining a cell-autonomous oncogenic role embedded in an AR feed-forward loop [PMID:35954173].","teleology":[{"year":2001,"claim":"Established UGT2B28 as a catalytically active glucuronosyltransferase and separated its enzymatic domains from the determinants of its ER localization, defining it as an ER-resident conjugating enzyme.","evidence":"Glucuronidation assays in heterologous expression with domain-deletion isoforms and subcellular localization of all isoforms","pmids":["11300766"],"confidence":"High","gaps":["Specific endogenous steroid substrates and kinetic preferences not fully delineated","Physiological tissue context of catalysis not addressed here"]},{"year":2011,"claim":"Distinguished UGT2B28 from the near-identical paralog UGT2B11 by tissue expression, showing UGT2B28 is restricted to breast and adipose and absent from liver.","evidence":"Isoform-specific quantitative RT-PCR across a human tissue panel","pmids":["21679149"],"confidence":"Medium","gaps":["mRNA expression not linked to protein levels or activity","Regulatory basis of the tissue-restricted pattern unknown"]},{"year":2015,"claim":"Connected UGT2B28 enzymatic activity to systemic physiology by demonstrating that its expression and gene copy number track circulating androgen levels in prostate cancer patients.","evidence":"Mass spectrometry of circulating steroids in patients stratified by UGT2B28 copy number plus tumor expression analysis","pmids":["26215610"],"confidence":"Medium","gaps":["Correlative human data without mechanistic causation in vivo","Does not establish whether systemic effects derive from tumor or peripheral metabolism"]},{"year":2022,"claim":"Revealed a non-catalytic, scaffold-like function: UGT2B28 binds and stabilizes HIP1 to activate AR and EGFR/ERK1/2 signaling and drive proliferation and EMT, expanding its role beyond steroid conjugation.","evidence":"Co-immunoprecipitation, HIP1 knockdown, AR/EGFR pharmacological inhibition, and proliferation/EMT rescue assays in prostate cancer cells","pmids":["36343786"],"confidence":"Medium","gaps":["Whether scaffold function requires catalytic activity not resolved","Structural basis of the UGT2B28-HIP1 interaction unknown","Single-lab interaction data"]},{"year":2022,"claim":"Placed UGT2B28 within an AR feed-forward circuit and demonstrated cell-autonomous tumor-promoting activity through loss-of-function with rescue.","evidence":"AR/AR-v7 modulation, siRNA knockdown across LNCaP/LAPC-4/VCaP, 3D organoid and xenograft assays with re-expression rescue","pmids":["35954173"],"confidence":"Medium","gaps":["Direct AR binding to the UGT2B28 promoter not mapped","Relative contribution of enzymatic versus scaffold function to tumor growth unresolved"]},{"year":null,"claim":"How UGT2B28's enzymatic conjugating activity, HIP1-scaffold signaling function, and AR-driven transcriptional regulation are mechanistically integrated within a single protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking catalytic and scaffold functions","Causal role of androgen modulation versus signaling in tumor progression not separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3]}],"complexes":[],"partners":["HIP1","AR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BY64","full_name":"UDP-glucuronosyltransferase 2B28","aliases":[],"length_aa":529,"mass_kda":60.9,"function":"UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:11300766). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:11300766). Catalyzes the glucuronidation of endogenous steroid hormones such as androgens (androsterone, 3alpha-androstanediol) and estrogens (estradiol, estrone) (PubMed:11300766). Catalyzes the glucuronidation of bile acid substrates, which are natural detergents for dietary lipids absorption (PubMed:11300766). Displays glucuronidation activity toward the phenolic compounds eugenol (PubMed:11300766) Lack UDP-glucuronosyltransferase (UGT) activity","subcellular_location":"Endoplasmic reticulum membrane; Cytoplasm, perinuclear region","url":"https://www.uniprot.org/uniprotkb/Q9BY64/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UGT2B28","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/UGT2B28","total_profiled":1310},"omim":[{"mim_id":"606497","title":"URIDINE DIPHOSPHATE GLYCOSYLTRANSFERASE 2 FAMILY, MEMBER B28; UGT2B28","url":"https://www.omim.org/entry/606497"},{"mim_id":"601903","title":"URIDINE DIPHOSPHATE GLYCOSYLTRANSFERASE 2 FAMILY, MEMBER B17; UGT2B17","url":"https://www.omim.org/entry/601903"},{"mim_id":"600069","title":"URIDINE DIPHOSPHATE GLYCOSYLTRANSFERASE 2 FAMILY, MEMBER B15; UGT2B15","url":"https://www.omim.org/entry/600069"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"breast","ntpm":186.9}],"url":"https://www.proteinatlas.org/search/UGT2B28"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9BY64","domains":[{"cath_id":"3.40.50.2000","chopping":"26-281_456-483","consensus_level":"high","plddt":93.7473,"start":26,"end":483},{"cath_id":"3.40.50.2000","chopping":"291-451","consensus_level":"high","plddt":96.4826,"start":291,"end":451}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BY64","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BY64-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BY64-F1-predicted_aligned_error_v6.png","plddt_mean":92.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UGT2B28","jax_strain_url":"https://www.jax.org/strain/search?query=UGT2B28"},"sequence":{"accession":"Q9BY64","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BY64.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BY64/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BY64"}},"corpus_meta":[{"pmid":"11300766","id":"PMC_11300766","title":"Isolation and characterization of the UGT2B28 cDNA encoding a novel human steroid conjugating UDP-glucuronosyltransferase.","date":"2001","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11300766","citation_count":96,"is_preprint":false},{"pmid":"19572376","id":"PMC_19572376","title":"Copy-number variations (CNVs) of the human sex steroid metabolizing genes UGT2B17 and UGT2B28 and their associations with a UGT2B15 functional polymorphism.","date":"2009","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/19572376","citation_count":48,"is_preprint":false},{"pmid":"23575887","id":"PMC_23575887","title":"The effect of copy number variation in the phase II detoxification genes UGT2B17 and UGT2B28 on colorectal cancer risk.","date":"2013","source":"Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23575887","citation_count":39,"is_preprint":false},{"pmid":"26215610","id":"PMC_26215610","title":"The UGT2B28 Sex-steroid Inactivation Pathway Is a Regulator of Steroidogenesis and Modifies the Risk of Prostate Cancer Progression.","date":"2015","source":"European urology","url":"https://pubmed.ncbi.nlm.nih.gov/26215610","citation_count":34,"is_preprint":false},{"pmid":"26693059","id":"PMC_26693059","title":"Germline copy number loss of UGT2B28 and gain of PLEC contribute to increased human esophageal squamous cell carcinoma risk in Southwest China.","date":"2015","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26693059","citation_count":13,"is_preprint":false},{"pmid":"21679149","id":"PMC_21679149","title":"Quantitative analysis of UGT2B28 mRNA expression by real-time RT-PCR and application to human tissue distribution study.","date":"2011","source":"Drug metabolism letters","url":"https://pubmed.ncbi.nlm.nih.gov/21679149","citation_count":9,"is_preprint":false},{"pmid":"28882566","id":"PMC_28882566","title":"Genetic variations in UGT2B28, UGT2B17, UGT2B15 genes and the risk of prostate cancer: A case-control study.","date":"2017","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/28882566","citation_count":9,"is_preprint":false},{"pmid":"36343786","id":"PMC_36343786","title":"UGT2B28 accelerates prostate cancer progression through stabilization of the endocytic adaptor protein HIP1 regulating AR and EGFR pathways.","date":"2022","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/36343786","citation_count":8,"is_preprint":false},{"pmid":"27665939","id":"PMC_27665939","title":"UGT2B28 genomic variation is associated with hepatitis B e-antigen seroconversion in response to antiviral therapy.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27665939","citation_count":4,"is_preprint":false},{"pmid":"35954173","id":"PMC_35954173","title":"Uridine Diphosphate Glucuronosyl Transferase 2B28 (UGT2B28) Promotes Tumor Progression and Is Elevated in African American Prostate Cancer Patients.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35954173","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7751,"output_tokens":1410,"usd":0.022201,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8125,"output_tokens":2148,"usd":0.047163,"stage2_stop_reason":"end_turn"},"total_usd":0.069364,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"UGT2B28 type I catalyzes the glucuronidation (transfer of glucuronic acid) of endogenous steroids and exogenous compounds; the cofactor-binding domain and substrate-binding domain are both required for glucuronidation activity, but neither is required for subcellular localization to the endoplasmic reticulum and perinuclear membrane.\",\n      \"method\": \"Glucuronidation assays in heterologous expression system; sequence analysis of deletion isoforms; subcellular localization studies of all three isoforms\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct enzymatic activity assay plus domain-deletion isoforms and subcellular localization, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"11300766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"UGT2B28 acts as a regulator of steroidogenesis: tumor overexpression of UGT2B28 correlates with ~30% higher circulating testosterone and DHT levels, while patients with zero genomic copies of UGT2B28 have lower levels of testosterone (19%), DHT (17%), their glucuronide metabolites (18–38%), and elevated androstenedione (36%), demonstrating that UGT2B28 enzymatic activity modulates systemic androgen bioavailability.\",\n      \"method\": \"Mass spectrometry measurement of circulating steroid hormones in prostate cancer patients stratified by UGT2B28 gene copy number; tumor tissue microarray expression analysis\",\n      \"journal\": \"European urology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative mass spectrometry of hormone levels in genotyped human cohort, single lab, two complementary approaches (copy number and expression)\",\n      \"pmids\": [\"26215610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UGT2B28 physically interacts with the endocytic adaptor protein HIP1 (huntingtin-interacting protein 1), stabilizing HIP1 protein and thereby activating AR and EGFR signaling pathways, leading to ERK1/2 activation, cell proliferation, and epithelial-to-mesenchymal transition (EMT) in prostate cancer cells; HIP1 knockdown or dual pharmacological targeting of AR and EGFR abolished the proliferative advantage conferred by UGT2B28.\",\n      \"method\": \"Co-immunoprecipitation/protein interaction assays; HIP1 knockdown; pharmacological inhibition of AR and EGFR; cell proliferation and EMT assays; functional rescue experiments\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal protein interaction plus genetic (siRNA) and pharmacological epistasis, single lab, multiple orthogonal functional readouts\",\n      \"pmids\": [\"36343786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UGT2B28 expression is transcriptionally regulated by full-length androgen receptor (AR) and the splice variant AR-v7; genetic knockdown of UGT2B28 in multiple PCa cell lines impairs 3D organoid formation and delays xenograft tumor growth, both rescued by re-expression of UGT2B28, establishing a cell-autonomous tumor-promoting role.\",\n      \"method\": \"AR/ARv7 modulation with expression readout; siRNA knockdown in LNCaP, LAPC-4, VCaP cell lines; 3D organoid formation assay; xenograft tumor growth assay with rescue by re-expression\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotype plus rescue experiment, multiple cell lines, single lab\",\n      \"pmids\": [\"35954173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"UGT2B28 mRNA is specifically expressed in breast and adipose tissue among human tissues examined; quantitative RT-PCR confirmed that UGT2B28 expression is distinct from the closely related UGT2B11 (97% cDNA identity), with UGT2B11 expressed in liver, breast, and kidney while UGT2B28 is not detected in liver.\",\n      \"method\": \"Quantitative real-time RT-PCR with isoform-specific primers across human tissue panel\",\n      \"journal\": \"Drug metabolism letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — specific and validated quantitative localization method, single lab, single method\",\n      \"pmids\": [\"21679149\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UGT2B28 is an endoplasmic reticulum-resident UDP-glucuronosyltransferase that glucuronidates androgens (testosterone, DHT) and other steroids to regulate systemic androgen bioavailability; beyond its conjugating enzyme role, UGT2B28 acts as a non-canonical signaling scaffold by binding and stabilizing the endocytic adaptor HIP1, thereby activating AR and EGFR/ERK1/2 pathways to drive prostate cancer cell proliferation and EMT, with its own expression regulated by AR and AR-v7.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UGT2B28 is an endoplasmic reticulum-resident UDP-glucuronosyltransferase that conjugates glucuronic acid onto endogenous steroids and exogenous compounds, with both its cofactor-binding and substrate-binding domains required for catalysis but dispensable for ER and perinuclear membrane localization [#0]. Functionally, its enzymatic activity sets systemic androgen tone: tumor overexpression correlates with elevated circulating testosterone and DHT, while loss of UGT2B28 gene copies lowers androgen and androgen-glucuronide levels and raises androstenedione, establishing UGT2B28 as a modulator of androgen bioavailability [#1]. Beyond conjugation, UGT2B28 functions as a tumor-promoting factor in prostate cancer: it physically binds and stabilizes the endocytic adaptor HIP1 to activate AR and EGFR/ERK1/2 signaling, driving proliferation and epithelial-to-mesenchymal transition, with HIP1 knockdown or combined AR/EGFR inhibition abolishing this advantage [#2]. UGT2B28 expression is itself controlled transcriptionally by full-length AR and the AR-v7 splice variant, and its knockdown impairs organoid formation and xenograft growth in a manner rescued by re-expression, defining a cell-autonomous oncogenic role embedded in an AR feed-forward loop [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established UGT2B28 as a catalytically active glucuronosyltransferase and separated its enzymatic domains from the determinants of its ER localization, defining it as an ER-resident conjugating enzyme.\",\n      \"evidence\": \"Glucuronidation assays in heterologous expression with domain-deletion isoforms and subcellular localization of all isoforms\",\n      \"pmids\": [\"11300766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific endogenous steroid substrates and kinetic preferences not fully delineated\", \"Physiological tissue context of catalysis not addressed here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Distinguished UGT2B28 from the near-identical paralog UGT2B11 by tissue expression, showing UGT2B28 is restricted to breast and adipose and absent from liver.\",\n      \"evidence\": \"Isoform-specific quantitative RT-PCR across a human tissue panel\",\n      \"pmids\": [\"21679149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mRNA expression not linked to protein levels or activity\", \"Regulatory basis of the tissue-restricted pattern unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected UGT2B28 enzymatic activity to systemic physiology by demonstrating that its expression and gene copy number track circulating androgen levels in prostate cancer patients.\",\n      \"evidence\": \"Mass spectrometry of circulating steroids in patients stratified by UGT2B28 copy number plus tumor expression analysis\",\n      \"pmids\": [\"26215610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative human data without mechanistic causation in vivo\", \"Does not establish whether systemic effects derive from tumor or peripheral metabolism\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a non-catalytic, scaffold-like function: UGT2B28 binds and stabilizes HIP1 to activate AR and EGFR/ERK1/2 signaling and drive proliferation and EMT, expanding its role beyond steroid conjugation.\",\n      \"evidence\": \"Co-immunoprecipitation, HIP1 knockdown, AR/EGFR pharmacological inhibition, and proliferation/EMT rescue assays in prostate cancer cells\",\n      \"pmids\": [\"36343786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether scaffold function requires catalytic activity not resolved\", \"Structural basis of the UGT2B28-HIP1 interaction unknown\", \"Single-lab interaction data\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed UGT2B28 within an AR feed-forward circuit and demonstrated cell-autonomous tumor-promoting activity through loss-of-function with rescue.\",\n      \"evidence\": \"AR/AR-v7 modulation, siRNA knockdown across LNCaP/LAPC-4/VCaP, 3D organoid and xenograft assays with re-expression rescue\",\n      \"pmids\": [\"35954173\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AR binding to the UGT2B28 promoter not mapped\", \"Relative contribution of enzymatic versus scaffold function to tumor growth unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How UGT2B28's enzymatic conjugating activity, HIP1-scaffold signaling function, and AR-driven transcriptional regulation are mechanistically integrated within a single protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking catalytic and scaffold functions\", \"Causal role of androgen modulation versus signaling in tumor progression not separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HIP1\", \"AR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}