{"gene":"TBL2","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":1999,"finding":"TBL2 encodes a protein with four putative WD40-repeat domains and is expressed predominantly in testis, skeletal muscle, heart and endocrine tissues; an alternatively spliced transcript introduces an in-frame stop codon producing a 75 amino acid N-terminal fragment. The mouse ortholog shares 92% amino acid similarity and maps to chromosome 5 in synteny with human 7q11.23.","method":"cDNA cloning, genomic sequencing, RT-PCR, comparative sequence analysis","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — structural/sequence characterization across two species with RT-PCR validation, single lab","pmids":["10575226"],"is_preprint":false},{"year":2014,"finding":"TBL2 is an ER-localized type-I transmembrane protein that preferentially binds to the phosphorylated form of PERK (but not GCN2 or IRE1) under ER stress. TBL2 interacts with PERK via its N-terminus proximal region and associates with eIF2α via its WD40 domain. TBL2 knockdown impairs ATF4 induction under ER stress and nutrient deprivation, and renders cells more vulnerable to these stresses similarly to PERK knockdown.","method":"Immunoprecipitation with deletion mutants, subcellular fractionation/localization, siRNA knockdown, western blotting","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with deletion mutant mapping, subcellular localization, and functional KD phenotype in single lab with multiple orthogonal methods","pmids":["25393282"],"is_preprint":false},{"year":2013,"finding":"TBL2 (WD40 repeat protein) directly binds TERE1 (UBIAD1) with high affinity; TBL2 localizes predominantly to mitochondria whereas TERE1 localizes to both mitochondrial and non-mitochondrial membranes. Multiple disease-specific single amino acid substitutions in TERE1 (causing hereditary corneal disease) strongly reduce binding to TBL2. The TERE1-TBL2 complex influences mitochondrial trans-membrane potential, ROS/RNS production, and SXR target gene activation.","method":"Biochemical binding assays (pulldown/Co-IP), subcellular fractionation, ectopic expression with functional readouts (ROS, NO, SXR targets)","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with mutagenesis validation and functional readouts, single lab","pmids":["23564352"],"is_preprint":false},{"year":2015,"finding":"TBL2 associates specifically with the eukaryotic 60S ribosomal subunit but not the 40S subunit; this association is ER stress-independent and requires the WD40 domain as shown by immunoprecipitation of deletion mutants.","method":"Immunoprecipitation with ribosomal subunit fractions, TBL2 deletion mutant analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with deletion mutant mapping, subunit specificity established, single lab","pmids":["25976671"],"is_preprint":false},{"year":2016,"finding":"TBL2 associates with ATF4 mRNA through its WD40 domain and regulates ATF4 translation during ER stress. RNA-immunoprecipitation with deletion mutants showed the WD40 domain is essential for ATF4 mRNA binding; knockdown of TBL2 or overexpression of WD40-defective TBL2 mutant diminishes ATF4 protein induction at the translational level.","method":"RNA-immunoprecipitation, TBL2 deletion mutant analysis, siRNA knockdown, western blotting","journal":"Journal of cellular biochemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RNA-IP with deletion mutant mapping plus functional KD validation with two complementary approaches (knockdown and dominant-negative mutant), single lab","pmids":["26239904"],"is_preprint":false},{"year":2021,"finding":"PKD2 (polycystin-2) interacts with TBL2 in the ER, and TBL2 functions as an adaptor bridging eIF2α to PERK. PKD2 depletion impairs the recruitment of eIF2α to TBL2, thereby attenuating PERK-eIF2α-ATF4 pathway activation and downstream amino acid biosynthesis (serine, arginine, cysteine) in ADPKD.","method":"Co-immunoprecipitation, siRNA knockdown in RCTEC cells, transcriptomic analysis of Pkd2-knockout mouse kidneys, western blotting","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing PKD2-TBL2-eIF2α complex plus functional KD phenotype in cell and mouse model, single lab","pmids":["34015761"],"is_preprint":false},{"year":2024,"finding":"TBL2 acts as a scaffolding protein that promotes interaction between PRMT5 and WDR77, enhancing PRMT5 methyltransferase activity, which leads to increased AKT phosphorylation and breast cancer cell proliferation. TBL2 suppression inhibits BC cell proliferation while overexpression promotes it, both in vitro and in vivo.","method":"Proteomic analysis, immunoprecipitation, protein immunoblotting, siRNA knockdown, overexpression, in vivo xenograft experiments","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing scaffolding function plus in vitro and in vivo functional validation, single lab","pmids":["39499734"],"is_preprint":false},{"year":2025,"finding":"TBL2 silencing in glioblastoma cells enhances autophagy via the AMPK/mTOR signaling pathway, and autophagy inhibition (chloroquine) attenuates the suppressive effects of TBL2 knockdown on GBM cell proliferation, migration, invasion, and EMT, placing TBL2 upstream of AMPK/mTOR-mediated autophagy regulation.","method":"siRNA-mediated knockdown, pharmacological AMPK activation and autophagy inhibition (chloroquine), cell proliferation/migration/invasion assays","journal":"Tissue & cell","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological epistasis without direct molecular interaction data, no reconstitution","pmids":["41101043"],"is_preprint":false}],"current_model":"TBL2 is an ER-localized type-I transmembrane WD40-repeat protein that functions as an adaptor in the PERK-eIF2α-ATF4 unfolded protein response pathway: it binds phosphorylated PERK via its N-terminus, recruits eIF2α and the 60S ribosomal subunit via its WD40 domain, associates with ATF4 mRNA to promote its translation under ER stress, and additionally acts as a scaffolding protein promoting PRMT5-WDR77 complex formation and AKT activation, while also interacting with the mitochondrial prenyltransferase TERE1 to regulate oxidative stress and lipid metabolism."},"narrative":{"mechanistic_narrative":"TBL2 is a WD40-repeat protein that functions principally as an adaptor in the PERK arm of the unfolded protein response, coupling ER stress sensing to selective translational control of the stress effector ATF4 [PMID:25393282, PMID:26239904]. As an ER-localized type-I transmembrane protein, TBL2 binds preferentially to the phosphorylated form of PERK—but not GCN2 or IRE1—through its N-terminal region, while its WD40 domain engages eIF2α, the 60S ribosomal subunit, and ATF4 mRNA, thereby promoting ATF4 translation under ER stress and nutrient deprivation; loss of TBL2 impairs ATF4 induction and sensitizes cells to stress comparably to PERK depletion [PMID:25393282, PMID:25976671, PMID:26239904]. The polycystin PKD2 interacts with TBL2 in the ER and is required for eIF2α recruitment to TBL2, linking this adaptor function to downstream amino acid biosynthesis [PMID:34015761]. Beyond UPR signaling, TBL2 has additional context-dependent roles: it acts as a scaffold promoting PRMT5–WDR77 complex formation to enhance PRMT5 methyltransferase activity and AKT phosphorylation in breast cancer proliferation [PMID:39499734], and it binds the prenyltransferase TERE1 (UBIAD1) at mitochondrial membranes, an interaction disrupted by disease-associated TERE1 substitutions and tied to mitochondrial membrane potential, ROS/RNS production, and SXR target gene activation [PMID:23564352].","teleology":[{"year":1999,"claim":"Initial cloning established TBL2 as a WD40-repeat protein with a defined tissue expression pattern and conserved mouse ortholog, providing the molecular starting point before any function was known.","evidence":"cDNA cloning, genomic sequencing, RT-PCR, and comparative sequence analysis across human and mouse","pmids":["10575226"],"confidence":"Medium","gaps":["No molecular function or interacting partners identified","Significance of the alternatively spliced 75-aa fragment unknown","Subcellular localization not determined"]},{"year":2013,"claim":"TBL2 was shown to be a high-affinity direct binding partner of TERE1/UBIAD1, the first identified molecular interaction, linking it to mitochondrial redox and lipid/SXR signaling.","evidence":"Biochemical pulldown/Co-IP with disease-mutant mapping, subcellular fractionation, and functional ROS/NO/SXR readouts","pmids":["23564352"],"confidence":"Medium","gaps":["Mechanism by which the TERE1-TBL2 complex alters mitochondrial potential and ROS not resolved","Mitochondrial localization here is at odds with later ER assignment","No structural model of the binding interface"]},{"year":2014,"claim":"TBL2 was defined as an ER-localized adaptor that selectively binds phospho-PERK and eIF2α, establishing its central role in the PERK-eIF2α-ATF4 UPR branch.","evidence":"Reciprocal Co-IP with deletion-mutant domain mapping, subcellular fractionation, and siRNA knockdown phenotype","pmids":["25393282"],"confidence":"High","gaps":["How phospho-PERK selectivity over GCN2/IRE1 is achieved structurally is unknown","Does not reconcile ER localization with earlier mitochondrial assignment","Direct effect on eIF2α phosphorylation status not established"]},{"year":2015,"claim":"TBL2 was found to associate constitutively with the 60S but not 40S ribosomal subunit via its WD40 domain, connecting the adaptor to the translational machinery independent of stress.","evidence":"Co-IP of ribosomal subunit fractions with TBL2 deletion mutants","pmids":["25976671"],"confidence":"Medium","gaps":["Functional consequence of 60S association for general or selective translation unclear","Whether binding is to free 60S or assembled ribosomes not distinguished","No identification of the 60S contact site"]},{"year":2016,"claim":"TBL2 was shown to bind ATF4 mRNA through its WD40 domain and to be required for ATF4 translation, providing the mechanistic link between TBL2 and selective stress-induced gene expression.","evidence":"RNA-immunoprecipitation with deletion mutants plus knockdown and WD40-defective dominant-negative validation","pmids":["26239904"],"confidence":"High","gaps":["The mRNA element/feature recognized by the WD40 domain is undefined","How 60S association and ATF4 mRNA binding are coordinated mechanistically is unknown","Direct RNA binding vs. bridging via other factors not distinguished"]},{"year":2021,"claim":"PKD2 was identified as a TBL2 partner required for eIF2α recruitment, integrating TBL2 adaptor function into ADPKD-relevant amino acid biosynthesis.","evidence":"Co-IP, siRNA knockdown in renal tubular epithelial cells, and transcriptomics of Pkd2-knockout mouse kidneys","pmids":["34015761"],"confidence":"Medium","gaps":["Whether PKD2 acts as a stable complex member or transient regulator unclear","Direct vs. indirect PKD2-TBL2 binding not mapped to domains","Physiological role in cyst formation not directly demonstrated"]},{"year":2024,"claim":"TBL2 was assigned a UPR-independent scaffolding role promoting PRMT5-WDR77 assembly and AKT activation, expanding its function into oncogenic signaling.","evidence":"Proteomics, Co-IP, knockdown/overexpression, and in vivo xenograft assays in breast cancer cells","pmids":["39499734"],"confidence":"Medium","gaps":["Whether the WD40 domain mediates PRMT5-WDR77 bridging not mapped","Relationship to TBL2's ER/UPR function unclear","Mechanism linking PRMT5 methylation to AKT phosphorylation not defined"]},{"year":2025,"claim":"TBL2 silencing was placed upstream of AMPK/mTOR-mediated autophagy in glioblastoma, linking it to tumor cell phenotypes through autophagy regulation.","evidence":"siRNA knockdown with pharmacological AMPK activation and chloroquine autophagy inhibition plus proliferation/migration/invasion assays","pmids":["41101043"],"confidence":"Low","gaps":["Pharmacological epistasis without direct molecular interaction data","No reconstitution and mechanism of AMPK/mTOR engagement undefined","Single lab, single cancer context"]},{"year":null,"claim":"How TBL2's distinct activities — ER/UPR adaptor, mitochondrial TERE1 partner, and cytoplasmic PRMT5 scaffold — are partitioned across compartments and reconciled into one protein's biology remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural basis for the multiple WD40-mediated interactions","Mechanism partitioning TBL2 between ER and mitochondria unknown","Whether oncogenic scaffolding roles depend on or are independent of UPR function untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[4]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,4]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4]}],"complexes":[],"partners":["PERK","EIF2A","ATF4","TERE1","UBIAD1","PKD2","PRMT5","WDR77"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y4P3","full_name":"Transducin beta-like protein 2","aliases":["WS beta-transducin repeats protein","WS-betaTRP","Williams-Beuren syndrome chromosomal region 13 protein"],"length_aa":447,"mass_kda":49.8,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9Y4P3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TBL2","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCDC47","stoichiometry":0.2},{"gene":"NCLN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TBL2","total_profiled":1310},"omim":[{"mim_id":"605842","title":"TRANSDUCIN-BETA-LIKE 2; TBL2","url":"https://www.omim.org/entry/605842"},{"mim_id":"194050","title":"WILLIAMS-BEUREN SYNDROME; WBS","url":"https://www.omim.org/entry/194050"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":12.7}],"url":"https://www.proteinatlas.org/search/TBL2"},"hgnc":{"alias_symbol":["WS-betaTRP","WBSCR13","DKFZP43N024"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y4P3","domains":[{"cath_id":"2.130.10.10","chopping":"91-384","consensus_level":"medium","plddt":95.9458,"start":91,"end":384},{"cath_id":"1.10.287","chopping":"410-445","consensus_level":"medium","plddt":89.2447,"start":410,"end":445}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4P3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y4P3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y4P3-F1-predicted_aligned_error_v6.png","plddt_mean":87.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TBL2","jax_strain_url":"https://www.jax.org/strain/search?query=TBL2"},"sequence":{"accession":"Q9Y4P3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y4P3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y4P3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4P3"}},"corpus_meta":[{"pmid":"10575226","id":"PMC_10575226","title":"TBL2, a novel transducin family member in the WBS deletion: characterization of the complete sequence, genomic structure, transcriptional variants and the mouse ortholog.","date":"1999","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10575226","citation_count":30,"is_preprint":false},{"pmid":"25393282","id":"PMC_25393282","title":"TBL2 is a novel PERK-binding protein that modulates stress-signaling and cell survival during endoplasmic reticulum stress.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25393282","citation_count":25,"is_preprint":false},{"pmid":"23564352","id":"PMC_23564352","title":"The TERE1 protein interacts with mitochondrial TBL2: regulation of trans-membrane potential, ROS/RNS and SXR target genes.","date":"2013","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23564352","citation_count":21,"is_preprint":false},{"pmid":"24160749","id":"PMC_24160749","title":"Association of the MLXIPL/TBL2 rs17145738 SNP and serum lipid levels in the Guangxi Mulao and Han populations.","date":"2013","source":"Lipids in health and disease","url":"https://pubmed.ncbi.nlm.nih.gov/24160749","citation_count":14,"is_preprint":false},{"pmid":"39499734","id":"PMC_39499734","title":"TBL2 Promotes Tumorigenesis via PRMT5/WDR77-Mediated AKT Activation in Breast Cancer.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39499734","citation_count":11,"is_preprint":false},{"pmid":"34015761","id":"PMC_34015761","title":"PKD2 deficiency suppresses amino acid biosynthesis in ADPKD by impairing the PERK-TBL2-eIF2ɑ-ATF4 pathway.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/34015761","citation_count":11,"is_preprint":false},{"pmid":"26239904","id":"PMC_26239904","title":"TBL2 Associates With ATF4 mRNA Via Its WD40 Domain and Regulates Its Translation During ER Stress.","date":"2016","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26239904","citation_count":10,"is_preprint":false},{"pmid":"32811528","id":"PMC_32811528","title":"TBL2 methylation is associated with hyper-low-density lipoprotein cholesterolemia: a case-control study.","date":"2020","source":"Lipids in health and disease","url":"https://pubmed.ncbi.nlm.nih.gov/32811528","citation_count":7,"is_preprint":false},{"pmid":"25976671","id":"PMC_25976671","title":"The endoplasmic reticulum-localized protein TBL2 interacts with the 60S ribosomal subunit.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/25976671","citation_count":6,"is_preprint":false},{"pmid":"41101043","id":"PMC_41101043","title":"TBL2 modulates glioblastoma progression by inducing autophagy through by the AMPK/mTOR signaling pathway.","date":"2025","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/41101043","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7444,"output_tokens":2161,"usd":0.027373,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9182,"output_tokens":3161,"usd":0.062468,"stage2_stop_reason":"end_turn"},"total_usd":0.089841,"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\": 1999,\n      \"finding\": \"TBL2 encodes a protein with four putative WD40-repeat domains and is expressed predominantly in testis, skeletal muscle, heart and endocrine tissues; an alternatively spliced transcript introduces an in-frame stop codon producing a 75 amino acid N-terminal fragment. The mouse ortholog shares 92% amino acid similarity and maps to chromosome 5 in synteny with human 7q11.23.\",\n      \"method\": \"cDNA cloning, genomic sequencing, RT-PCR, comparative sequence analysis\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — structural/sequence characterization across two species with RT-PCR validation, single lab\",\n      \"pmids\": [\"10575226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TBL2 is an ER-localized type-I transmembrane protein that preferentially binds to the phosphorylated form of PERK (but not GCN2 or IRE1) under ER stress. TBL2 interacts with PERK via its N-terminus proximal region and associates with eIF2α via its WD40 domain. TBL2 knockdown impairs ATF4 induction under ER stress and nutrient deprivation, and renders cells more vulnerable to these stresses similarly to PERK knockdown.\",\n      \"method\": \"Immunoprecipitation with deletion mutants, subcellular fractionation/localization, siRNA knockdown, western blotting\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with deletion mutant mapping, subcellular localization, and functional KD phenotype in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25393282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TBL2 (WD40 repeat protein) directly binds TERE1 (UBIAD1) with high affinity; TBL2 localizes predominantly to mitochondria whereas TERE1 localizes to both mitochondrial and non-mitochondrial membranes. Multiple disease-specific single amino acid substitutions in TERE1 (causing hereditary corneal disease) strongly reduce binding to TBL2. The TERE1-TBL2 complex influences mitochondrial trans-membrane potential, ROS/RNS production, and SXR target gene activation.\",\n      \"method\": \"Biochemical binding assays (pulldown/Co-IP), subcellular fractionation, ectopic expression with functional readouts (ROS, NO, SXR targets)\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with mutagenesis validation and functional readouts, single lab\",\n      \"pmids\": [\"23564352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TBL2 associates specifically with the eukaryotic 60S ribosomal subunit but not the 40S subunit; this association is ER stress-independent and requires the WD40 domain as shown by immunoprecipitation of deletion mutants.\",\n      \"method\": \"Immunoprecipitation with ribosomal subunit fractions, TBL2 deletion mutant analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with deletion mutant mapping, subunit specificity established, single lab\",\n      \"pmids\": [\"25976671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TBL2 associates with ATF4 mRNA through its WD40 domain and regulates ATF4 translation during ER stress. RNA-immunoprecipitation with deletion mutants showed the WD40 domain is essential for ATF4 mRNA binding; knockdown of TBL2 or overexpression of WD40-defective TBL2 mutant diminishes ATF4 protein induction at the translational level.\",\n      \"method\": \"RNA-immunoprecipitation, TBL2 deletion mutant analysis, siRNA knockdown, western blotting\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-IP with deletion mutant mapping plus functional KD validation with two complementary approaches (knockdown and dominant-negative mutant), single lab\",\n      \"pmids\": [\"26239904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PKD2 (polycystin-2) interacts with TBL2 in the ER, and TBL2 functions as an adaptor bridging eIF2α to PERK. PKD2 depletion impairs the recruitment of eIF2α to TBL2, thereby attenuating PERK-eIF2α-ATF4 pathway activation and downstream amino acid biosynthesis (serine, arginine, cysteine) in ADPKD.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown in RCTEC cells, transcriptomic analysis of Pkd2-knockout mouse kidneys, western blotting\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing PKD2-TBL2-eIF2α complex plus functional KD phenotype in cell and mouse model, single lab\",\n      \"pmids\": [\"34015761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TBL2 acts as a scaffolding protein that promotes interaction between PRMT5 and WDR77, enhancing PRMT5 methyltransferase activity, which leads to increased AKT phosphorylation and breast cancer cell proliferation. TBL2 suppression inhibits BC cell proliferation while overexpression promotes it, both in vitro and in vivo.\",\n      \"method\": \"Proteomic analysis, immunoprecipitation, protein immunoblotting, siRNA knockdown, overexpression, in vivo xenograft experiments\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing scaffolding function plus in vitro and in vivo functional validation, single lab\",\n      \"pmids\": [\"39499734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TBL2 silencing in glioblastoma cells enhances autophagy via the AMPK/mTOR signaling pathway, and autophagy inhibition (chloroquine) attenuates the suppressive effects of TBL2 knockdown on GBM cell proliferation, migration, invasion, and EMT, placing TBL2 upstream of AMPK/mTOR-mediated autophagy regulation.\",\n      \"method\": \"siRNA-mediated knockdown, pharmacological AMPK activation and autophagy inhibition (chloroquine), cell proliferation/migration/invasion assays\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological epistasis without direct molecular interaction data, no reconstitution\",\n      \"pmids\": [\"41101043\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TBL2 is an ER-localized type-I transmembrane WD40-repeat protein that functions as an adaptor in the PERK-eIF2α-ATF4 unfolded protein response pathway: it binds phosphorylated PERK via its N-terminus, recruits eIF2α and the 60S ribosomal subunit via its WD40 domain, associates with ATF4 mRNA to promote its translation under ER stress, and additionally acts as a scaffolding protein promoting PRMT5-WDR77 complex formation and AKT activation, while also interacting with the mitochondrial prenyltransferase TERE1 to regulate oxidative stress and lipid metabolism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TBL2 is a WD40-repeat protein that functions principally as an adaptor in the PERK arm of the unfolded protein response, coupling ER stress sensing to selective translational control of the stress effector ATF4 [#1, #4]. As an ER-localized type-I transmembrane protein, TBL2 binds preferentially to the phosphorylated form of PERK—but not GCN2 or IRE1—through its N-terminal region, while its WD40 domain engages eIF2\\u03b1, the 60S ribosomal subunit, and ATF4 mRNA, thereby promoting ATF4 translation under ER stress and nutrient deprivation; loss of TBL2 impairs ATF4 induction and sensitizes cells to stress comparably to PERK depletion [#1, #3, #4]. The polycystin PKD2 interacts with TBL2 in the ER and is required for eIF2\\u03b1 recruitment to TBL2, linking this adaptor function to downstream amino acid biosynthesis [#5]. Beyond UPR signaling, TBL2 has additional context-dependent roles: it acts as a scaffold promoting PRMT5\\u2013WDR77 complex formation to enhance PRMT5 methyltransferase activity and AKT phosphorylation in breast cancer proliferation [#6], and it binds the prenyltransferase TERE1 (UBIAD1) at mitochondrial membranes, an interaction disrupted by disease-associated TERE1 substitutions and tied to mitochondrial membrane potential, ROS/RNS production, and SXR target gene activation [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Initial cloning established TBL2 as a WD40-repeat protein with a defined tissue expression pattern and conserved mouse ortholog, providing the molecular starting point before any function was known.\",\n      \"evidence\": \"cDNA cloning, genomic sequencing, RT-PCR, and comparative sequence analysis across human and mouse\",\n      \"pmids\": [\"10575226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular function or interacting partners identified\", \"Significance of the alternatively spliced 75-aa fragment unknown\", \"Subcellular localization not determined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"TBL2 was shown to be a high-affinity direct binding partner of TERE1/UBIAD1, the first identified molecular interaction, linking it to mitochondrial redox and lipid/SXR signaling.\",\n      \"evidence\": \"Biochemical pulldown/Co-IP with disease-mutant mapping, subcellular fractionation, and functional ROS/NO/SXR readouts\",\n      \"pmids\": [\"23564352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which the TERE1-TBL2 complex alters mitochondrial potential and ROS not resolved\", \"Mitochondrial localization here is at odds with later ER assignment\", \"No structural model of the binding interface\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"TBL2 was defined as an ER-localized adaptor that selectively binds phospho-PERK and eIF2\\u03b1, establishing its central role in the PERK-eIF2\\u03b1-ATF4 UPR branch.\",\n      \"evidence\": \"Reciprocal Co-IP with deletion-mutant domain mapping, subcellular fractionation, and siRNA knockdown phenotype\",\n      \"pmids\": [\"25393282\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phospho-PERK selectivity over GCN2/IRE1 is achieved structurally is unknown\", \"Does not reconcile ER localization with earlier mitochondrial assignment\", \"Direct effect on eIF2\\u03b1 phosphorylation status not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"TBL2 was found to associate constitutively with the 60S but not 40S ribosomal subunit via its WD40 domain, connecting the adaptor to the translational machinery independent of stress.\",\n      \"evidence\": \"Co-IP of ribosomal subunit fractions with TBL2 deletion mutants\",\n      \"pmids\": [\"25976671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of 60S association for general or selective translation unclear\", \"Whether binding is to free 60S or assembled ribosomes not distinguished\", \"No identification of the 60S contact site\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"TBL2 was shown to bind ATF4 mRNA through its WD40 domain and to be required for ATF4 translation, providing the mechanistic link between TBL2 and selective stress-induced gene expression.\",\n      \"evidence\": \"RNA-immunoprecipitation with deletion mutants plus knockdown and WD40-defective dominant-negative validation\",\n      \"pmids\": [\"26239904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The mRNA element/feature recognized by the WD40 domain is undefined\", \"How 60S association and ATF4 mRNA binding are coordinated mechanistically is unknown\", \"Direct RNA binding vs. bridging via other factors not distinguished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"PKD2 was identified as a TBL2 partner required for eIF2\\u03b1 recruitment, integrating TBL2 adaptor function into ADPKD-relevant amino acid biosynthesis.\",\n      \"evidence\": \"Co-IP, siRNA knockdown in renal tubular epithelial cells, and transcriptomics of Pkd2-knockout mouse kidneys\",\n      \"pmids\": [\"34015761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PKD2 acts as a stable complex member or transient regulator unclear\", \"Direct vs. indirect PKD2-TBL2 binding not mapped to domains\", \"Physiological role in cyst formation not directly demonstrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"TBL2 was assigned a UPR-independent scaffolding role promoting PRMT5-WDR77 assembly and AKT activation, expanding its function into oncogenic signaling.\",\n      \"evidence\": \"Proteomics, Co-IP, knockdown/overexpression, and in vivo xenograft assays in breast cancer cells\",\n      \"pmids\": [\"39499734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the WD40 domain mediates PRMT5-WDR77 bridging not mapped\", \"Relationship to TBL2's ER/UPR function unclear\", \"Mechanism linking PRMT5 methylation to AKT phosphorylation not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"TBL2 silencing was placed upstream of AMPK/mTOR-mediated autophagy in glioblastoma, linking it to tumor cell phenotypes through autophagy regulation.\",\n      \"evidence\": \"siRNA knockdown with pharmacological AMPK activation and chloroquine autophagy inhibition plus proliferation/migration/invasion assays\",\n      \"pmids\": [\"41101043\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pharmacological epistasis without direct molecular interaction data\", \"No reconstitution and mechanism of AMPK/mTOR engagement undefined\", \"Single lab, single cancer context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TBL2's distinct activities — ER/UPR adaptor, mitochondrial TERE1 partner, and cytoplasmic PRMT5 scaffold — are partitioned across compartments and reconciled into one protein's biology remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural basis for the multiple WD40-mediated interactions\", \"Mechanism partitioning TBL2 between ER and mitochondria unknown\", \"Whether oncogenic scaffolding roles depend on or are independent of UPR function untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PERK\", \"EIF2A\", \"ATF4\", \"TERE1\", \"UBIAD1\", \"PKD2\", \"PRMT5\", \"WDR77\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":4,"faith_pct":75.0}}