{"gene":"TLE2","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":1998,"finding":"TLE2 contains two separate transcriptional repression domains: one within a Gln-rich amino-terminal region and one within an internal Ser/Thr/Pro-rich domain. TLE2 can homo- and heterodimerize with TLE1 through a short region within the amino-terminal repression domain. TLE2 physically interacts with mammalian HES proteins.","method":"Gal4 fusion transcriptional repression assays, dimerization mapping, co-expression/interaction studies in neural and non-neural tissues","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (repression domain mapping, dimerization, HES interaction) in a single study; single lab","pmids":["9874198"],"is_preprint":false},{"year":1999,"finding":"TLE2 (along with hGrg and TLE1) interacts specifically with the minimal repression domain of PRDI-BF1/Blimp-1 and is recruited to DNA to mediate transcriptional repression of the IFN-beta promoter. The amino-terminal glutamine-rich domain of TLE proteins mediates dimerization and can act as a dominant-negative inhibitor of PRDI-BF1 repression.","method":"Co-immunoprecipitation, Gal4 fusion repression assays, dominant-negative overexpression, IFN-beta promoter reporter assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding and functional repression assays with domain mapping; replicated across multiple TLE family members with multiple orthogonal methods","pmids":["9887105"],"is_preprint":false},{"year":1999,"finding":"TLE1 and TLE2 interact with mammalian UTY/X proteins (related to yeast SSN6), suggesting a conserved TUP1-SSN6-like repression mechanism in mammals. Yeast SSN6 binds TLE1 and mediates transcriptional repression in mammalian cells.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, transcriptional repression assays in mammalian cells","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding assays plus functional repression assay; single lab","pmids":["9854018"],"is_preprint":false},{"year":2000,"finding":"TLE2 associates with the nuclear matrix and co-localizes with AML/RUNX transcription factors at nuclear matrix sites in a manner dependent on the C-terminus of AML family members. TLE proteins repress AML-dependent activation of osteocalcin gene transcription.","method":"Digital immunofluorescence microscopy, subcellular fractionation (nuclear matrix isolation), co-transfection/reporter assays, yeast two-hybrid","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence (repression of OC promoter), multiple methods; single lab","pmids":["10825294"],"is_preprint":false},{"year":2001,"finding":"TLE1 and TLE2 co-expression does not influence Cbfa/Runx repression of the bone sialoprotein (BSP) promoter, and removal of the TLE interaction motif of Cbfa1 does not relieve BSP suppression, indicating TLE proteins are not involved in Cbfa-mediated repression of BSP.","method":"Co-transfection reporter assays, promoter deletion/mutation analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean negative result established by multiple promoter mutant assays; single lab, single study","pmids":["11283267"],"is_preprint":false},{"year":2001,"finding":"The E2A-HLF oncoprotein transcriptionally upregulates Grg2 (TLE2) and Grg6 10- to 50-fold in pro-B cells. Grg2 upregulation correlates with E2A-HLF-mediated pro-B cell survival and downregulation of RUNX1.","method":"Representational difference analysis (RDA), immunoblot analysis, stable transfection with zinc-inducible E2A-HLF","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional target identified by RDA and confirmed by western blot with inducible system; single lab","pmids":["11486032"],"is_preprint":false},{"year":2008,"finding":"TLE2 (Tle2) physically interacts with pancreatic transcription factors Nkx2-2, Hes1, Arx, and Nkx6-1 in pancreatic cells. Tle2 modulates the repressive activity of Arx in a beta-cell line.","method":"Co-immunoprecipitation, transcriptional reporter assays in beta-cell line","journal":"BMC developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for multiple interaction partners plus functional repression assay; single lab","pmids":["18778483"],"is_preprint":false},{"year":2009,"finding":"TLE2 interacts with the KSHV replication and transcription activator (RTA) protein via its Q (Gln-rich), SP (Ser-Pro-rich), and WDR (Trp-Asp repeat) domains binding to the Pro-rich domain of RTA. This interaction recruits TLE2 to RTA-bound DNA, represses RTA auto-activation and transactivation, inhibits lytic replication, and reduces virion production. TLE2 competes with RBP-Jkappa for binding to the same Pro-rich domain of RTA.","method":"Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, immunofluorescence co-localization, luciferase reporter assays, virion production assay, domain mapping by deletion constructs","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (yeast two-hybrid, GST pulldown, Co-IP, co-localization, functional reporter, virion assays) in a single study with domain mapping","pmids":["19939918"],"is_preprint":false},{"year":2010,"finding":"TLE2 (Xenopus tropicalis) co-repressor interacts with FoxG1 through FoxG1's N-terminal eh1 motif (primary binding) and C-terminal YWPMSPF motif (required for functional synergism). TLE2 and FoxG1 cooperate to regulate ventral telencephalon specification; knockdown of either disrupts ventral telencephalic development and Nkx2.1 induction.","method":"Co-expression/interaction assays, ectopic neurogenesis assay in Xenopus, morpholino knockdown, mutational analysis of TLE-binding motifs, in situ hybridization","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional cooperation established by multiple orthogonal methods (binding domain mutagenesis, loss-of-function, ectopic assay, in vivo phenotype); replicated across multiple assays in a single rigorous study","pmids":["20356955"],"is_preprint":false},{"year":2013,"finding":"Rx1 transcription factor activates TLE2 and Hes4 expression to repress endomesodermal gene expression in retinal precursors, thereby specifying retinal progenitor identity. Rx1 knockdown leads retinogenic blastomeres to adopt an endomesodermal fate.","method":"High-throughput screen for Rx1-regulated genes, gain- and loss-of-function (morpholino knockdown) in Xenopus, reporter assays","journal":"Stem cells (Dayton, Ohio)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional epistasis by knockdown with defined phenotypic readout, TLE2 identified as downstream effector; single lab","pmids":["24038725"],"is_preprint":false},{"year":2016,"finding":"NDRG1 physically associates with TLE2 and β-catenin in ESCC cells. NDRG1 overexpression decreases TLE2 expression and increases β-catenin, activating Wnt signaling. TLE2 overexpression abrogates NDRG1-mediated Wnt pathway activation, indicating TLE2 acts as a suppressor of Wnt signaling downstream of NDRG1.","method":"Co-immunoprecipitation, lentiviral overexpression, RNA interference, reporter/western blot assays","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms physical interaction; rescue experiment with TLE2 overexpression establishes functional epistasis; single lab","pmids":["27414086"],"is_preprint":false},{"year":2019,"finding":"TLE2 suppression in ovarian cancer cells (by shRNA) increases the proportion of side population (SP) cells, sphere formation, single-cell clonogenicity, and in vivo tumorigenicity. Conversely, TLE2 overexpression decreases SP cells and sphere formation. TLE2 suppression enhances hedgehog pathway activity.","method":"shRNA library screen, flow cytometry for SP cells, sphere formation assay, in vivo xenograft, pathway analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional functional manipulation (KD and OE) with multiple cellular readouts and pathway placement; single lab","pmids":["31578411"],"is_preprint":false},{"year":2025,"finding":"DDX3X destabilizes TLE2 mRNA in pancreatic ductal adenocarcinoma, reducing TLE2 protein levels. TLE2 normally interacts with KLF4 transcription factor to repress MYL9 expression. Loss of TLE2 increases MYL9 expression, remodeling F-actin and enhancing tumor cell traction forces to facilitate metastasis. Targeting the DDX3X-TLE2-MYL9 pathway reduces PDAC progression.","method":"CRISPR-Cas9 screen in orthotopic xenograft, mRNA stability assays, co-immunoprecipitation (TLE2-KLF4 interaction), F-actin remodeling assays, traction force microscopy, in vivo tumor models","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR screen plus multiple mechanistic follow-ups (mRNA stability, Co-IP, actin assays, traction force, in vivo rescue) establishing a defined pathway; single lab but multiple orthogonal methods","pmids":["40938994"],"is_preprint":false}],"current_model":"TLE2 is a nuclear transcriptional corepressor of the Groucho/TLE family that lacks intrinsic DNA-binding activity and is recruited to target promoters through direct protein-protein interactions with multiple transcription factors (including HES proteins, PRDI-BF1/Blimp-1, RUNX/AML proteins, FoxG1, Nkx2-2, Arx, Nkx6-1, KLF4, and viral RTA); it harbors two repression domains (N-terminal Gln-rich and internal Ser/Thr/Pro-rich), homo- and heterodimerizes via its N-terminal domain, associates with the nuclear matrix, suppresses Wnt and hedgehog signaling, and stabilizes viral latency by competing with RBP-Jkappa for KSHV RTA binding, while in cancer contexts its mRNA is destabilized by DDX3X, relieving KLF4-dependent repression of MYL9 to promote cytoskeletal remodeling and metastasis."},"narrative":{"mechanistic_narrative":"TLE2 is a nuclear transcriptional corepressor of the Groucho/TLE family that lacks intrinsic DNA-binding activity and is recruited to target promoters through direct protein-protein interactions with sequence-specific transcription factors [PMID:9874198, PMID:9887105]. It carries two separable repression domains — an N-terminal Gln-rich domain and an internal Ser/Thr/Pro-rich domain — and homo- and heterodimerizes through a short region within the N-terminal repression domain, where the Gln-rich domain can act dominant-negatively against partner-mediated repression [PMID:9874198, PMID:9887105]. TLE2 engages a broad set of DNA-binding factors to mediate repression, including HES proteins [PMID:9874198], PRDI-BF1/Blimp-1 at the IFN-beta promoter [PMID:9887105], RUNX/AML factors at nuclear matrix sites where it suppresses osteocalcin transcription [PMID:10825294], and the pancreatic factors Nkx2-2, Hes1, Arx, and Nkx6-1 [PMID:18778483]. Through cooperation with FoxG1 via its eh1 and YWPMSPF motifs, and as a downstream effector of Rx1, TLE2 participates in telencephalic and retinal progenitor specification [PMID:20356955, PMID:24038725]. In viral latency, TLE2 binds the KSHV RTA protein and competes with RBP-Jkappa for the same Pro-rich domain, repressing RTA transactivation and lytic replication [PMID:19939918]. In cancer, TLE2 acts as a suppressor of Wnt and hedgehog signaling [PMID:27414086, PMID:31578411], and its mRNA is destabilized by DDX3X in pancreatic ductal adenocarcinoma, relieving TLE2-KLF4-dependent repression of MYL9 to drive F-actin remodeling and metastasis [PMID:40938994].","teleology":[{"year":1998,"claim":"Established the molecular architecture of TLE2 as a corepressor — defining where its repression activity resides and how it oligomerizes — and linked it to HES factors.","evidence":"Gal4 fusion repression assays, dimerization mapping, and interaction studies in neural/non-neural tissues","pmids":["9874198"],"confidence":"Medium","gaps":["Does not identify the chromatin-modifying machinery downstream of repression","HES interaction not mapped to specific domains","Single lab"]},{"year":1999,"claim":"Showed TLE2 is recruited by a sequence-specific repressor (PRDI-BF1/Blimp-1) to a defined promoter, demonstrating the recruitment-to-DNA mechanism and the dominant-negative potential of the dimerization domain.","evidence":"Co-IP, Gal4 fusion repression, dominant-negative overexpression, and IFN-beta promoter reporter assays","pmids":["9887105"],"confidence":"High","gaps":["Endogenous IFN-beta regulation not tested","Co-repressor effector machinery not defined"]},{"year":1999,"claim":"Connected TLE proteins to a conserved TUP1-SSN6-like repression mechanism through interaction with UTY/X proteins.","evidence":"Yeast two-hybrid, GST pulldown, Co-IP, and repression assays in mammalian cells","pmids":["9854018"],"confidence":"Medium","gaps":["Physiological promoters using this mechanism not identified","TLE2-specific (vs TLE1) contribution unresolved"]},{"year":2000,"claim":"Demonstrated TLE2 localizes to the nuclear matrix and is targeted there with RUNX/AML factors, tying its subnuclear positioning to repression of a defined target gene.","evidence":"Immunofluorescence, nuclear matrix fractionation, reporter assays, yeast two-hybrid","pmids":["10825294"],"confidence":"Medium","gaps":["Mechanism of nuclear matrix tethering unknown","Single target promoter (osteocalcin)"]},{"year":2001,"claim":"Defined the boundary of TLE-dependent repression by showing TLE proteins are dispensable for Cbfa/Runx repression of the BSP promoter, indicating promoter-context-specific recruitment.","evidence":"Co-transfection reporter assays with promoter deletion/mutation analysis","pmids":["11283267"],"confidence":"Medium","gaps":["Does not explain which features select TLE-dependent vs independent promoters"]},{"year":2001,"claim":"Identified TLE2 (Grg2) as a transcriptional target of an oncoprotein, linking its induction to leukemic pro-B cell survival.","evidence":"Representational difference analysis, immunoblot, inducible E2A-HLF expression","pmids":["11486032"],"confidence":"Medium","gaps":["Direct vs indirect transcriptional activation not resolved","Functional requirement of Grg2 for survival not tested by loss-of-function"]},{"year":2008,"claim":"Extended the partner repertoire to pancreatic transcription factors and showed TLE2 modulates Arx repressive activity, placing it in islet cell-fate regulation.","evidence":"Co-IP for multiple partners and reporter assays in a beta-cell line","pmids":["18778483"],"confidence":"Medium","gaps":["In vivo pancreatic requirement not tested","Direct vs indirect modulation of Arx unresolved"]},{"year":2010,"claim":"Established TLE2 as a functional cooperating corepressor for FoxG1 in vivo, mapping the binding motifs required for telencephalon specification.","evidence":"Binding-motif mutagenesis, morpholino knockdown, ectopic neurogenesis assay, and in situ hybridization in Xenopus","pmids":["20356955"],"confidence":"High","gaps":["Mammalian conservation of this requirement not addressed","Downstream repressed genes only partly defined"]},{"year":2013,"claim":"Placed TLE2 downstream of Rx1 as an effector that represses endomesodermal genes to specify retinal progenitor identity.","evidence":"Rx1-regulated gene screen with gain/loss-of-function and reporter assays in Xenopus","pmids":["24038725"],"confidence":"Medium","gaps":["Direct target promoters of TLE2 in retinal precursors not mapped","Partner transcription factor in this context not defined"]},{"year":2009,"claim":"Revealed a virological role: TLE2 represses KSHV RTA by competing with RBP-Jkappa for the same domain, stabilizing latency.","evidence":"Yeast two-hybrid, GST pulldown, Co-IP, co-localization, reporter and virion production assays with domain mapping","pmids":["19939918"],"confidence":"High","gaps":["Endogenous TLE2 contribution to natural latency reactivation not quantified","Relative affinities of TLE2 vs RBP-Jkappa not measured"]},{"year":2016,"claim":"Positioned TLE2 as a suppressor of Wnt signaling acting downstream of NDRG1 in esophageal squamous carcinoma cells.","evidence":"Co-IP, lentiviral overexpression, RNAi, and rescue reporter/western assays","pmids":["27414086"],"confidence":"Medium","gaps":["Direct vs indirect effect on beta-catenin unresolved","Transcriptional targets in Wnt suppression not identified"]},{"year":2019,"claim":"Linked TLE2 to suppression of cancer stem-like properties via the hedgehog pathway in ovarian cancer.","evidence":"shRNA screen with side-population flow cytometry, sphere/clonogenicity assays, xenografts, and pathway analysis","pmids":["31578411"],"confidence":"Medium","gaps":["Mechanism connecting TLE2 to hedgehog output not defined","Direct hedgehog-component interactions untested"]},{"year":2025,"claim":"Defined a complete regulatory axis in PDAC: DDX3X destabilizes TLE2 mRNA, and TLE2-KLF4 repression of MYL9 controls cytoskeletal mechanics and metastasis.","evidence":"CRISPR-Cas9 orthotopic screen, mRNA stability assays, Co-IP, F-actin and traction force microscopy, in vivo models","pmids":["40938994"],"confidence":"High","gaps":["Whether KLF4-MYL9 repression operates outside PDAC unknown","Direct binding of TLE2 to the MYL9 promoter region not detailed"]},{"year":null,"claim":"The chromatin-level effector machinery through which TLE2 enforces repression and the rules selecting its partner transcription factors across tissues remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No histone-modifier or chromatin remodeler defined as TLE2 effector","Structural basis of partner discrimination unknown","Endogenous genome-wide TLE2 occupancy not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,3,6,7,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,7]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,9]}],"complexes":[],"partners":["TLE1","HES1","PRDM1","RUNX1","FOXG1","KLF4","ARX","NKX2-2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q04725","full_name":"Transducin-like enhancer protein 2","aliases":["Enhancer of split groucho-like protein 2","ESG2"],"length_aa":743,"mass_kda":79.8,"function":"Transcriptional corepressor that binds to a number of transcription factors. Inhibits the transcriptional activation mediated by CTNNB1 and TCF family members in Wnt signaling. The effects of full-length TLE family members may be modulated by association with dominant-negative AES (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q04725/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TLE2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TLE2","total_profiled":1310},"omim":[{"mim_id":"605132","title":"TLE FAMILY MEMBER 4, TRANSCRIPTIONAL COREPRESSOR; TLE4","url":"https://www.omim.org/entry/605132"},{"mim_id":"601041","title":"TLE FAMILY MEMBER 2, TRANSCRIPTIONAL COREPRESSOR; TLE2","url":"https://www.omim.org/entry/601041"},{"mim_id":"600190","title":"TLE FAMILY MEMBER 3, TRANSCRIPTIONAL COREPRESSOR; TLE3","url":"https://www.omim.org/entry/600190"},{"mim_id":"600189","title":"TLE FAMILY MEMBER 1, TRANSCRIPTIONAL COREPRESSOR; TLE1","url":"https://www.omim.org/entry/600189"},{"mim_id":"209850","title":"AUTISM","url":"https://www.omim.org/entry/209850"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"},{"location":"Focal adhesion sites","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":285.6}],"url":"https://www.proteinatlas.org/search/TLE2"},"hgnc":{"alias_symbol":["ESG2","GRG2","ESG","FLJ41188"],"prev_symbol":[]},"alphafold":{"accession":"Q04725","domains":[{"cath_id":"2.40.10.480","chopping":"660-743","consensus_level":"medium","plddt":96.4721,"start":660,"end":743}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q04725","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q04725-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q04725-F1-predicted_aligned_error_v6.png","plddt_mean":67.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TLE2","jax_strain_url":"https://www.jax.org/strain/search?query=TLE2"},"sequence":{"accession":"Q04725","fasta_url":"https://rest.uniprot.org/uniprotkb/Q04725.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q04725/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q04725"}},"corpus_meta":[{"pmid":"9887105","id":"PMC_9887105","title":"PRDI-BF1/Blimp-1 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TLE2 can homo- and heterodimerize with TLE1 through a short region within the amino-terminal repression domain. TLE2 physically interacts with mammalian HES proteins.\",\n      \"method\": \"Gal4 fusion transcriptional repression assays, dimerization mapping, co-expression/interaction studies in neural and non-neural tissues\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (repression domain mapping, dimerization, HES interaction) in a single study; single lab\",\n      \"pmids\": [\"9874198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"TLE2 (along with hGrg and TLE1) interacts specifically with the minimal repression domain of PRDI-BF1/Blimp-1 and is recruited to DNA to mediate transcriptional repression of the IFN-beta promoter. The amino-terminal glutamine-rich domain of TLE proteins mediates dimerization and can act as a dominant-negative inhibitor of PRDI-BF1 repression.\",\n      \"method\": \"Co-immunoprecipitation, Gal4 fusion repression assays, dominant-negative overexpression, IFN-beta promoter reporter assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding and functional repression assays with domain mapping; replicated across multiple TLE family members with multiple orthogonal methods\",\n      \"pmids\": [\"9887105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"TLE1 and TLE2 interact with mammalian UTY/X proteins (related to yeast SSN6), suggesting a conserved TUP1-SSN6-like repression mechanism in mammals. Yeast SSN6 binds TLE1 and mediates transcriptional repression in mammalian cells.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, transcriptional repression assays in mammalian cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding assays plus functional repression assay; single lab\",\n      \"pmids\": [\"9854018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TLE2 associates with the nuclear matrix and co-localizes with AML/RUNX transcription factors at nuclear matrix sites in a manner dependent on the C-terminus of AML family members. TLE proteins repress AML-dependent activation of osteocalcin gene transcription.\",\n      \"method\": \"Digital immunofluorescence microscopy, subcellular fractionation (nuclear matrix isolation), co-transfection/reporter assays, yeast two-hybrid\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence (repression of OC promoter), multiple methods; single lab\",\n      \"pmids\": [\"10825294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TLE1 and TLE2 co-expression does not influence Cbfa/Runx repression of the bone sialoprotein (BSP) promoter, and removal of the TLE interaction motif of Cbfa1 does not relieve BSP suppression, indicating TLE proteins are not involved in Cbfa-mediated repression of BSP.\",\n      \"method\": \"Co-transfection reporter assays, promoter deletion/mutation analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean negative result established by multiple promoter mutant assays; single lab, single study\",\n      \"pmids\": [\"11283267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The E2A-HLF oncoprotein transcriptionally upregulates Grg2 (TLE2) and Grg6 10- to 50-fold in pro-B cells. Grg2 upregulation correlates with E2A-HLF-mediated pro-B cell survival and downregulation of RUNX1.\",\n      \"method\": \"Representational difference analysis (RDA), immunoblot analysis, stable transfection with zinc-inducible E2A-HLF\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional target identified by RDA and confirmed by western blot with inducible system; single lab\",\n      \"pmids\": [\"11486032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TLE2 (Tle2) physically interacts with pancreatic transcription factors Nkx2-2, Hes1, Arx, and Nkx6-1 in pancreatic cells. Tle2 modulates the repressive activity of Arx in a beta-cell line.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assays in beta-cell line\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for multiple interaction partners plus functional repression assay; single lab\",\n      \"pmids\": [\"18778483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TLE2 interacts with the KSHV replication and transcription activator (RTA) protein via its Q (Gln-rich), SP (Ser-Pro-rich), and WDR (Trp-Asp repeat) domains binding to the Pro-rich domain of RTA. This interaction recruits TLE2 to RTA-bound DNA, represses RTA auto-activation and transactivation, inhibits lytic replication, and reduces virion production. TLE2 competes with RBP-Jkappa for binding to the same Pro-rich domain of RTA.\",\n      \"method\": \"Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, immunofluorescence co-localization, luciferase reporter assays, virion production assay, domain mapping by deletion constructs\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (yeast two-hybrid, GST pulldown, Co-IP, co-localization, functional reporter, virion assays) in a single study with domain mapping\",\n      \"pmids\": [\"19939918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TLE2 (Xenopus tropicalis) co-repressor interacts with FoxG1 through FoxG1's N-terminal eh1 motif (primary binding) and C-terminal YWPMSPF motif (required for functional synergism). TLE2 and FoxG1 cooperate to regulate ventral telencephalon specification; knockdown of either disrupts ventral telencephalic development and Nkx2.1 induction.\",\n      \"method\": \"Co-expression/interaction assays, ectopic neurogenesis assay in Xenopus, morpholino knockdown, mutational analysis of TLE-binding motifs, in situ hybridization\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional cooperation established by multiple orthogonal methods (binding domain mutagenesis, loss-of-function, ectopic assay, in vivo phenotype); replicated across multiple assays in a single rigorous study\",\n      \"pmids\": [\"20356955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rx1 transcription factor activates TLE2 and Hes4 expression to repress endomesodermal gene expression in retinal precursors, thereby specifying retinal progenitor identity. Rx1 knockdown leads retinogenic blastomeres to adopt an endomesodermal fate.\",\n      \"method\": \"High-throughput screen for Rx1-regulated genes, gain- and loss-of-function (morpholino knockdown) in Xenopus, reporter assays\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional epistasis by knockdown with defined phenotypic readout, TLE2 identified as downstream effector; single lab\",\n      \"pmids\": [\"24038725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NDRG1 physically associates with TLE2 and β-catenin in ESCC cells. NDRG1 overexpression decreases TLE2 expression and increases β-catenin, activating Wnt signaling. TLE2 overexpression abrogates NDRG1-mediated Wnt pathway activation, indicating TLE2 acts as a suppressor of Wnt signaling downstream of NDRG1.\",\n      \"method\": \"Co-immunoprecipitation, lentiviral overexpression, RNA interference, reporter/western blot assays\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms physical interaction; rescue experiment with TLE2 overexpression establishes functional epistasis; single lab\",\n      \"pmids\": [\"27414086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TLE2 suppression in ovarian cancer cells (by shRNA) increases the proportion of side population (SP) cells, sphere formation, single-cell clonogenicity, and in vivo tumorigenicity. Conversely, TLE2 overexpression decreases SP cells and sphere formation. TLE2 suppression enhances hedgehog pathway activity.\",\n      \"method\": \"shRNA library screen, flow cytometry for SP cells, sphere formation assay, in vivo xenograft, pathway analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional functional manipulation (KD and OE) with multiple cellular readouts and pathway placement; single lab\",\n      \"pmids\": [\"31578411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DDX3X destabilizes TLE2 mRNA in pancreatic ductal adenocarcinoma, reducing TLE2 protein levels. TLE2 normally interacts with KLF4 transcription factor to repress MYL9 expression. Loss of TLE2 increases MYL9 expression, remodeling F-actin and enhancing tumor cell traction forces to facilitate metastasis. Targeting the DDX3X-TLE2-MYL9 pathway reduces PDAC progression.\",\n      \"method\": \"CRISPR-Cas9 screen in orthotopic xenograft, mRNA stability assays, co-immunoprecipitation (TLE2-KLF4 interaction), F-actin remodeling assays, traction force microscopy, in vivo tumor models\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR screen plus multiple mechanistic follow-ups (mRNA stability, Co-IP, actin assays, traction force, in vivo rescue) establishing a defined pathway; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"40938994\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TLE2 is a nuclear transcriptional corepressor of the Groucho/TLE family that lacks intrinsic DNA-binding activity and is recruited to target promoters through direct protein-protein interactions with multiple transcription factors (including HES proteins, PRDI-BF1/Blimp-1, RUNX/AML proteins, FoxG1, Nkx2-2, Arx, Nkx6-1, KLF4, and viral RTA); it harbors two repression domains (N-terminal Gln-rich and internal Ser/Thr/Pro-rich), homo- and heterodimerizes via its N-terminal domain, associates with the nuclear matrix, suppresses Wnt and hedgehog signaling, and stabilizes viral latency by competing with RBP-Jkappa for KSHV RTA binding, while in cancer contexts its mRNA is destabilized by DDX3X, relieving KLF4-dependent repression of MYL9 to promote cytoskeletal remodeling and metastasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TLE2 is a nuclear transcriptional corepressor of the Groucho/TLE family that lacks intrinsic DNA-binding activity and is recruited to target promoters through direct protein-protein interactions with sequence-specific transcription factors [#0, #1]. It carries two separable repression domains — an N-terminal Gln-rich domain and an internal Ser/Thr/Pro-rich domain — and homo- and heterodimerizes through a short region within the N-terminal repression domain, where the Gln-rich domain can act dominant-negatively against partner-mediated repression [#0, #1]. TLE2 engages a broad set of DNA-binding factors to mediate repression, including HES proteins [#0], PRDI-BF1/Blimp-1 at the IFN-beta promoter [#1], RUNX/AML factors at nuclear matrix sites where it suppresses osteocalcin transcription [#3], and the pancreatic factors Nkx2-2, Hes1, Arx, and Nkx6-1 [#6]. Through cooperation with FoxG1 via its eh1 and YWPMSPF motifs, and as a downstream effector of Rx1, TLE2 participates in telencephalic and retinal progenitor specification [#8, #9]. In viral latency, TLE2 binds the KSHV RTA protein and competes with RBP-Jkappa for the same Pro-rich domain, repressing RTA transactivation and lytic replication [#7]. In cancer, TLE2 acts as a suppressor of Wnt and hedgehog signaling [#10, #11], and its mRNA is destabilized by DDX3X in pancreatic ductal adenocarcinoma, relieving TLE2-KLF4-dependent repression of MYL9 to drive F-actin remodeling and metastasis [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the molecular architecture of TLE2 as a corepressor — defining where its repression activity resides and how it oligomerizes — and linked it to HES factors.\",\n      \"evidence\": \"Gal4 fusion repression assays, dimerization mapping, and interaction studies in neural/non-neural tissues\",\n      \"pmids\": [\"9874198\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the chromatin-modifying machinery downstream of repression\", \"HES interaction not mapped to specific domains\", \"Single lab\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed TLE2 is recruited by a sequence-specific repressor (PRDI-BF1/Blimp-1) to a defined promoter, demonstrating the recruitment-to-DNA mechanism and the dominant-negative potential of the dimerization domain.\",\n      \"evidence\": \"Co-IP, Gal4 fusion repression, dominant-negative overexpression, and IFN-beta promoter reporter assays\",\n      \"pmids\": [\"9887105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous IFN-beta regulation not tested\", \"Co-repressor effector machinery not defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Connected TLE proteins to a conserved TUP1-SSN6-like repression mechanism through interaction with UTY/X proteins.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, Co-IP, and repression assays in mammalian cells\",\n      \"pmids\": [\"9854018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological promoters using this mechanism not identified\", \"TLE2-specific (vs TLE1) contribution unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated TLE2 localizes to the nuclear matrix and is targeted there with RUNX/AML factors, tying its subnuclear positioning to repression of a defined target gene.\",\n      \"evidence\": \"Immunofluorescence, nuclear matrix fractionation, reporter assays, yeast two-hybrid\",\n      \"pmids\": [\"10825294\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of nuclear matrix tethering unknown\", \"Single target promoter (osteocalcin)\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the boundary of TLE-dependent repression by showing TLE proteins are dispensable for Cbfa/Runx repression of the BSP promoter, indicating promoter-context-specific recruitment.\",\n      \"evidence\": \"Co-transfection reporter assays with promoter deletion/mutation analysis\",\n      \"pmids\": [\"11283267\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not explain which features select TLE-dependent vs independent promoters\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified TLE2 (Grg2) as a transcriptional target of an oncoprotein, linking its induction to leukemic pro-B cell survival.\",\n      \"evidence\": \"Representational difference analysis, immunoblot, inducible E2A-HLF expression\",\n      \"pmids\": [\"11486032\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect transcriptional activation not resolved\", \"Functional requirement of Grg2 for survival not tested by loss-of-function\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended the partner repertoire to pancreatic transcription factors and showed TLE2 modulates Arx repressive activity, placing it in islet cell-fate regulation.\",\n      \"evidence\": \"Co-IP for multiple partners and reporter assays in a beta-cell line\",\n      \"pmids\": [\"18778483\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo pancreatic requirement not tested\", \"Direct vs indirect modulation of Arx unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established TLE2 as a functional cooperating corepressor for FoxG1 in vivo, mapping the binding motifs required for telencephalon specification.\",\n      \"evidence\": \"Binding-motif mutagenesis, morpholino knockdown, ectopic neurogenesis assay, and in situ hybridization in Xenopus\",\n      \"pmids\": [\"20356955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian conservation of this requirement not addressed\", \"Downstream repressed genes only partly defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed TLE2 downstream of Rx1 as an effector that represses endomesodermal genes to specify retinal progenitor identity.\",\n      \"evidence\": \"Rx1-regulated gene screen with gain/loss-of-function and reporter assays in Xenopus\",\n      \"pmids\": [\"24038725\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct target promoters of TLE2 in retinal precursors not mapped\", \"Partner transcription factor in this context not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed a virological role: TLE2 represses KSHV RTA by competing with RBP-Jkappa for the same domain, stabilizing latency.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, Co-IP, co-localization, reporter and virion production assays with domain mapping\",\n      \"pmids\": [\"19939918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous TLE2 contribution to natural latency reactivation not quantified\", \"Relative affinities of TLE2 vs RBP-Jkappa not measured\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Positioned TLE2 as a suppressor of Wnt signaling acting downstream of NDRG1 in esophageal squamous carcinoma cells.\",\n      \"evidence\": \"Co-IP, lentiviral overexpression, RNAi, and rescue reporter/western assays\",\n      \"pmids\": [\"27414086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect effect on beta-catenin unresolved\", \"Transcriptional targets in Wnt suppression not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked TLE2 to suppression of cancer stem-like properties via the hedgehog pathway in ovarian cancer.\",\n      \"evidence\": \"shRNA screen with side-population flow cytometry, sphere/clonogenicity assays, xenografts, and pathway analysis\",\n      \"pmids\": [\"31578411\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting TLE2 to hedgehog output not defined\", \"Direct hedgehog-component interactions untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a complete regulatory axis in PDAC: DDX3X destabilizes TLE2 mRNA, and TLE2-KLF4 repression of MYL9 controls cytoskeletal mechanics and metastasis.\",\n      \"evidence\": \"CRISPR-Cas9 orthotopic screen, mRNA stability assays, Co-IP, F-actin and traction force microscopy, in vivo models\",\n      \"pmids\": [\"40938994\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KLF4-MYL9 repression operates outside PDAC unknown\", \"Direct binding of TLE2 to the MYL9 promoter region not detailed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The chromatin-level effector machinery through which TLE2 enforces repression and the rules selecting its partner transcription factors across tissues remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No histone-modifier or chromatin remodeler defined as TLE2 effector\", \"Structural basis of partner discrimination unknown\", \"Endogenous genome-wide TLE2 occupancy not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 3, 6, 7, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TLE1\", \"HES1\", \"PRDM1\", \"RUNX1\", \"FOXG1\", \"KLF4\", \"ARX\", \"NKX2-2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}