{"gene":"IBTK","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2001,"finding":"IBtk (IBTK) directly binds to the PH domain of Bruton's tyrosine kinase (Btk) and inhibits Btk kinase activity, Btk-mediated calcium mobilization, and NF-κB-driven transcription, acting as a trans-inhibitor of Btk.","method":"Binding assay (PH domain interaction), kinase activity assay, calcium mobilization assay, NF-κB transcription reporter assay","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct biochemical binding to defined domain, functional kinase inhibition assay, and multiple orthogonal downstream readouts in a single focused study","pmids":["11577348"],"is_preprint":false},{"year":2008,"finding":"The human IBTK locus encodes three distinct protein isoforms (IBtkα, IBtkβ, and IBtkγ) arising from two distinct promoter regions, alternative polyadenylation, and a second transcription start site with a distinct ATG; all three proteins were detected in human cells and mouse tissues by specific antibodies.","method":"Northern blot, 5′RACE, 3′RACE, isoform-specific antibody detection","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal molecular biology methods (Northern blot, RACE, protein detection) in a single focused study establishing locus architecture and isoform existence","pmids":["18596081"],"is_preprint":false},{"year":2009,"finding":"The IBTK gene encodes a microRNA precursor (pre-miR-IBTK3) from intron 26 that serves as an effective substrate for RNase III Dicer in vitro and gives rise to a mature IBtk miRNA in vivo.","method":"Computational prediction (Pro-MirII), in vitro Dicer cleavage assay, in vivo miRNA detection","journal":"Computational biology and chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro Dicer assay plus in vivo detection, but single lab and limited mechanistic follow-up on the miRNA product itself; note this concerns a non-coding RNA product of the locus, not the canonical IBTK protein","pmids":["19782003"],"is_preprint":false},{"year":2019,"finding":"Loss of murine Ibtk in Eμ-myc transgenic mice reduces pre-cancerous B cell viability and increases apoptosis (measured by Annexin V binding and Caspase 3/7 cleavage) without affecting proliferation, demonstrating that Ibtk sustains B cell survival downstream of Myc by modulating MCL-1 and p53-dependent apoptotic pathways.","method":"Ibtk knockout × Eμ-myc transgenic mouse model, Annexin V assay, Caspase 3/7 cleavage assay, cell cycle analysis, ChIP-seq data analysis, tet-repressible Myc system","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with multiple orthogonal apoptosis readouts, in vivo tumor onset data, and mechanistic pathway placement (MCL-1/p53) with ChIP-seq validation of Myc-dependent IBTK regulation","pmids":["30975981"],"is_preprint":false},{"year":2020,"finding":"Haploinsufficiency of Ibtk in Eμ-myc mice alters the immunophenotype of Myc-driven B cell lymphomas, increasing pre-B cell rates and enhancing tumor angiogenesis/lymphangiogenesis with elevated VEGF, MMP-9, CCL2, and VEGFD, and increased recruitment of tumor-associated macrophages.","method":"Ibtk hemizygous × Eμ-myc transgenic mouse model, immunophenotyping, angiogenic factor measurement, macrophage quantification","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo genetic model with multiple readouts but single lab, and mechanistic link between IBTK haploinsufficiency and microenvironmental changes is correlative rather than biochemically resolved","pmids":["32019112"],"is_preprint":false},{"year":2024,"finding":"IBTK, acting as a substrate-binding adaptor of the Cullin 3-RING ubiquitin ligase (CRL3) complex, interacts with eIF4A1 and promotes its non-degradative ubiquitination, which enhances cap-dependent translational initiation and nascent protein synthesis; furthermore, mTORC1 and S6K1 directly phosphorylate IBTK to augment eIF4A1 ubiquitination and sustain oncogenic translation in cervical tumor cells.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, in vitro kinase assay (mTORC1/S6K1 phosphorylation of IBTK), polysome profiling/nascent protein synthesis assay, in vivo tumor xenograft, mutagenesis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted CRL3IBTK ubiquitination in vitro, in vitro kinase phosphorylation assay, multiple orthogonal functional readouts (translation, tumor growth in vivo), and mutagenesis in a single rigorous study","pmids":["38738857"],"is_preprint":false},{"year":2024,"finding":"IBTK silencing in non-Hodgkin lymphoma B cells increases apoptosis when combined with Rituximab both in vitro and in vivo (transplanted Eμ-myc lymphoma model), and is associated with reduced MYC oncogene expression.","method":"siRNA knockdown, Annexin V assay, cell cycle analysis, in vivo transplanted lymphoma model, MYC expression analysis","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with defined apoptotic phenotype and MYC expression link, in vivo validation, but single lab and mechanistic connection between IBTK and MYC not biochemically resolved","pmids":["38371626"],"is_preprint":false}],"current_model":"IBTK (IBtk) is a multifunctional adaptor protein that: (1) directly binds the PH domain of Bruton's tyrosine kinase (Btk) to trans-inhibit its kinase activity and downstream NF-κB and calcium signaling in B cells; (2) acts as the substrate-recognition subunit of a CRL3IBTK ubiquitin ligase complex that non-degradatively ubiquitinates eIF4A1 to promote cap-dependent translation, a process amplified by direct mTORC1/S6K1 phosphorylation of IBTK; and (3) sustains Myc-driven B cell survival by modulating MCL-1- and p53-dependent apoptotic pathways, with its expression transcriptionally regulated by Myc."},"narrative":{"mechanistic_narrative":"IBTK is a multifunctional adaptor protein that operates in two distinct regulatory regimes: negative control of B cell receptor signaling and positive control of cap-dependent translation [PMID:11577348, PMID:38738857]. It was first defined as a trans-inhibitor of Bruton's tyrosine kinase, binding directly to the Btk PH domain and suppressing Btk kinase activity, calcium mobilization, and NF-κB-driven transcription [PMID:11577348]. In a separate, later-defined role, IBTK serves as the substrate-recognition subunit of a Cullin 3-RING ubiquitin ligase (CRL3IBTK), recruiting eIF4A1 for non-degradative ubiquitination that enhances translational initiation and nascent protein synthesis; mTORC1 and S6K1 directly phosphorylate IBTK to amplify this activity and sustain oncogenic translation [PMID:38738857]. In Myc-driven B cell contexts, IBTK sustains pre-cancerous B cell survival by limiting MCL-1- and p53-dependent apoptosis without affecting proliferation, and its expression is itself transcriptionally regulated by Myc [PMID:30975981]. Consistent with this pro-survival role, IBTK loss shapes the lymphoma immunophenotype and microenvironment [PMID:32019112] and sensitizes lymphoma B cells to Rituximab-induced apoptosis with reduced MYC expression [PMID:38371626]. The human locus is structurally complex, producing three protein isoforms from distinct promoters and a Dicer-processed intronic miRNA precursor [PMID:18596081, PMID:19782003].","teleology":[{"year":2001,"claim":"Established the founding molecular function of IBTK as a direct negative regulator of Btk, answering whether B cell signaling kinases are subject to dedicated trans-inhibitory partners.","evidence":"PH-domain binding assay, kinase activity assay, calcium mobilization, and NF-κB reporter readouts","pmids":["11577348"],"confidence":"High","gaps":["Structural basis of the PH-domain interaction not resolved","In vivo physiological consequence of Btk inhibition not tested genetically","Did not address other IBTK functions later discovered"]},{"year":2008,"claim":"Defined the architecture of the human IBTK locus, showing the gene produces three distinct protein isoforms and clarifying which products exist before functional studies could be attributed.","evidence":"Northern blot, 5'/3' RACE, and isoform-specific antibody detection in human cells and mouse tissues","pmids":["18596081"],"confidence":"High","gaps":["Distinct functions of the three isoforms not assigned","Tissue- and context-specific isoform regulation not mapped"]},{"year":2009,"claim":"Showed the IBTK locus encodes a non-coding regulatory output, identifying an intronic pre-miRNA processed by Dicer and broadening the locus beyond its protein products.","evidence":"Computational prediction, in vitro Dicer cleavage assay, and in vivo mature miRNA detection","pmids":["19782003"],"confidence":"Medium","gaps":["Targets and physiological role of the mature miRNA not identified","Single-lab finding without mechanistic follow-up on the miRNA product"]},{"year":2019,"claim":"Placed IBTK in the Myc oncogenic axis in vivo, answering whether IBTK contributes to B cell transformation by demonstrating it sustains pre-cancerous B cell survival rather than proliferation.","evidence":"Ibtk knockout x Eμ-myc mice with Annexin V, Caspase 3/7, cell cycle, ChIP-seq, and tet-repressible Myc readouts","pmids":["30975981"],"confidence":"High","gaps":["Biochemical mechanism linking IBTK to MCL-1 and p53 not resolved","How Myc transcriptionally drives IBTK at the molecular level not detailed"]},{"year":2020,"claim":"Extended IBTK's tumor role to the microenvironment, testing whether IBTK dosage influences lymphoma immunophenotype and angiogenesis.","evidence":"Ibtk hemizygous x Eμ-myc mice with immunophenotyping, angiogenic factor measurement, and macrophage quantification","pmids":["32019112"],"confidence":"Medium","gaps":["Link between IBTK dosage and microenvironmental changes is correlative, not biochemically resolved","Mechanism of angiogenic factor induction unknown"]},{"year":2024,"claim":"Revealed an entirely distinct enzymatic-adaptor function, answering how IBTK promotes oncogenic protein synthesis: as the CRL3 substrate adaptor that ubiquitinates eIF4A1 non-degradatively, with mTORC1/S6K1 phosphorylation as an upstream amplifier.","evidence":"Co-IP, reconstituted in vitro ubiquitination, in vitro kinase assay, polysome/nascent synthesis profiling, mutagenesis, and tumor xenografts","pmids":["38738857"],"confidence":"High","gaps":["Ubiquitination sites and consequence for eIF4A1 conformation/activity not fully defined","Relationship between the CRL3 role and the Btk-inhibitory role not integrated","Phosphorylation sites on IBTK not exhaustively mapped"]},{"year":2024,"claim":"Tested therapeutic relevance, showing IBTK silencing synergizes with Rituximab to drive lymphoma apoptosis and lowers MYC expression.","evidence":"siRNA knockdown with Annexin V, cell cycle analysis, transplanted Eμ-myc lymphoma model, and MYC expression analysis","pmids":["38371626"],"confidence":"Medium","gaps":["Mechanistic connection between IBTK and MYC expression not biochemically resolved","Single-lab loss-of-function study"]},{"year":null,"claim":"How IBTK's two opposing roles — Btk inhibition versus CRL3-mediated promotion of translation — are coordinated within a single cell, and whether specific isoforms partition between them, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["Isoform-to-function mapping not established","No integrated model reconciling signaling-inhibitory and ubiquitin-ligase activities","Structural data for IBTK absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3]}],"complexes":["CRL3IBTK (Cullin 3-RING ubiquitin ligase)"],"partners":["BTK","EIF4A1","MTOR","RPS6KB1","CUL3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P2D0","full_name":"Inhibitor of Bruton tyrosine kinase","aliases":[],"length_aa":1353,"mass_kda":150.5,"function":"Acts as an inhibitor of BTK tyrosine kinase activity, thereby playing a role in B-cell development. Down-regulates BTK kinase activity, leading to interference with BTK-mediated calcium mobilization and NF-kappa-B-driven transcription","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9P2D0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IBTK","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":[{"gene":"EIF4A1","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"PTGES3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IBTK","total_profiled":1310},"omim":[{"mim_id":"606457","title":"INHIBITOR OF BRUTON AGAMMAGLOBULINEMIA TYROSINE KINASE; IBTK","url":"https://www.omim.org/entry/606457"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IBTK"},"hgnc":{"alias_symbol":["DKFZP564B116","BTBD26"],"prev_symbol":["BTKI"]},"alphafold":{"accession":"Q9P2D0","domains":[{"cath_id":"1.25.40.20","chopping":"2-130_934-954","consensus_level":"medium","plddt":89.8295,"start":2,"end":954},{"cath_id":"2.130.10.30","chopping":"143-467_498-530","consensus_level":"medium","plddt":93.3119,"start":143,"end":530},{"cath_id":"3.30.710.10","chopping":"545-651_715-758","consensus_level":"medium","plddt":85.4562,"start":545,"end":758}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2D0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2D0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2D0-F1-predicted_aligned_error_v6.png","plddt_mean":70.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IBTK","jax_strain_url":"https://www.jax.org/strain/search?query=IBTK"},"sequence":{"accession":"Q9P2D0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P2D0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P2D0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2D0"}},"corpus_meta":[{"pmid":"11577348","id":"PMC_11577348","title":"Direct inhibition of Bruton's tyrosine kinase by IBtk, a Btk-binding protein.","date":"2001","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11577348","citation_count":60,"is_preprint":false},{"pmid":"31861854","id":"PMC_31861854","title":"Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31861854","citation_count":47,"is_preprint":false},{"pmid":"35836241","id":"PMC_35836241","title":"Hypertension and incident cardiovascular events after next-generation BTKi therapy initiation.","date":"2022","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35836241","citation_count":33,"is_preprint":false},{"pmid":"18596081","id":"PMC_18596081","title":"Physical and functional characterization of the genetic locus of IBtk, an inhibitor of Bruton's tyrosine kinase: evidence for three protein isoforms of 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immunocompromised patient receiving a second-generation Bruton Tyrosine Kinase inhibitor (BTKi).","date":"2026","source":"Diagnostic microbiology and infectious disease","url":"https://pubmed.ncbi.nlm.nih.gov/41548496","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.25.684506","title":"High-Throughput Screening Identifies PLK1 Inhibition as a Strategy to Potentiate BTK Blockade in Marginal Zone Lymphoma","date":"2025-10-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.25.684506","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.02.673601","title":"Leveraging BRG1 Driven Ferroptosis Resistance to Overcome Treatment Resistance","date":"2025-09-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.02.673601","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.13.623398","title":"Small molecule inhibitor combination treatment effectively represses global B-cell signaling in diffuse 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Cancer","date":"2024-11-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.04.621884","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23939,"output_tokens":2001,"usd":0.050916,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8950,"output_tokens":2764,"usd":0.056925,"stage2_stop_reason":"end_turn"},"total_usd":0.107841,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"IBtk (IBTK) directly binds to the PH domain of Bruton's tyrosine kinase (Btk) and inhibits Btk kinase activity, Btk-mediated calcium mobilization, and NF-κB-driven transcription, acting as a trans-inhibitor of Btk.\",\n      \"method\": \"Binding assay (PH domain interaction), kinase activity assay, calcium mobilization assay, NF-κB transcription reporter assay\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct biochemical binding to defined domain, functional kinase inhibition assay, and multiple orthogonal downstream readouts in a single focused study\",\n      \"pmids\": [\"11577348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The human IBTK locus encodes three distinct protein isoforms (IBtkα, IBtkβ, and IBtkγ) arising from two distinct promoter regions, alternative polyadenylation, and a second transcription start site with a distinct ATG; all three proteins were detected in human cells and mouse tissues by specific antibodies.\",\n      \"method\": \"Northern blot, 5′RACE, 3′RACE, isoform-specific antibody detection\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal molecular biology methods (Northern blot, RACE, protein detection) in a single focused study establishing locus architecture and isoform existence\",\n      \"pmids\": [\"18596081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The IBTK gene encodes a microRNA precursor (pre-miR-IBTK3) from intron 26 that serves as an effective substrate for RNase III Dicer in vitro and gives rise to a mature IBtk miRNA in vivo.\",\n      \"method\": \"Computational prediction (Pro-MirII), in vitro Dicer cleavage assay, in vivo miRNA detection\",\n      \"journal\": \"Computational biology and chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro Dicer assay plus in vivo detection, but single lab and limited mechanistic follow-up on the miRNA product itself; note this concerns a non-coding RNA product of the locus, not the canonical IBTK protein\",\n      \"pmids\": [\"19782003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of murine Ibtk in Eμ-myc transgenic mice reduces pre-cancerous B cell viability and increases apoptosis (measured by Annexin V binding and Caspase 3/7 cleavage) without affecting proliferation, demonstrating that Ibtk sustains B cell survival downstream of Myc by modulating MCL-1 and p53-dependent apoptotic pathways.\",\n      \"method\": \"Ibtk knockout × Eμ-myc transgenic mouse model, Annexin V assay, Caspase 3/7 cleavage assay, cell cycle analysis, ChIP-seq data analysis, tet-repressible Myc system\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with multiple orthogonal apoptosis readouts, in vivo tumor onset data, and mechanistic pathway placement (MCL-1/p53) with ChIP-seq validation of Myc-dependent IBTK regulation\",\n      \"pmids\": [\"30975981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Haploinsufficiency of Ibtk in Eμ-myc mice alters the immunophenotype of Myc-driven B cell lymphomas, increasing pre-B cell rates and enhancing tumor angiogenesis/lymphangiogenesis with elevated VEGF, MMP-9, CCL2, and VEGFD, and increased recruitment of tumor-associated macrophages.\",\n      \"method\": \"Ibtk hemizygous × Eμ-myc transgenic mouse model, immunophenotyping, angiogenic factor measurement, macrophage quantification\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo genetic model with multiple readouts but single lab, and mechanistic link between IBTK haploinsufficiency and microenvironmental changes is correlative rather than biochemically resolved\",\n      \"pmids\": [\"32019112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IBTK, acting as a substrate-binding adaptor of the Cullin 3-RING ubiquitin ligase (CRL3) complex, interacts with eIF4A1 and promotes its non-degradative ubiquitination, which enhances cap-dependent translational initiation and nascent protein synthesis; furthermore, mTORC1 and S6K1 directly phosphorylate IBTK to augment eIF4A1 ubiquitination and sustain oncogenic translation in cervical tumor cells.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, in vitro kinase assay (mTORC1/S6K1 phosphorylation of IBTK), polysome profiling/nascent protein synthesis assay, in vivo tumor xenograft, mutagenesis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted CRL3IBTK ubiquitination in vitro, in vitro kinase phosphorylation assay, multiple orthogonal functional readouts (translation, tumor growth in vivo), and mutagenesis in a single rigorous study\",\n      \"pmids\": [\"38738857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IBTK silencing in non-Hodgkin lymphoma B cells increases apoptosis when combined with Rituximab both in vitro and in vivo (transplanted Eμ-myc lymphoma model), and is associated with reduced MYC oncogene expression.\",\n      \"method\": \"siRNA knockdown, Annexin V assay, cell cycle analysis, in vivo transplanted lymphoma model, MYC expression analysis\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with defined apoptotic phenotype and MYC expression link, in vivo validation, but single lab and mechanistic connection between IBTK and MYC not biochemically resolved\",\n      \"pmids\": [\"38371626\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IBTK (IBtk) is a multifunctional adaptor protein that: (1) directly binds the PH domain of Bruton's tyrosine kinase (Btk) to trans-inhibit its kinase activity and downstream NF-κB and calcium signaling in B cells; (2) acts as the substrate-recognition subunit of a CRL3IBTK ubiquitin ligase complex that non-degradatively ubiquitinates eIF4A1 to promote cap-dependent translation, a process amplified by direct mTORC1/S6K1 phosphorylation of IBTK; and (3) sustains Myc-driven B cell survival by modulating MCL-1- and p53-dependent apoptotic pathways, with its expression transcriptionally regulated by Myc.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IBTK is a multifunctional adaptor protein that operates in two distinct regulatory regimes: negative control of B cell receptor signaling and positive control of cap-dependent translation [#0, #5]. It was first defined as a trans-inhibitor of Bruton's tyrosine kinase, binding directly to the Btk PH domain and suppressing Btk kinase activity, calcium mobilization, and NF-\\u03baB-driven transcription [#0]. In a separate, later-defined role, IBTK serves as the substrate-recognition subunit of a Cullin 3-RING ubiquitin ligase (CRL3IBTK), recruiting eIF4A1 for non-degradative ubiquitination that enhances translational initiation and nascent protein synthesis; mTORC1 and S6K1 directly phosphorylate IBTK to amplify this activity and sustain oncogenic translation [#5]. In Myc-driven B cell contexts, IBTK sustains pre-cancerous B cell survival by limiting MCL-1- and p53-dependent apoptosis without affecting proliferation, and its expression is itself transcriptionally regulated by Myc [#3]. Consistent with this pro-survival role, IBTK loss shapes the lymphoma immunophenotype and microenvironment [#4] and sensitizes lymphoma B cells to Rituximab-induced apoptosis with reduced MYC expression [#6]. The human locus is structurally complex, producing three protein isoforms from distinct promoters and a Dicer-processed intronic miRNA precursor [#1, #2].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the founding molecular function of IBTK as a direct negative regulator of Btk, answering whether B cell signaling kinases are subject to dedicated trans-inhibitory partners.\",\n      \"evidence\": \"PH-domain binding assay, kinase activity assay, calcium mobilization, and NF-\\u03baB reporter readouts\",\n      \"pmids\": [\"11577348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the PH-domain interaction not resolved\", \"In vivo physiological consequence of Btk inhibition not tested genetically\", \"Did not address other IBTK functions later discovered\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the architecture of the human IBTK locus, showing the gene produces three distinct protein isoforms and clarifying which products exist before functional studies could be attributed.\",\n      \"evidence\": \"Northern blot, 5'/3' RACE, and isoform-specific antibody detection in human cells and mouse tissues\",\n      \"pmids\": [\"18596081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distinct functions of the three isoforms not assigned\", \"Tissue- and context-specific isoform regulation not mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed the IBTK locus encodes a non-coding regulatory output, identifying an intronic pre-miRNA processed by Dicer and broadening the locus beyond its protein products.\",\n      \"evidence\": \"Computational prediction, in vitro Dicer cleavage assay, and in vivo mature miRNA detection\",\n      \"pmids\": [\"19782003\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Targets and physiological role of the mature miRNA not identified\", \"Single-lab finding without mechanistic follow-up on the miRNA product\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed IBTK in the Myc oncogenic axis in vivo, answering whether IBTK contributes to B cell transformation by demonstrating it sustains pre-cancerous B cell survival rather than proliferation.\",\n      \"evidence\": \"Ibtk knockout x E\\u03bc-myc mice with Annexin V, Caspase 3/7, cell cycle, ChIP-seq, and tet-repressible Myc readouts\",\n      \"pmids\": [\"30975981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical mechanism linking IBTK to MCL-1 and p53 not resolved\", \"How Myc transcriptionally drives IBTK at the molecular level not detailed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended IBTK's tumor role to the microenvironment, testing whether IBTK dosage influences lymphoma immunophenotype and angiogenesis.\",\n      \"evidence\": \"Ibtk hemizygous x E\\u03bc-myc mice with immunophenotyping, angiogenic factor measurement, and macrophage quantification\",\n      \"pmids\": [\"32019112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between IBTK dosage and microenvironmental changes is correlative, not biochemically resolved\", \"Mechanism of angiogenic factor induction unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed an entirely distinct enzymatic-adaptor function, answering how IBTK promotes oncogenic protein synthesis: as the CRL3 substrate adaptor that ubiquitinates eIF4A1 non-degradatively, with mTORC1/S6K1 phosphorylation as an upstream amplifier.\",\n      \"evidence\": \"Co-IP, reconstituted in vitro ubiquitination, in vitro kinase assay, polysome/nascent synthesis profiling, mutagenesis, and tumor xenografts\",\n      \"pmids\": [\"38738857\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitination sites and consequence for eIF4A1 conformation/activity not fully defined\", \"Relationship between the CRL3 role and the Btk-inhibitory role not integrated\", \"Phosphorylation sites on IBTK not exhaustively mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Tested therapeutic relevance, showing IBTK silencing synergizes with Rituximab to drive lymphoma apoptosis and lowers MYC expression.\",\n      \"evidence\": \"siRNA knockdown with Annexin V, cell cycle analysis, transplanted E\\u03bc-myc lymphoma model, and MYC expression analysis\",\n      \"pmids\": [\"38371626\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic connection between IBTK and MYC expression not biochemically resolved\", \"Single-lab loss-of-function study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IBTK's two opposing roles \\u2014 Btk inhibition versus CRL3-mediated promotion of translation \\u2014 are coordinated within a single cell, and whether specific isoforms partition between them, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Isoform-to-function mapping not established\", \"No integrated model reconciling signaling-inhibitory and ubiquitin-ligase activities\", \"Structural data for IBTK absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\"CRL3IBTK (Cullin 3-RING ubiquitin ligase)\"],\n    \"partners\": [\"BTK\", \"EIF4A1\", \"MTOR\", \"RPS6KB1\", \"CUL3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}