{"gene":"MBIP","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2000,"finding":"MBIP (MUK-binding inhibitory protein) physically interacts with the leucine-zipper-like motif of MUK/DLK/ZPK (MAP3K12) and inhibits its ability to activate JNK/SAPK signaling. Overexpression of MBIP partially inhibits JNK activation by hyperosmotic stress (0.3 M sorbitol) in 293T cells. The inhibitory effect was specific to MUK/DLK/ZPK and was not observed with another JNK-activating MAPKKK, COT/Tpl-2.","method":"Co-immunoprecipitation/protein interaction assay, overexpression in 293T cells with JNK/SAPK activity assay, specificity controls with COT/Tpl-2","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated, functional inhibition shown in cells with specificity control, single lab with two orthogonal methods (binding + kinase activity assay)","pmids":["10801814"],"is_preprint":false},{"year":2008,"finding":"MBIP (MAP3K12 binding inhibitory protein) is a component of the human ATAC (Ada Two-A containing) histone acetyltransferase complex, which contains GCN5 or PCAF along with ADA2-A, ADA3, STAF36, WDR5, POLE3/CHRAC17, POLE4, TAK1/MAP3K7, YEATS2-NC2beta, and other subunits. The complex interacts with TBP via the YEATS2-NC2beta histone fold module.","method":"Biochemical purification of ATAC complex followed by mass spectrometry identification of subunits; functional characterization of TBP interaction","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical purification with MS identification, multiple orthogonal methods, complex composition rigorously established","pmids":["18838386"],"is_preprint":false},{"year":2012,"finding":"The Drosophila homolog of MBIP (CG10238/dMoaE) functions as a subunit of the ATAC histone acetyltransferase complex and inhibits JNK activation. The MoaE-related N-terminal region of MBIP contains sequence determinants responsible for regulating MAPK signaling. MBIP protein sequences across metazoa have an N-terminal region derived from MoaE (molybdopterin synthase large subunit) but have lost residues responsible for catalytic activity, indicating a non-catalytic role in MAPK signaling as part of ATAC.","method":"Biochemical interaction assays (dMoaE with dMoaD and with itself), mass spectrometry-based proteomics of ATAC complex subunits, sequence analysis with mutagenesis-based functional mapping of MAPK regulatory determinants","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based complex identification plus functional domain mapping, single lab, Drosophila ortholog study","pmids":["22345504"],"is_preprint":false},{"year":2020,"finding":"MBIP expression in NSCLC cells promotes cellular proliferation, migration, invasion in vitro and metastasis in vivo. Mechanistically, MBIP mediates activation of the JNK pathway and induces expression of matrix metalloproteinases (MMPs), which are required for the invasive and metastatic phenotype.","method":"Gain-of-function and loss-of-function experiments in NSCLC cell lines (migration/invasion assays), in vivo metastasis assays, JNK pathway activation assays, MMP expression analysis, rescue experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular phenotype with pathway placement (JNK→MMP axis), multiple orthogonal methods (in vitro and in vivo), single lab","pmids":["32963352"],"is_preprint":false},{"year":2024,"finding":"MBIP promotes metastasis in esophageal squamous cell carcinoma (ESCC) by activating the MAPK pathway, specifically through phosphorylation of JNK and p38, leading to epithelial-mesenchymal transition (EMT). MBIP is a component of the ATAC (Ada2A-containing) complex.","method":"RNA-seq, qRT-PCR, western blotting, Transwell migration/invasion assays, mouse xenograft assay, rescue experiments with pathway inhibitors","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional data with pathway placement (JNK/p38 phosphorylation → EMT), single lab, multiple orthogonal methods","pmids":["38199596"],"is_preprint":false},{"year":2018,"finding":"MBIP deletion (without deletion of NKX2-1) in a three-generation family with benign hereditary chorea leads to reduced NKX2-1 transcript levels in patient fibroblasts compared to controls, suggesting MBIP deletion affects NKX2-1 expression and mimics NKX2-1 haploinsufficiency.","method":"Array CGH for genomic deletion mapping, RT-PCR/transcript quantification in patient fibroblasts versus controls","journal":"European journal of medical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single family, single method (transcript quantification), indirect evidence of regulatory role on NKX2-1 expression","pmids":["29621620"],"is_preprint":false},{"year":2008,"finding":"Mbip expression in the developing mouse forebrain is enriched in the medial ganglionic eminence (MGE) progenitor population. This expression is lost when MGE cells are propagated as neurospheres, indicating that the forebrain-extrinsic signals are required for this expression pattern.","method":"In situ hybridization in wild-type and mutant (Pax6Sey/Sey, Shh-/-, Gli3XtJ/XtJ) forebrain tissue; neurosphere assay comparison","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization by ISH without direct functional perturbation of Mbip itself; expression pattern only","pmids":["18799682"],"is_preprint":false}],"current_model":"MBIP (MAP3K12 Binding Inhibitory Protein) is a component of the metazoan ATAC histone acetyltransferase complex that also functions as a negative regulator of MUK/DLK/ZPK (MAP3K12)-mediated JNK/SAPK signaling by directly binding to MAP3K12's leucine-zipper motif; in cancer contexts, MBIP paradoxically drives JNK and p38 MAPK activation, inducing MMP expression and EMT to promote tumor invasion and metastasis, and its N-terminal domain is evolutionarily derived from the MoaE subunit of molybdopterin synthase but has lost catalytic activity in favor of this non-catalytic MAPK regulatory role within ATAC."},"narrative":{"mechanistic_narrative":"MBIP is a dual-function protein that operates both as a structural component of the metazoan ATAC histone acetyltransferase complex and as a regulator of stress-activated MAP kinase signaling [PMID:18838386, PMID:22345504]. It was first defined biochemically through its direct physical interaction with the leucine-zipper-like motif of the MAP3K MUK/DLK/ZPK (MAP3K12), where binding inhibits MAP3K12-driven JNK/SAPK activation in a kinase-specific manner [PMID:10801814]. MBIP is a stable subunit of the human ATAC complex assembled around the GCN5/PCAF acetyltransferases, ADA2-A, ADA3, WDR5, and additional histone-fold subunits that engage TBP, and its N-terminal region is derived from the MoaE molybdopterin synthase subunit but has lost catalytic residues, repurposing this fold as a non-catalytic MAPK-regulatory module within ATAC [PMID:18838386, PMID:22345504]. In cancer, MBIP acts as a pro-metastatic effector: in non-small-cell lung carcinoma it activates the JNK pathway and induces matrix metalloproteinase expression to drive proliferation, migration, invasion, and metastasis [PMID:32963352], and in esophageal squamous cell carcinoma it promotes JNK and p38 phosphorylation to trigger epithelial-mesenchymal transition and metastasis [PMID:38199596]. Beyond these MAPK-linked roles and its ATAC membership, the biochemical mechanism by which MBIP integrates chromatin acetylation and kinase regulation has not been resolved in the available corpus.","teleology":[{"year":2000,"claim":"Established MBIP's founding molecular activity by showing it directly binds a specific MAP3K and selectively dampens stress-induced JNK signaling, defining it as a kinase-binding inhibitory protein rather than a general signaling modulator.","evidence":"Co-immunoprecipitation and JNK/SAPK kinase activity assays in 293T cells with COT/Tpl-2 specificity control","pmids":["10801814"],"confidence":"Medium","gaps":["Inhibition was only partial and tested by overexpression, not endogenous loss-of-function","No structural basis for leucine-zipper binding determined","Did not connect MBIP to any chromatin role"]},{"year":2008,"claim":"Reframed MBIP as a bona fide subunit of the ATAC histone acetyltransferase complex, revealing a chromatin-associated context independent of its prior MAPK role.","evidence":"Biochemical purification of human ATAC followed by mass spectrometry subunit identification and TBP interaction characterization","pmids":["18838386"],"confidence":"High","gaps":["Did not define MBIP's specific contribution to ATAC acetyltransferase activity or assembly","Relationship between ATAC membership and MAP3K12 inhibition left unaddressed"]},{"year":2012,"claim":"Reconciled the two functions by mapping the MAPK-regulatory determinants to MBIP's MoaE-derived N-terminal region and showing the fold is catalytically dead, establishing a non-catalytic, repurposed domain within ATAC.","evidence":"Drosophila ortholog (CG10238/dMoaE) interaction assays, ATAC proteomics, and mutagenesis-based domain mapping with cross-metazoan sequence analysis","pmids":["22345504"],"confidence":"Medium","gaps":["Mechanistic link between the MoaE-derived domain and JNK inhibition not biochemically resolved","Based on Drosophila ortholog","How ATAC incorporation gates MAPK regulation unknown"]},{"year":2018,"claim":"Implicated MBIP in regulating expression of the neighboring gene NKX2-1, raising a possible chromatin/regulatory role in disease, though through indirect genetic evidence.","evidence":"Array CGH deletion mapping and transcript quantification in fibroblasts from a single benign hereditary chorea family","pmids":["29621620"],"confidence":"Low","gaps":["Single family with indirect transcript-level evidence only","Causality between MBIP deletion and NKX2-1 reduction not mechanistically established","Possible positional/regulatory artifact not excluded"]},{"year":2020,"claim":"Inverted the original inhibitory model in a disease context by showing MBIP drives, rather than suppresses, JNK signaling to promote an invasive MMP-dependent metastatic phenotype in lung cancer.","evidence":"Gain- and loss-of-function in NSCLC lines, in vivo metastasis assays, JNK and MMP readouts with rescue","pmids":["32963352"],"confidence":"Medium","gaps":["Molecular basis for activating rather than inhibiting JNK not defined","Role of ATAC membership in this phenotype untested","Single cancer-type, single lab"]},{"year":2024,"claim":"Extended the pro-metastatic MAPK role to a second tumor type, showing MBIP activates both JNK and p38 to drive EMT, reinforcing a context-dependent activating function.","evidence":"RNA-seq, western blotting, Transwell assays, mouse xenografts, and pathway-inhibitor rescue in ESCC","pmids":["38199596"],"confidence":"Medium","gaps":["Direct biochemical mechanism of JNK/p38 activation not shown","Does not reconcile activating versus inhibitory effects on the same pathway","Contribution of ATAC acetyltransferase activity not separated from MAPK effects"]},{"year":null,"claim":"It remains unresolved how MBIP's MoaE-derived non-catalytic domain mechanistically toggles between inhibiting and activating stress MAPK signaling, and how this is coupled to its function within the ATAC histone acetyltransferase complex.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biochemical model explains the inhibitory-to-activating switch across cell contexts","The functional interplay between ATAC membership and MAP3K binding is uncharacterized","No defined substrate or chromatin target attributable specifically to MBIP"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,4]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,2]}],"complexes":["ATAC histone acetyltransferase complex"],"partners":["MAP3K12"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NS73","full_name":"MAP3K12-binding inhibitory protein 1","aliases":["MAPK upstream kinase-binding inhibitory protein","MUK-binding inhibitory protein"],"length_aa":344,"mass_kda":39.3,"function":"Functions as part of the ATAC complex, a complex with histone acetyltransferase activity on histones H3 and H4 (PubMed:19103755). Inhibits the MAP3K12 activity to induce the activation of the JNK/SAPK pathway (PubMed:10801814). Together with MOCS2B, inhibits the activity of stress kinase EIF2AK2/PKR; this may lead to effects such as suppression of JNK activation and subsequent stress-responsive transcription, or suppression of eIF2a phosphorylation to favor translation (PubMed:26705305)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9NS73/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MBIP","classification":"Not Classified","n_dependent_lines":10,"n_total_lines":1208,"dependency_fraction":0.008278145695364239},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTB","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGN5","stoichiometry":0.2},{"gene":"MIF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MBIP","total_profiled":1310},"omim":[{"mim_id":"617501","title":"LYSINE ACETYLTRANSFERASE 14; KAT14","url":"https://www.omim.org/entry/617501"},{"mim_id":"613373","title":"YEATS DOMAIN-CONTAINING PROTEIN 2; YEATS2","url":"https://www.omim.org/entry/613373"},{"mim_id":"610978","title":"CHOREOATHETOSIS AND CONGENITAL HYPOTHYROIDISM WITH OR WITHOUT PULMONARY DYSFUNCTION; CAHTP","url":"https://www.omim.org/entry/610978"},{"mim_id":"609431","title":"MAP3K12-BINDING INHIBITORY PROTEIN; MBIP","url":"https://www.omim.org/entry/609431"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MBIP"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9NS73","domains":[{"cath_id":"-","chopping":"25-92","consensus_level":"high","plddt":78.2207,"start":25,"end":92},{"cath_id":"-","chopping":"156-220","consensus_level":"medium","plddt":80.8603,"start":156,"end":220},{"cath_id":"-","chopping":"244-263_270-296","consensus_level":"medium","plddt":82.4109,"start":244,"end":296}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NS73","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NS73-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NS73-F1-predicted_aligned_error_v6.png","plddt_mean":68.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MBIP","jax_strain_url":"https://www.jax.org/strain/search?query=MBIP"},"sequence":{"accession":"Q9NS73","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NS73.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NS73/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NS73"}},"corpus_meta":[{"pmid":"16412867","id":"PMC_16412867","title":"Long-term 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Overexpression of MBIP partially inhibits JNK activation by hyperosmotic stress (0.3 M sorbitol) in 293T cells. The inhibitory effect was specific to MUK/DLK/ZPK and was not observed with another JNK-activating MAPKKK, COT/Tpl-2.\",\n      \"method\": \"Co-immunoprecipitation/protein interaction assay, overexpression in 293T cells with JNK/SAPK activity assay, specificity controls with COT/Tpl-2\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated, functional inhibition shown in cells with specificity control, single lab with two orthogonal methods (binding + kinase activity assay)\",\n      \"pmids\": [\"10801814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MBIP (MAP3K12 binding inhibitory protein) is a component of the human ATAC (Ada Two-A containing) histone acetyltransferase complex, which contains GCN5 or PCAF along with ADA2-A, ADA3, STAF36, WDR5, POLE3/CHRAC17, POLE4, TAK1/MAP3K7, YEATS2-NC2beta, and other subunits. The complex interacts with TBP via the YEATS2-NC2beta histone fold module.\",\n      \"method\": \"Biochemical purification of ATAC complex followed by mass spectrometry identification of subunits; functional characterization of TBP interaction\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical purification with MS identification, multiple orthogonal methods, complex composition rigorously established\",\n      \"pmids\": [\"18838386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The Drosophila homolog of MBIP (CG10238/dMoaE) functions as a subunit of the ATAC histone acetyltransferase complex and inhibits JNK activation. The MoaE-related N-terminal region of MBIP contains sequence determinants responsible for regulating MAPK signaling. MBIP protein sequences across metazoa have an N-terminal region derived from MoaE (molybdopterin synthase large subunit) but have lost residues responsible for catalytic activity, indicating a non-catalytic role in MAPK signaling as part of ATAC.\",\n      \"method\": \"Biochemical interaction assays (dMoaE with dMoaD and with itself), mass spectrometry-based proteomics of ATAC complex subunits, sequence analysis with mutagenesis-based functional mapping of MAPK regulatory determinants\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based complex identification plus functional domain mapping, single lab, Drosophila ortholog study\",\n      \"pmids\": [\"22345504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MBIP expression in NSCLC cells promotes cellular proliferation, migration, invasion in vitro and metastasis in vivo. Mechanistically, MBIP mediates activation of the JNK pathway and induces expression of matrix metalloproteinases (MMPs), which are required for the invasive and metastatic phenotype.\",\n      \"method\": \"Gain-of-function and loss-of-function experiments in NSCLC cell lines (migration/invasion assays), in vivo metastasis assays, JNK pathway activation assays, MMP expression analysis, rescue experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular phenotype with pathway placement (JNK→MMP axis), multiple orthogonal methods (in vitro and in vivo), single lab\",\n      \"pmids\": [\"32963352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MBIP promotes metastasis in esophageal squamous cell carcinoma (ESCC) by activating the MAPK pathway, specifically through phosphorylation of JNK and p38, leading to epithelial-mesenchymal transition (EMT). MBIP is a component of the ATAC (Ada2A-containing) complex.\",\n      \"method\": \"RNA-seq, qRT-PCR, western blotting, Transwell migration/invasion assays, mouse xenograft assay, rescue experiments with pathway inhibitors\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional data with pathway placement (JNK/p38 phosphorylation → EMT), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38199596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MBIP deletion (without deletion of NKX2-1) in a three-generation family with benign hereditary chorea leads to reduced NKX2-1 transcript levels in patient fibroblasts compared to controls, suggesting MBIP deletion affects NKX2-1 expression and mimics NKX2-1 haploinsufficiency.\",\n      \"method\": \"Array CGH for genomic deletion mapping, RT-PCR/transcript quantification in patient fibroblasts versus controls\",\n      \"journal\": \"European journal of medical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single family, single method (transcript quantification), indirect evidence of regulatory role on NKX2-1 expression\",\n      \"pmids\": [\"29621620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Mbip expression in the developing mouse forebrain is enriched in the medial ganglionic eminence (MGE) progenitor population. This expression is lost when MGE cells are propagated as neurospheres, indicating that the forebrain-extrinsic signals are required for this expression pattern.\",\n      \"method\": \"In situ hybridization in wild-type and mutant (Pax6Sey/Sey, Shh-/-, Gli3XtJ/XtJ) forebrain tissue; neurosphere assay comparison\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization by ISH without direct functional perturbation of Mbip itself; expression pattern only\",\n      \"pmids\": [\"18799682\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MBIP (MAP3K12 Binding Inhibitory Protein) is a component of the metazoan ATAC histone acetyltransferase complex that also functions as a negative regulator of MUK/DLK/ZPK (MAP3K12)-mediated JNK/SAPK signaling by directly binding to MAP3K12's leucine-zipper motif; in cancer contexts, MBIP paradoxically drives JNK and p38 MAPK activation, inducing MMP expression and EMT to promote tumor invasion and metastasis, and its N-terminal domain is evolutionarily derived from the MoaE subunit of molybdopterin synthase but has lost catalytic activity in favor of this non-catalytic MAPK regulatory role within ATAC.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MBIP is a dual-function protein that operates both as a structural component of the metazoan ATAC histone acetyltransferase complex and as a regulator of stress-activated MAP kinase signaling [#1, #2]. It was first defined biochemically through its direct physical interaction with the leucine-zipper-like motif of the MAP3K MUK/DLK/ZPK (MAP3K12), where binding inhibits MAP3K12-driven JNK/SAPK activation in a kinase-specific manner [#0]. MBIP is a stable subunit of the human ATAC complex assembled around the GCN5/PCAF acetyltransferases, ADA2-A, ADA3, WDR5, and additional histone-fold subunits that engage TBP, and its N-terminal region is derived from the MoaE molybdopterin synthase subunit but has lost catalytic residues, repurposing this fold as a non-catalytic MAPK-regulatory module within ATAC [#1, #2]. In cancer, MBIP acts as a pro-metastatic effector: in non-small-cell lung carcinoma it activates the JNK pathway and induces matrix metalloproteinase expression to drive proliferation, migration, invasion, and metastasis [#3], and in esophageal squamous cell carcinoma it promotes JNK and p38 phosphorylation to trigger epithelial-mesenchymal transition and metastasis [#4]. Beyond these MAPK-linked roles and its ATAC membership, the biochemical mechanism by which MBIP integrates chromatin acetylation and kinase regulation has not been resolved in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established MBIP's founding molecular activity by showing it directly binds a specific MAP3K and selectively dampens stress-induced JNK signaling, defining it as a kinase-binding inhibitory protein rather than a general signaling modulator.\",\n      \"evidence\": \"Co-immunoprecipitation and JNK/SAPK kinase activity assays in 293T cells with COT/Tpl-2 specificity control\",\n      \"pmids\": [\"10801814\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Inhibition was only partial and tested by overexpression, not endogenous loss-of-function\", \"No structural basis for leucine-zipper binding determined\", \"Did not connect MBIP to any chromatin role\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Reframed MBIP as a bona fide subunit of the ATAC histone acetyltransferase complex, revealing a chromatin-associated context independent of its prior MAPK role.\",\n      \"evidence\": \"Biochemical purification of human ATAC followed by mass spectrometry subunit identification and TBP interaction characterization\",\n      \"pmids\": [\"18838386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define MBIP's specific contribution to ATAC acetyltransferase activity or assembly\", \"Relationship between ATAC membership and MAP3K12 inhibition left unaddressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Reconciled the two functions by mapping the MAPK-regulatory determinants to MBIP's MoaE-derived N-terminal region and showing the fold is catalytically dead, establishing a non-catalytic, repurposed domain within ATAC.\",\n      \"evidence\": \"Drosophila ortholog (CG10238/dMoaE) interaction assays, ATAC proteomics, and mutagenesis-based domain mapping with cross-metazoan sequence analysis\",\n      \"pmids\": [\"22345504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between the MoaE-derived domain and JNK inhibition not biochemically resolved\", \"Based on Drosophila ortholog\", \"How ATAC incorporation gates MAPK regulation unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Implicated MBIP in regulating expression of the neighboring gene NKX2-1, raising a possible chromatin/regulatory role in disease, though through indirect genetic evidence.\",\n      \"evidence\": \"Array CGH deletion mapping and transcript quantification in fibroblasts from a single benign hereditary chorea family\",\n      \"pmids\": [\"29621620\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single family with indirect transcript-level evidence only\", \"Causality between MBIP deletion and NKX2-1 reduction not mechanistically established\", \"Possible positional/regulatory artifact not excluded\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Inverted the original inhibitory model in a disease context by showing MBIP drives, rather than suppresses, JNK signaling to promote an invasive MMP-dependent metastatic phenotype in lung cancer.\",\n      \"evidence\": \"Gain- and loss-of-function in NSCLC lines, in vivo metastasis assays, JNK and MMP readouts with rescue\",\n      \"pmids\": [\"32963352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis for activating rather than inhibiting JNK not defined\", \"Role of ATAC membership in this phenotype untested\", \"Single cancer-type, single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the pro-metastatic MAPK role to a second tumor type, showing MBIP activates both JNK and p38 to drive EMT, reinforcing a context-dependent activating function.\",\n      \"evidence\": \"RNA-seq, western blotting, Transwell assays, mouse xenografts, and pathway-inhibitor rescue in ESCC\",\n      \"pmids\": [\"38199596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical mechanism of JNK/p38 activation not shown\", \"Does not reconcile activating versus inhibitory effects on the same pathway\", \"Contribution of ATAC acetyltransferase activity not separated from MAPK effects\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how MBIP's MoaE-derived non-catalytic domain mechanistically toggles between inhibiting and activating stress MAPK signaling, and how this is coupled to its function within the ATAC histone acetyltransferase complex.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural or biochemical model explains the inhibitory-to-activating switch across cell contexts\", \"The functional interplay between ATAC membership and MAP3K binding is uncharacterized\", \"No defined substrate or chromatin target attributable specifically to MBIP\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\"ATAC histone acetyltransferase complex\"],\n    \"partners\": [\"MAP3K12\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}