{"gene":"BRAP","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2004,"finding":"BRAP/IMP (Impedes Mitogenic signal Propagation) is a Ras-responsive E3 ubiquitin ligase that inhibits KSR (a scaffold/adaptor protein), thereby limiting functional assembly of Raf-MEK complexes and suppressing MAP kinase cascade activation. Upon Ras activation, IMP undergoes auto-polyubiquitination, which releases its inhibition of Raf-MEK complex formation. IMP depletion increases stimulus-dependent MEK activation without altering timing or duration of the response, establishing IMP as a threshold modulator.","method":"siRNA depletion, ubiquitination assays, epistasis with Ras, Co-IP, MEK activation assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional assays, epistasis, E3 ligase activity demonstrated, foundational paper replicated by subsequent studies","pmids":["14724641"],"is_preprint":false},{"year":2004,"finding":"BRAP2 directly interacts with the cell cycle inhibitor p21 in vitro and in vivo through the nuclear localization signal (NLS) of p21 and the C-terminal portion of BRAP2. Co-transfection of BRAP2 causes p21 to localize to the cytoplasm. During monocytic differentiation of U937 and HL-60 cells, BRAP2 expression is upregulated concomitantly with cytoplasmic relocalization of p21, indicating BRAP2 acts as a cytoplasmic retention protein for p21.","method":"Co-immunoprecipitation in vitro and in vivo, co-transfection localization assays, immunoblotting during monocyte differentiation","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, co-transfection functional localization assay, single lab","pmids":["15340083"],"is_preprint":false},{"year":2008,"finding":"IMP inhibits signal propagation through Raf to MEK by disrupting KSR1 homo-oligomerization and B-Raf/c-Raf hetero-oligomerization, thereby impairing both MEK recruitment to activated Raf and c-Raf kinase activation. Human KSR1 promotes assembly of multivalent Raf-MEK complexes required for c-Raf kinase activation, and IMP exploits this property to modulate signal amplitude.","method":"Co-immunoprecipitation, KSR1 oligomerization assays, kinase activity assays, IMP expression/depletion","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional kinase assays, single lab, extends mechanism from Nature 2004 paper","pmids":["18332145"],"is_preprint":false},{"year":2008,"finding":"IMP concentrations are directly regulated by Ras through induction of IMP autoubiquitination (autodegradation), permitting productive Raf-MEK complex assembly. The mechanism of inhibition involves KSR inactivation as the key downstream target.","method":"Ubiquitination assays, Ras activation experiments, functional rescue assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays with Ras activation, single lab, corroborates prior findings","pmids":["19091743"],"is_preprint":false},{"year":2009,"finding":"BRAP was identified as a galectin-2-binding protein. SNPs in BRAP are associated with myocardial infarction. BRAP knockdown by siRNA in cultured coronary endothelial cells suppressed activation of NF-κB.","method":"Binding assay (galectin-2 pulldown), siRNA knockdown, NF-κB activation assay","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — binding assay and siRNA knockdown with NF-κB readout, single lab, limited mechanistic depth","pmids":["19198608"],"is_preprint":false},{"year":2011,"finding":"BRAP knockdown in human aortic smooth muscle cells attenuated cell proliferation and reduced secretion of MCP-1 and IL-8 in response to LPS, and prohibited NF-κB nuclear translocation without affecting NF-κB protein levels. Co-immunoprecipitation confirmed interaction between BRAP and IκBβ and IKKβ, two major components of the IKK signalosome.","method":"siRNA knockdown, co-immunoprecipitation, NF-κB nuclear translocation assay, cytokine ELISA","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, siRNA with NF-κB localization and cytokine readout, single lab","pmids":["21670849"],"is_preprint":false},{"year":2012,"finding":"BRAP/IMP E3 ubiquitin ligase interacts with deubiquitylases USP15 and USP4 through the N-terminal DUSP-UBL domain of USP15 and the coiled-coil region of BRAP. USP15 and USP4 oppose BRAP autoubiquitination, while BRAP promotes USP15 ubiquitylation. USP15 depletion destabilizes BRAP via proteasomal degradation; catalytically active USP15 rescues BRAP levels. USP15 depletion decreases MAPK signaling amplitude in response to EGF and PDGF, in part through decreased CRAF levels.","method":"Co-immunoprecipitation, domain mapping, ubiquitination assays, siRNA depletion, proteasomal degradation assay, EGF/PDGF signaling assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ubiquitination, degradation rescue), single lab","pmids":["23105109"],"is_preprint":false},{"year":2013,"finding":"Brap directly interacts with Lis1, and a Nde1-Lis1-Brap complex regulates MAPK signaling thresholds in the developing mammalian CNS. Nde1-Lis1 deficiency causes spatially dependent alterations of the MAPK scaffold KSR and hyperactivation of MAPK. Epistasis analyses supported synergistic Brap and Lis1 functions in controlling neural progenitor proliferation and differentiation.","method":"Genetic epistasis analysis (double mutant), co-immunoprecipitation (Lis1-Brap interaction), MAPK activation assays in vivo, mouse CNS developmental phenotype analysis","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus direct protein interaction, single lab, in vivo CNS context","pmids":["23673330"],"is_preprint":false},{"year":2013,"finding":"Brap2 is a novel Nedd8-binding protein that interacts with the SCF ubiquitin ligase complex and is involved in NF-κB nuclear translocation following TNF-α stimulation. A putative neddylation site in Brap2 is associated with NF-κB activity. Brap2 modulates temporal control of NF-κB nuclear translocation mediated by inflammatory response.","method":"Co-immunoprecipitation, Nedd8 binding assay, TNF-α stimulation assay, NF-κB localization assay, neddylation site mutant analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding and functional assays, single lab, corroborates prior NF-κB findings","pmids":["23554956"],"is_preprint":false},{"year":2009,"finding":"BRAP2 inhibits nuclear import of specific viral proteins (SV40 large T antigen and HCMV ppUL44) in a manner dependent on phosphorylation sites flanking their nuclear localization signals. Substitution of CDK phosphorylation site T124 of T-ag with Ala prevented BRAP2 inhibition, while Asp (phosphomimetic) enhanced it. Direct high-affinity binding of BRAP2(442-592) to T-ag(111-135) was strictly dependent on negative charge at T124 and the NLS, demonstrated by pulldown/AlphaScreen assays. No effect of BRAP2 was observed on HSV-1 pUL30 (which lacks a phosphorylation site near its NLS) or HIV-1 Tat.","method":"Ectopic expression in COS-7 and HL-60 cells, nuclear import quantification, site-directed mutagenesis, pulldown/AlphaScreen binding assay","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro binding with mutagenesis, cellular localization assays, multiple orthogonal methods, phosphorylation-dependence established","pmids":["20040518"],"is_preprint":false},{"year":2013,"finding":"BRAP2 acts as a cytoplasmic retention factor for testicular nuclear proteins HMG20A and NuMA1, and prevents nuclear envelope accumulation of SYNE2. Co-immunoprecipitation confirmed association of BRAP2 with HMG20A, NuMA1, and SYNE2 in testis. Ectopic expression of BRAP2 inhibited nuclear localization of HMG20A and NuMA1, and prevented nuclear envelope accumulation of SYNE2 in cultured cells.","method":"Yeast two-hybrid screen, co-immunoprecipitation from testis tissue, quantitative confocal microscopy of ectopic BRAP2 expression","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP from tissue plus quantitative imaging, single lab","pmids":["23707952"],"is_preprint":false},{"year":2017,"finding":"Loss of Brap in mouse neural progenitor cells results in premature G1/S phase transition due to elevated Skp2 (SCF ubiquitin ligase component), which increases p27Kip1 destruction. Brap-mediated polyubiquitination of Skp2 was identified as a key regulatory step. Loss of Brap led to elevated Skp2, shortened G1 phase, premature S phase entry, hindered S phase progression, increased G2 arrest, impeded neuronal differentiation, and microcephaly.","method":"Conditional Brap mouse knockout, cell cycle analysis, ubiquitination assays for Skp2, p27 protein levels, neuronal differentiation assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined cellular/molecular phenotype, polyubiquitination assay identifying Skp2 as substrate, multiple readouts in vivo and in vitro","pmids":["28768199"],"is_preprint":false},{"year":2018,"finding":"In C. elegans, BRAP-2 promotes DNA damage-induced germline apoptosis by attenuating pro-survival signals of AKT-1 and PMK-1/SKN-1. Loss of brap-2 reduces germline apoptosis after DNA damage and increases skn-1 mRNA. The interaction between BRAP-2 and the AKT-1 phosphatase (C. elegans homolog of PHLPP1/2) is conserved. SKN-1 RNAi or loss of pmk-1 in brap-2 mutants restored apoptosis to wild-type levels.","method":"C. elegans brap-2 deletion mutant, germline apoptosis assays, genetic epistasis with brc-1/akt-1/pmk-1/skn-1, mRNA quantification, co-immunoprecipitation of BRAP-2 with AKT-1 phosphatase","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple alleles plus protein interaction, C. elegans model, single lab","pmids":["29358669"],"is_preprint":false},{"year":2010,"finding":"In C. elegans, developmental arrest of brap-2 deletion mutants under oxidative stress is dependent on brc-1 (BRCA1 ortholog) and requires enhanced expression of the cell cycle inhibitor cki-1 through brc-1. Loss of brap-2 sensitizes animals to paraquat-induced larval arrest at the L1 stage.","method":"C. elegans genetic analysis, paraquat exposure, double mutant epistasis with brc-1, cki-1 expression analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in C. elegans model with molecular readout (cki-1 expression), single lab","pmids":["20207739"],"is_preprint":false},{"year":2015,"finding":"BRAP overexpression in human bronchial epithelial cells inhibited both basal and inducible NF-κB transcriptional activity, while BRAP knockdown had the opposite effect. BRAP regulates NF-κB activity by enhancing histone deacetylase (HDAC) activity, mediated through its putative C-terminal domain.","method":"Gene transfer overexpression, siRNA knockdown, NF-κB reporter assay, HDAC activity assay, domain truncation analysis","journal":"Journal of cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, NF-κB reporter and HDAC assay but limited mechanistic dissection; C-terminal domain inference is partial","pmids":["26460487"],"is_preprint":false},{"year":2022,"finding":"Deletion of Brap in mouse brain causes persistent DNA double-strand breaks and elevation of histone H2A mono- and poly-ubiquitination (H2Aub), leading to cellular senescence, proteasome-mediated histone H2A proteolysis, neuroinflammation, impaired proteostasis, accelerated neurodegeneration, and shortened lifespan. H2Aub elevation also occurs in human Alzheimer's disease brain tissue, suggesting H2Aub chromatin aberrations act as a nexus linking multiple aging hallmarks.","method":"Conditional Brap mouse brain knockout, DNA damage assays, H2A ubiquitination assays, proteasome activity assays, lifespan analysis, human AD brain tissue immunostaining","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple molecular readouts including ubiquitination and DNA damage, single lab with in vivo and human tissue validation","pmids":["35754718"],"is_preprint":false}],"current_model":"BRAP (also known as BRAP2, RNF52, IMP) is a Ras-responsive RING-domain E3 ubiquitin ligase that acts as a threshold modulator of the Ras-Raf-MEK-ERK MAP kinase cascade by targeting KSR1 to inhibit its homo-oligomerization and its scaffolding of Raf-MEK complexes; upon Ras activation, BRAP undergoes auto-polyubiquitination and is degraded, relieving this inhibition. Beyond MAPK regulation, BRAP functions as a cytoplasmic retention factor for nuclear proteins (including p21/CDKN1A) by binding their NLS in a phosphorylation-dependent manner, ubiquitinates Skp2 to control G1/S phase timing in neural progenitors, interacts with the IKK signalosome components IκBβ and IKKβ as well as Nedd8-SCF complexes to regulate NF-κB nuclear translocation, and promotes DNA damage-induced apoptosis by attenuating AKT-1 and PMK-1/SKN-1 pro-survival signaling."},"narrative":{"mechanistic_narrative":"BRAP (also IMP, BRAP2, RNF52) is a cytoplasmic RING-domain E3 ubiquitin ligase that sets activation thresholds for mitogenic and stress-signaling cascades [PMID:14724641]. Its founding function is as a Ras-responsive brake on the Raf-MEK-ERK pathway: BRAP inhibits the scaffold KSR1 by disrupting KSR1 homo-oligomerization and B-Raf/c-Raf hetero-oligomerization, thereby limiting MEK recruitment and c-Raf activation and acting as a threshold modulator rather than altering response timing [PMID:14724641, PMID:18332145]. Ras activation drives BRAP auto-polyubiquitination and autodegradation, relieving this inhibition and permitting productive Raf-MEK assembly [PMID:14724641, PMID:19091743]; BRAP stability is in turn opposed by the deubiquitylases USP15 and USP4, which counter its autoubiquitination [PMID:23105109]. In the developing CNS, BRAP partners with the Nde1-Lis1 complex to tune MAPK thresholds during neural progenitor proliferation and differentiation [PMID:23673330], and BRAP-mediated polyubiquitination of Skp2 restrains G1/S transition, with its loss causing premature S-phase entry and microcephaly [PMID:28768199]. Independently of catalysis-driven signaling, BRAP serves as a cytoplasmic retention factor that binds nuclear-localization signals in a phosphorylation-dependent manner to sequester nuclear proteins including p21/CDKN1A, HMG20A, NuMA1, and certain viral cargoes such as SV40 large T antigen [PMID:15340083, PMID:20040518, PMID:23707952]. BRAP also restrains NF-κB nuclear translocation through interaction with IKK signalosome components IκBβ and IKKβ and with Nedd8/SCF complexes [PMID:21670849, PMID:23554956], and its loss in mouse brain produces persistent DNA double-strand breaks and elevated histone H2A ubiquitination linked to senescence and neurodegeneration [PMID:35754718]. BRAP variants are genetically associated with myocardial infarction [PMID:19198608].","teleology":[{"year":2004,"claim":"Established BRAP/IMP as a Ras-responsive E3 ligase that sets the activation threshold of the MAP kinase cascade by inhibiting the KSR scaffold, answering how mitogenic signal amplitude is gated.","evidence":"siRNA depletion, ubiquitination assays, Ras epistasis and MEK activation readouts in mammalian cells","pmids":["14724641"],"confidence":"High","gaps":["Did not resolve the molecular target of KSR inhibition at the oligomerization level","Direct ubiquitination substrate within the Raf-MEK module not defined"]},{"year":2004,"claim":"Showed BRAP2 binds the p21 NLS and retains p21 in the cytoplasm, revealing a ubiquitination-independent role as a nuclear-protein sequestration factor.","evidence":"Reciprocal Co-IP and co-transfection localization assays during monocytic differentiation","pmids":["15340083"],"confidence":"Medium","gaps":["Single lab","Physiological signal triggering p21 release not defined"]},{"year":2008,"claim":"Defined the mechanism of KSR inhibition, showing IMP disrupts KSR1 homo-oligomerization and Raf hetero-oligomerization to impair MEK recruitment and c-Raf activation.","evidence":"Co-IP, oligomerization and kinase activity assays with IMP expression/depletion","pmids":["18332145"],"confidence":"Medium","gaps":["Single lab","Structural basis of the IMP-KSR interaction not resolved"]},{"year":2008,"claim":"Demonstrated that Ras controls IMP levels through induction of autoubiquitination/autodegradation, establishing the feedback that licenses signal propagation.","evidence":"Ubiquitination assays, Ras activation experiments, functional rescue","pmids":["19091743"],"confidence":"Medium","gaps":["Identity of any cofactor enabling auto-degradation not defined","Single lab"]},{"year":2009,"claim":"Extended cytoplasmic retention to phosphorylation-gated NLS recognition, showing BRAP2 blocks nuclear import of cargo whose NLS-flanking residues are phosphorylated.","evidence":"Nuclear import quantification, site-directed mutagenesis of CDK site T124, pulldown/AlphaScreen binding using SV40 T-ag and HCMV ppUL44","pmids":["20040518"],"confidence":"High","gaps":["Generality of phospho-NLS recognition across endogenous substrates not mapped","Kinase responsible for substrate priming not identified"]},{"year":2009,"claim":"Linked BRAP to cardiovascular disease and NF-κB control, showing BRAP is a galectin-2 binding protein whose knockdown suppresses NF-κB in endothelial cells.","evidence":"Galectin-2 pulldown, siRNA knockdown, NF-κB activation assay; BRAP SNP-MI association","pmids":["19198608"],"confidence":"Medium","gaps":["Mechanism connecting galectin-2 binding to NF-κB not established","SNP association does not establish causal mechanism"]},{"year":2010,"claim":"Placed BRAP in an oxidative-stress checkpoint, showing brap-2 loss sensitizes C. elegans to paraquat via brc-1-dependent cki-1 induction.","evidence":"C. elegans genetic epistasis with brc-1, paraquat exposure, cki-1 expression analysis","pmids":["20207739"],"confidence":"Medium","gaps":["Direct molecular link between BRAP-2 and brc-1/cki-1 not defined","Mammalian conservation untested here"]},{"year":2011,"claim":"Mapped BRAP onto the IKK signalosome, showing it interacts with IκBβ and IKKβ and is required for NF-κB nuclear translocation and inflammatory cytokine output.","evidence":"siRNA knockdown, reciprocal Co-IP, NF-κB translocation assay, cytokine ELISA in aortic smooth muscle cells","pmids":["21670849"],"confidence":"Medium","gaps":["Whether BRAP ubiquitinates IKK components not tested","Single lab"]},{"year":2012,"claim":"Identified USP15/USP4 as deubiquitylases that stabilize BRAP, defining a ubiquitin-cycle regulatory loop affecting MAPK amplitude.","evidence":"Co-IP, domain mapping, ubiquitination and proteasomal degradation rescue, EGF/PDGF signaling assays","pmids":["23105109"],"confidence":"Medium","gaps":["Single lab","In vivo relevance of the USP15-BRAP axis not established"]},{"year":2013,"claim":"Connected BRAP to neurodevelopmental MAPK threshold control via a Nde1-Lis1-Brap complex acting on KSR.","evidence":"Genetic epistasis (double mutant), Co-IP of Lis1-Brap, in vivo MAPK activation assays in mouse CNS","pmids":["23673330"],"confidence":"Medium","gaps":["Biochemical role of Lis1 in BRAP catalysis not resolved","Single lab"]},{"year":2013,"claim":"Broadened the cytoplasmic-retention substrate set, showing BRAP2 sequesters HMG20A and NuMA1 and limits SYNE2 nuclear-envelope accumulation in testis.","evidence":"Yeast two-hybrid, Co-IP from testis tissue, quantitative confocal imaging of ectopic BRAP2","pmids":["23707952"],"confidence":"Medium","gaps":["Functional consequence of retention in spermatogenesis not defined","Phospho-dependence of these substrates not tested"]},{"year":2013,"claim":"Implicated BRAP2 in neddylation-coupled NF-κB timing, showing it binds Nedd8 and the SCF complex to modulate TNF-α-induced nuclear translocation.","evidence":"Co-IP, Nedd8 binding assay, TNF-α stimulation, NF-κB localization, neddylation-site mutant analysis","pmids":["23554956"],"confidence":"Medium","gaps":["Whether BRAP2 is itself neddylated functionally unresolved","Single lab"]},{"year":2017,"claim":"Identified Skp2 as a BRAP ubiquitination substrate controlling G1/S timing, explaining how Brap loss causes premature S-phase entry and microcephaly.","evidence":"Conditional mouse knockout, cell cycle analysis, Skp2 ubiquitination assays, p27 levels, differentiation assays","pmids":["28768199"],"confidence":"High","gaps":["Direct ubiquitin linkage type on Skp2 not specified","Relationship to BRAP's MAPK role in the same cells not integrated"]},{"year":2018,"claim":"Established a pro-apoptotic role for BRAP in DNA-damage response, showing BRAP-2 attenuates AKT-1 and PMK-1/SKN-1 survival signaling to permit germline apoptosis.","evidence":"C. elegans deletion mutant, germline apoptosis assays, epistasis with akt-1/pmk-1/skn-1, Co-IP of BRAP-2 with AKT-1 phosphatase","pmids":["29358669"],"confidence":"Medium","gaps":["Mammalian conservation of the apoptotic axis not demonstrated","Mechanism of AKT-1 phosphatase regulation by BRAP-2 not resolved"]},{"year":2022,"claim":"Linked Brap loss to chromatin and aging pathology, showing brain Brap deletion causes persistent DNA breaks, elevated H2A ubiquitination, senescence and neurodegeneration, with H2Aub also raised in human AD tissue.","evidence":"Conditional mouse brain knockout, DNA damage and H2Aub assays, proteasome and lifespan analysis, human AD brain immunostaining","pmids":["35754718"],"confidence":"Medium","gaps":["Whether elevated H2Aub is a direct or indirect consequence of BRAP loss not resolved","Causal versus correlative role in human AD undefined"]},{"year":null,"claim":"How BRAP's distinct activities — KSR/MAPK gating, Skp2 ubiquitination, cytoplasmic NLS retention, NF-κB control and chromatin/H2Aub regulation — are coordinated within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating ligase activity with non-catalytic retention function","Structural basis of substrate selection unknown","Whether disease associations reflect MAPK, NF-κB, or chromatin roles unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,3,11]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,11]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[1,9,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,9,10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,8]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,9,10]}],"complexes":["Nde1-Lis1-Brap complex","IKK signalosome","SCF/Nedd8 complex"],"partners":["KSR1","USP15","USP4","LIS1","IKBKB","SKP2","NUMA1","HMG20A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6UWU4","full_name":"Bombesin receptor-activated protein C6orf89","aliases":["Amfion"],"length_aa":347,"mass_kda":39.9,"function":"Exhibits histone deacetylase (HDAC) enhancer properties (PubMed:23460338). May play a role in cell cycle progression and wound repair of bronchial epithelial cells (PubMed:21857995)","subcellular_location":"Cytoplasm; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q6UWU4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BRAP","classification":"Not Classified","n_dependent_lines":219,"n_total_lines":1208,"dependency_fraction":0.18129139072847683},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BRAP","total_profiled":1310},"omim":[{"mim_id":"616642","title":"CHROMOSOME 6 OPEN READING FRAME 89; C6ORF89","url":"https://www.omim.org/entry/616642"},{"mim_id":"604986","title":"BRCA1-ASSOCIATED PROTEIN; BRAP","url":"https://www.omim.org/entry/604986"},{"mim_id":"116899","title":"CYCLIN-DEPENDENT KINASE INHIBITOR 1A; CDKN1A","url":"https://www.omim.org/entry/116899"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nuclear membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"testis","ntpm":63.5}],"url":"https://www.proteinatlas.org/search/BRAP"},"hgnc":{"alias_symbol":["BRAP2","RNF52","IMP"],"prev_symbol":[]},"alphafold":{"accession":"Q6UWU4","domains":[{"cath_id":"2.60.120","chopping":"162-227_236-343","consensus_level":"high","plddt":82.198,"start":162,"end":343},{"cath_id":"1.10.287","chopping":"11-45","consensus_level":"high","plddt":85.78,"start":11,"end":45}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UWU4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UWU4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UWU4-F1-predicted_aligned_error_v6.png","plddt_mean":72.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BRAP","jax_strain_url":"https://www.jax.org/strain/search?query=BRAP"},"sequence":{"accession":"Q6UWU4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6UWU4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6UWU4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UWU4"}},"corpus_meta":[{"pmid":"7903306","id":"PMC_7903306","title":"Characterization of human type I and type II IMP dehydrogenases.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7903306","citation_count":317,"is_preprint":false},{"pmid":"12207697","id":"PMC_12207697","title":"Imp/OstA is required for cell envelope biogenesis in Escherichia coli.","date":"2002","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12207697","citation_count":218,"is_preprint":false},{"pmid":"14724641","id":"PMC_14724641","title":"Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP.","date":"2004","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/14724641","citation_count":161,"is_preprint":false},{"pmid":"7395984","id":"PMC_7395984","title":"AMP deamination and IMP reamination in working skeletal muscle.","date":"1980","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/7395984","citation_count":147,"is_preprint":false},{"pmid":"31371825","id":"PMC_31371825","title":"IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma.","date":"2019","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31371825","citation_count":142,"is_preprint":false},{"pmid":"22660319","id":"PMC_22660319","title":"The let-7-Imp axis regulates ageing of the Drosophila testis stem-cell niche.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22660319","citation_count":135,"is_preprint":false},{"pmid":"11302793","id":"PMC_11302793","title":"Plasmid-encoded metallo-beta-lactamase (IMP-6) conferring resistance to carbapenems, especially meropenem.","date":"2001","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/11302793","citation_count":124,"is_preprint":false},{"pmid":"27068461","id":"PMC_27068461","title":"Enhanced CLIP Uncovers IMP Protein-RNA Targets in Human Pluripotent Stem Cells Important for Cell Adhesion and Survival.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27068461","citation_count":120,"is_preprint":false},{"pmid":"10390601","id":"PMC_10390601","title":"Consequences of IMP dehydrogenase inhibition, and its relationship to cancer and apoptosis.","date":"1999","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10390601","citation_count":112,"is_preprint":false},{"pmid":"11713986","id":"PMC_11713986","title":"A family of IGF-II mRNA binding proteins (IMP) involved in RNA trafficking.","date":"2001","source":"Scandinavian journal of clinical and laboratory investigation. Supplementum","url":"https://pubmed.ncbi.nlm.nih.gov/11713986","citation_count":111,"is_preprint":false},{"pmid":"21252116","id":"PMC_21252116","title":"IMP-1 displays cross-talk with K-Ras and modulates colon cancer cell survival through the novel proapoptotic protein CYFIP2.","date":"2011","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/21252116","citation_count":104,"is_preprint":false},{"pmid":"31514446","id":"PMC_31514446","title":"Anti-Tumor Potential of IMP Dehydrogenase Inhibitors: A Century-Long Story.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31514446","citation_count":101,"is_preprint":false},{"pmid":"21707466","id":"PMC_21707466","title":"IMP-type metallo-β-lactamases in Gram-negative bacilli: distribution, phylogeny, and association with integrons.","date":"2011","source":"Critical reviews in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/21707466","citation_count":85,"is_preprint":false},{"pmid":"19198608","id":"PMC_19198608","title":"SNPs in BRAP associated with risk of myocardial infarction in Asian populations.","date":"2009","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19198608","citation_count":81,"is_preprint":false},{"pmid":"22022282","id":"PMC_22022282","title":"A phenomics-based strategy identifies loci on APOC1, BRAP, and PLCG1 associated with metabolic syndrome phenotype domains.","date":"2011","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22022282","citation_count":80,"is_preprint":false},{"pmid":"10390603","id":"PMC_10390603","title":"Nucleoside and non-nucleoside IMP dehydrogenase inhibitors as antitumor and antiviral agents.","date":"1999","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10390603","citation_count":77,"is_preprint":false},{"pmid":"10390600","id":"PMC_10390600","title":"IMP dehydrogenase: mechanism of action and inhibition.","date":"1999","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10390600","citation_count":74,"is_preprint":false},{"pmid":"29946345","id":"PMC_29946345","title":"IMP/GTP balance modulates cytoophidium assembly and IMPDH activity.","date":"2018","source":"Cell division","url":"https://pubmed.ncbi.nlm.nih.gov/29946345","citation_count":73,"is_preprint":false},{"pmid":"25918153","id":"PMC_25918153","title":"Dominance of IMP-4-producing enterobacter cloacae among carbapenemase-producing Enterobacteriaceae in Australia.","date":"2015","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/25918153","citation_count":69,"is_preprint":false},{"pmid":"31934860","id":"PMC_31934860","title":"Imp/IGF2BP levels modulate individual neural stem cell growth and division through myc mRNA stability.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31934860","citation_count":68,"is_preprint":false},{"pmid":"1967583","id":"PMC_1967583","title":"Cell differentiation and altered IMP dehydrogenase expression induced in human T-lymphoblastoid leukemia cells by mycophenolic acid and tiazofurin.","date":"1990","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/1967583","citation_count":65,"is_preprint":false},{"pmid":"16505121","id":"PMC_16505121","title":"IMP dehydrogenase inhibitor mycophenolate mofetil induces caspase-dependent apoptosis and cell cycle inhibition in multiple myeloma cells.","date":"2006","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/16505121","citation_count":64,"is_preprint":false},{"pmid":"21517780","id":"PMC_21517780","title":"The antibiotic potential of prokaryotic IMP dehydrogenase inhibitors.","date":"2011","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21517780","citation_count":63,"is_preprint":false},{"pmid":"28851709","id":"PMC_28851709","title":"Imp and Syp RNA-binding proteins govern decommissioning of Drosophila neural stem cells.","date":"2017","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/28851709","citation_count":62,"is_preprint":false},{"pmid":"27767038","id":"PMC_27767038","title":"Isolation and plasmid characterization of carbapenemase (IMP-4) producing Salmonella enterica Typhimurium from cats.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27767038","citation_count":62,"is_preprint":false},{"pmid":"16476777","id":"PMC_16476777","title":"A repeated IMP-binding motif controls oskar mRNA translation and anchoring independently of Drosophila melanogaster IMP.","date":"2006","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16476777","citation_count":59,"is_preprint":false},{"pmid":"31570709","id":"PMC_31570709","title":"The structural basis for RNA selectivity by the IMP family of RNA-binding proteins.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31570709","citation_count":58,"is_preprint":false},{"pmid":"23277500","id":"PMC_23277500","title":"bla(IMP) and bla(VIM) mediated carbapenem resistance in Pseudomonas and Acinetobacter species in India.","date":"2012","source":"Journal of infection in developing countries","url":"https://pubmed.ncbi.nlm.nih.gov/23277500","citation_count":58,"is_preprint":false},{"pmid":"11441018","id":"PMC_11441018","title":"Regulation of an IMP dehydrogenase gene and its overexpression in drug-sensitive transcription elongation mutants of yeast.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11441018","citation_count":56,"is_preprint":false},{"pmid":"1967537","id":"PMC_1967537","title":"Expression of IMP dehydrogenase in differentiating HL-60 cells.","date":"1990","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/1967537","citation_count":55,"is_preprint":false},{"pmid":"15469912","id":"PMC_15469912","title":"The Caenorhabditis elegans IMPAS gene, imp-2, is essential for development and is functionally distinct from related presenilins.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15469912","citation_count":50,"is_preprint":false},{"pmid":"24656828","id":"PMC_24656828","title":"Imp promotes axonal remodeling by regulating profilin mRNA during brain development.","date":"2014","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/24656828","citation_count":50,"is_preprint":false},{"pmid":"20956565","id":"PMC_20956565","title":"Role of the RNA-binding protein IMP-2 in muscle cell motility.","date":"2010","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20956565","citation_count":49,"is_preprint":false},{"pmid":"16919497","id":"PMC_16919497","title":"IMP dehydrogenase: structural schizophrenia and an unusual base.","date":"2006","source":"Current opinion in chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/16919497","citation_count":47,"is_preprint":false},{"pmid":"30555474","id":"PMC_30555474","title":"Immune Response-Dependent Assembly of IMP Dehydrogenase Filaments.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30555474","citation_count":45,"is_preprint":false},{"pmid":"15340083","id":"PMC_15340083","title":"Brap2 functions as a cytoplasmic retention protein for p21 during monocyte differentiation.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15340083","citation_count":43,"is_preprint":false},{"pmid":"23105109","id":"PMC_23105109","title":"Direct and indirect control of mitogen-activated protein kinase pathway-associated components, BRAP/IMP E3 ubiquitin ligase and CRAF/RAF1 kinase, by the deubiquitylating enzyme USP15.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23105109","citation_count":42,"is_preprint":false},{"pmid":"10760293","id":"PMC_10760293","title":"IMP and AMP deaminase in reperfusion injury down-regulates neutrophil recruitment.","date":"2000","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10760293","citation_count":42,"is_preprint":false},{"pmid":"17030623","id":"PMC_17030623","title":"Imp associates with squid and Hrp48 and contributes to localized expression of gurken in the oocyte.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17030623","citation_count":41,"is_preprint":false},{"pmid":"21670849","id":"PMC_21670849","title":"BRAP Activates Inflammatory Cascades and Increases the Risk for Carotid Atherosclerosis.","date":"2011","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/21670849","citation_count":40,"is_preprint":false},{"pmid":"19698973","id":"PMC_19698973","title":"IMP-3 is differentially expressed in normal and neoplastic lymphoid tissue.","date":"2009","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19698973","citation_count":40,"is_preprint":false},{"pmid":"33519761","id":"PMC_33519761","title":"Evaluation of the Immunochromatographic NG-Test Carba 5, RESIST-5 O.O.K.N.V., and IMP K-SeT for Rapid Detection of KPC-, NDM-, IMP-, VIM-type, and OXA-48-like Carbapenemase Among Enterobacterales.","date":"2021","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/33519761","citation_count":40,"is_preprint":false},{"pmid":"20040518","id":"PMC_20040518","title":"The BRCA-1 binding protein BRAP2 is a novel, negative regulator of nuclear import of viral proteins, dependent on phosphorylation flanking the nuclear localization signal.","date":"2009","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/20040518","citation_count":37,"is_preprint":false},{"pmid":"27343244","id":"PMC_27343244","title":"'Rod and ring' formation from IMP dehydrogenase is regulated through the one-carbon metabolic pathway.","date":"2016","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/27343244","citation_count":36,"is_preprint":false},{"pmid":"7746281","id":"PMC_7746281","title":"GTP depletion induced by IMP dehydrogenase inhibitors blocks RNA-primed DNA synthesis.","date":"1995","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/7746281","citation_count":36,"is_preprint":false},{"pmid":"35203838","id":"PMC_35203838","title":"Comprehensive Analysis of Imipenemase (IMP)-Type Metallo-β-Lactamase: A Global Distribution Threatening Asia.","date":"2022","source":"Antibiotics (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35203838","citation_count":35,"is_preprint":false},{"pmid":"27226123","id":"PMC_27226123","title":"Mcp3 is a novel mitochondrial outer membrane protein that follows a unique IMP-dependent biogenesis pathway.","date":"2016","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/27226123","citation_count":35,"is_preprint":false},{"pmid":"34704778","id":"PMC_34704778","title":"Emergence of Tigecycline Nonsusceptible and IMP-4 Carbapenemase-Producing K2-ST65 Hypervirulent Klebsiella pneumoniae in China.","date":"2021","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/34704778","citation_count":35,"is_preprint":false},{"pmid":"32110070","id":"PMC_32110070","title":"Carbapenem-Resistant Enterobacter hormaechei ST1103 with IMP-26 Carbapenemase and ESBL Gene bla SHV-178.","date":"2020","source":"Infection and drug resistance","url":"https://pubmed.ncbi.nlm.nih.gov/32110070","citation_count":34,"is_preprint":false},{"pmid":"22577105","id":"PMC_22577105","title":"Molecular characterization of IMP-type metallo-β-lactamases among multidrug-resistant Achromobacter xylosoxidans.","date":"2012","source":"The Journal of antimicrobial chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/22577105","citation_count":33,"is_preprint":false},{"pmid":"12004071","id":"PMC_12004071","title":"IMP, GTP, and 6-phosphoryl-IMP complexes of recombinant mouse muscle adenylosuccinate synthetase.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12004071","citation_count":31,"is_preprint":false},{"pmid":"10390598","id":"PMC_10390598","title":"IMP dehydrogenase : structural aspects of inhibitor binding.","date":"1999","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10390598","citation_count":31,"is_preprint":false},{"pmid":"23673330","id":"PMC_23673330","title":"Spatially dependent dynamic MAPK modulation by the Nde1-Lis1-Brap complex patterns mammalian CNS.","date":"2013","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/23673330","citation_count":30,"is_preprint":false},{"pmid":"37471423","id":"PMC_37471423","title":"In silico designing and immunoinformatics analysis of a novel peptide vaccine against metallo-beta-lactamase (VIM and IMP) variants.","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/37471423","citation_count":27,"is_preprint":false},{"pmid":"25347121","id":"PMC_25347121","title":"The role of IMP dehydrogenase 2 in Inauhzin-induced ribosomal stress.","date":"2014","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/25347121","citation_count":27,"is_preprint":false},{"pmid":"1357518","id":"PMC_1357518","title":"Cell cycle dependent regulation of IMP dehydrogenase activity and effect of tiazofurin.","date":"1992","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/1357518","citation_count":27,"is_preprint":false},{"pmid":"22012575","id":"PMC_22012575","title":"Oncofetal protein, IMP-3, a potential marker for prediction of postoperative peritoneal dissemination in gastric adenocarcinoma.","date":"2011","source":"Journal of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/22012575","citation_count":27,"is_preprint":false},{"pmid":"26054396","id":"PMC_26054396","title":"Drosophila Imp iCLIP identifies an RNA assemblage coordinating F-actin formation.","date":"2015","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/26054396","citation_count":26,"is_preprint":false},{"pmid":"9094207","id":"PMC_9094207","title":"IMP-L3, A 20-hydroxyecdysone-responsive gene encodes Drosophila lactate dehydrogenase: structural characterization and developmental studies.","date":"1997","source":"Developmental genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9094207","citation_count":26,"is_preprint":false},{"pmid":"36040265","id":"PMC_36040265","title":"The gateway to guanine nucleotides: Allosteric regulation of IMP dehydrogenases.","date":"2022","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/36040265","citation_count":25,"is_preprint":false},{"pmid":"22122968","id":"PMC_22122968","title":"Additive effect of ANRIL and BRAP polymorphisms on ankle-brachial index in a Taiwanese population.","date":"2011","source":"Circulation journal : official journal of the Japanese Circulation Society","url":"https://pubmed.ncbi.nlm.nih.gov/22122968","citation_count":25,"is_preprint":false},{"pmid":"8098009","id":"PMC_8098009","title":"Chromosomal localization and structure of the human type II IMP dehydrogenase gene (IMPDH2).","date":"1993","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8098009","citation_count":24,"is_preprint":false},{"pmid":"30133460","id":"PMC_30133460","title":"Specific expression pattern of IMP metabolism related-genes in chicken muscle between cage and free range conditions.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30133460","citation_count":24,"is_preprint":false},{"pmid":"31416831","id":"PMC_31416831","title":"The Bateman domain of IMP dehydrogenase is a binding target for dinucleoside polyphosphates.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31416831","citation_count":24,"is_preprint":false},{"pmid":"38181792","id":"PMC_38181792","title":"The conserved RNA-binding protein Imp is required for the specification and function of olfactory navigation circuitry in Drosophila.","date":"2024","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/38181792","citation_count":23,"is_preprint":false},{"pmid":"28768199","id":"PMC_28768199","title":"Loss of Brap Results in Premature G1/S Phase Transition and Impeded Neural Progenitor Differentiation.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28768199","citation_count":23,"is_preprint":false},{"pmid":"8103312","id":"PMC_8103312","title":"IMP dehydrogenase inhibitors as immunomodulators.","date":"1993","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/8103312","citation_count":23,"is_preprint":false},{"pmid":"6140264","id":"PMC_6140264","title":"IMP dehydrogenase. II. Purification and properties of the enzyme from Yoshida sarcoma ascites tumor cells.","date":"1983","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/6140264","citation_count":23,"is_preprint":false},{"pmid":"19788446","id":"PMC_19788446","title":"IMP-3 expression in melanocytic lesions.","date":"2009","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19788446","citation_count":22,"is_preprint":false},{"pmid":"2115480","id":"PMC_2115480","title":"The Drosophila IMP-E2 gene encodes an apically secreted protein expressed during imaginal disc morphogenesis.","date":"1990","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/2115480","citation_count":22,"is_preprint":false},{"pmid":"29496594","id":"PMC_29496594","title":"blaIMP-27 on transferable plasmids in Proteus mirabilis and Providencia rettgeri.","date":"2018","source":"Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/29496594","citation_count":22,"is_preprint":false},{"pmid":"28807916","id":"PMC_28807916","title":"Inhibition of Calcineurin or IMP Dehydrogenase Exerts Moderate to Potent Antiviral Activity against Norovirus Replication.","date":"2017","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/28807916","citation_count":20,"is_preprint":false},{"pmid":"28424761","id":"PMC_28424761","title":"Sequencing of blaIMP-Carrying IncN2 Plasmids, and Comparative Genomics of IncN2 Plasmids Harboring Class 1 Integrons.","date":"2017","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28424761","citation_count":20,"is_preprint":false},{"pmid":"31666316","id":"PMC_31666316","title":"IMP-68, a Novel IMP-Type Metallo-β-Lactamase in Imipenem-Susceptible Klebsiella pneumoniae.","date":"2019","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/31666316","citation_count":19,"is_preprint":false},{"pmid":"18332145","id":"PMC_18332145","title":"IMP modulates KSR1-dependent multivalent complex formation to specify ERK1/2 pathway activation and response thresholds.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18332145","citation_count":19,"is_preprint":false},{"pmid":"23549465","id":"PMC_23549465","title":"IMP-3 expression in keratoacanthomas and squamous cell carcinomas of the skin: an immunohistochemical study.","date":"2013","source":"European journal of histochemistry : EJH","url":"https://pubmed.ncbi.nlm.nih.gov/23549465","citation_count":19,"is_preprint":false},{"pmid":"11966442","id":"PMC_11966442","title":"Metabolism of the novel IMP dehydrogenase inhibitor benzamide riboside.","date":"2002","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11966442","citation_count":19,"is_preprint":false},{"pmid":"28562329","id":"PMC_28562329","title":"Identification of polymorphisms in 12q24.1, ACAD10, and BRAP as novel genetic determinants of blood pressure in Japanese by exome-wide association studies.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28562329","citation_count":19,"is_preprint":false},{"pmid":"23554956","id":"PMC_23554956","title":"Brap2 regulates temporal control of NF-κB localization mediated by inflammatory response.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23554956","citation_count":18,"is_preprint":false},{"pmid":"19091743","id":"PMC_19091743","title":"Signaling threshold regulation by the Ras effector IMP.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19091743","citation_count":16,"is_preprint":false},{"pmid":"25857773","id":"PMC_25857773","title":"IMP-GMP specific cytosolic 5'-nucleotidase regulates nucleotide pool and prodrug metabolism.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25857773","citation_count":16,"is_preprint":false},{"pmid":"23707952","id":"PMC_23707952","title":"The BRCA1-binding protein BRAP2 can act as a cytoplasmic retention factor for nuclear and nuclear envelope-localizing testicular proteins.","date":"2013","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23707952","citation_count":15,"is_preprint":false},{"pmid":"37409948","id":"PMC_37409948","title":"Identification of IMP Dehydrogenase as a Potential Target for Anti-Mpox Virus Agents.","date":"2023","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/37409948","citation_count":15,"is_preprint":false},{"pmid":"34659175","id":"PMC_34659175","title":"First Report of bla IMP-4 and bla SRT-2 Coproducing Serratia marcescens Clinical Isolate in China.","date":"2021","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34659175","citation_count":15,"is_preprint":false},{"pmid":"33790873","id":"PMC_33790873","title":"Emergence of IMP-8-Producing Comamonas thiooxydans Causing Urinary Tract Infection in China.","date":"2021","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/33790873","citation_count":15,"is_preprint":false},{"pmid":"36174533","id":"PMC_36174533","title":"Structural insights into the substrate specificity of IMP-6 and IMP-1 metallo-β-lactamases.","date":"2022","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36174533","citation_count":14,"is_preprint":false},{"pmid":"32205343","id":"PMC_32205343","title":"Structure and Molecular Recognition Mechanism of IMP-13 Metallo-β-Lactamase.","date":"2020","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/32205343","citation_count":14,"is_preprint":false},{"pmid":"7906545","id":"PMC_7906545","title":"Gene amplification and dual point mutations of mouse IMP dehydrogenase associated with cellular resistance to mycophenolic acid.","date":"1994","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/7906545","citation_count":14,"is_preprint":false},{"pmid":"1292892","id":"PMC_1292892","title":"Sequence and expression of IMP-L1, an ecdysone-inducible gene expressed during Drosophila imaginal disc morphogenesis.","date":"1992","source":"Developmental genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1292892","citation_count":14,"is_preprint":false},{"pmid":"8141771","id":"PMC_8141771","title":"Purification and some properties of an IMP-specific 5'-nucleotidase from yeast.","date":"1994","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/8141771","citation_count":14,"is_preprint":false},{"pmid":"29358669","id":"PMC_29358669","title":"BRAP-2 promotes DNA damage induced germline apoptosis in C. elegans through the regulation of SKN-1 and AKT-1.","date":"2018","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/29358669","citation_count":13,"is_preprint":false},{"pmid":"26460487","id":"PMC_26460487","title":"Bombesin Receptor-Activated Protein (BRAP) Modulates NF-κB Activation in Bronchial Epithelial Cells by Enhancing HDAC Activity.","date":"2015","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26460487","citation_count":13,"is_preprint":false},{"pmid":"37870445","id":"PMC_37870445","title":"IMP: bridging the gap for medicinal plant genomics.","date":"2024","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/37870445","citation_count":13,"is_preprint":false},{"pmid":"35754718","id":"PMC_35754718","title":"Histone H2A ubiquitination resulting from Brap loss of function connects multiple aging hallmarks and accelerates neurodegeneration.","date":"2022","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/35754718","citation_count":13,"is_preprint":false},{"pmid":"26386725","id":"PMC_26386725","title":"EGF enhances low-invasive cancer cell invasion by promoting IMP-3 expression.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26386725","citation_count":13,"is_preprint":false},{"pmid":"36625668","id":"PMC_36625668","title":"Characterization of a Conjugative Hybrid Plasmid Coharboring blaKPC-2 and blaIMP-4 in a Klebsiella quasipneumoniae Clinical Isolate.","date":"2023","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/36625668","citation_count":13,"is_preprint":false},{"pmid":"19594901","id":"PMC_19594901","title":"Synergistic effect of imp/ostA and msbA in hydrophobic drug resistance of Helicobacter pylori.","date":"2009","source":"BMC microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/19594901","citation_count":13,"is_preprint":false},{"pmid":"20207739","id":"PMC_20207739","title":"Developmental arrest of Caenorhabditis elegans BRAP-2 mutant exposed to oxidative stress is dependent on BRC-1.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20207739","citation_count":12,"is_preprint":false},{"pmid":"19111951","id":"PMC_19111951","title":"Embryonic expression of Drosophila IMP in the developing CNS and PNS.","date":"2008","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/19111951","citation_count":12,"is_preprint":false},{"pmid":"22965072","id":"PMC_22965072","title":"The single nucleotide polymorphisms in BRAP decrease the risk of metabolic syndrome in a Chinese young adult population.","date":"2012","source":"Diabetes & vascular disease research","url":"https://pubmed.ncbi.nlm.nih.gov/22965072","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48766,"output_tokens":4545,"usd":0.107236,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12579,"output_tokens":4770,"usd":0.091073,"stage2_stop_reason":"end_turn"},"total_usd":0.198309,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"BRAP/IMP (Impedes Mitogenic signal Propagation) is a Ras-responsive E3 ubiquitin ligase that inhibits KSR (a scaffold/adaptor protein), thereby limiting functional assembly of Raf-MEK complexes and suppressing MAP kinase cascade activation. Upon Ras activation, IMP undergoes auto-polyubiquitination, which releases its inhibition of Raf-MEK complex formation. IMP depletion increases stimulus-dependent MEK activation without altering timing or duration of the response, establishing IMP as a threshold modulator.\",\n      \"method\": \"siRNA depletion, ubiquitination assays, epistasis with Ras, Co-IP, MEK activation assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional assays, epistasis, E3 ligase activity demonstrated, foundational paper replicated by subsequent studies\",\n      \"pmids\": [\"14724641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"BRAP2 directly interacts with the cell cycle inhibitor p21 in vitro and in vivo through the nuclear localization signal (NLS) of p21 and the C-terminal portion of BRAP2. Co-transfection of BRAP2 causes p21 to localize to the cytoplasm. During monocytic differentiation of U937 and HL-60 cells, BRAP2 expression is upregulated concomitantly with cytoplasmic relocalization of p21, indicating BRAP2 acts as a cytoplasmic retention protein for p21.\",\n      \"method\": \"Co-immunoprecipitation in vitro and in vivo, co-transfection localization assays, immunoblotting during monocyte differentiation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, co-transfection functional localization assay, single lab\",\n      \"pmids\": [\"15340083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IMP inhibits signal propagation through Raf to MEK by disrupting KSR1 homo-oligomerization and B-Raf/c-Raf hetero-oligomerization, thereby impairing both MEK recruitment to activated Raf and c-Raf kinase activation. Human KSR1 promotes assembly of multivalent Raf-MEK complexes required for c-Raf kinase activation, and IMP exploits this property to modulate signal amplitude.\",\n      \"method\": \"Co-immunoprecipitation, KSR1 oligomerization assays, kinase activity assays, IMP expression/depletion\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional kinase assays, single lab, extends mechanism from Nature 2004 paper\",\n      \"pmids\": [\"18332145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IMP concentrations are directly regulated by Ras through induction of IMP autoubiquitination (autodegradation), permitting productive Raf-MEK complex assembly. The mechanism of inhibition involves KSR inactivation as the key downstream target.\",\n      \"method\": \"Ubiquitination assays, Ras activation experiments, functional rescue assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays with Ras activation, single lab, corroborates prior findings\",\n      \"pmids\": [\"19091743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BRAP was identified as a galectin-2-binding protein. SNPs in BRAP are associated with myocardial infarction. BRAP knockdown by siRNA in cultured coronary endothelial cells suppressed activation of NF-κB.\",\n      \"method\": \"Binding assay (galectin-2 pulldown), siRNA knockdown, NF-κB activation assay\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — binding assay and siRNA knockdown with NF-κB readout, single lab, limited mechanistic depth\",\n      \"pmids\": [\"19198608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BRAP knockdown in human aortic smooth muscle cells attenuated cell proliferation and reduced secretion of MCP-1 and IL-8 in response to LPS, and prohibited NF-κB nuclear translocation without affecting NF-κB protein levels. Co-immunoprecipitation confirmed interaction between BRAP and IκBβ and IKKβ, two major components of the IKK signalosome.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, NF-κB nuclear translocation assay, cytokine ELISA\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, siRNA with NF-κB localization and cytokine readout, single lab\",\n      \"pmids\": [\"21670849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BRAP/IMP E3 ubiquitin ligase interacts with deubiquitylases USP15 and USP4 through the N-terminal DUSP-UBL domain of USP15 and the coiled-coil region of BRAP. USP15 and USP4 oppose BRAP autoubiquitination, while BRAP promotes USP15 ubiquitylation. USP15 depletion destabilizes BRAP via proteasomal degradation; catalytically active USP15 rescues BRAP levels. USP15 depletion decreases MAPK signaling amplitude in response to EGF and PDGF, in part through decreased CRAF levels.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, ubiquitination assays, siRNA depletion, proteasomal degradation assay, EGF/PDGF signaling assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ubiquitination, degradation rescue), single lab\",\n      \"pmids\": [\"23105109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Brap directly interacts with Lis1, and a Nde1-Lis1-Brap complex regulates MAPK signaling thresholds in the developing mammalian CNS. Nde1-Lis1 deficiency causes spatially dependent alterations of the MAPK scaffold KSR and hyperactivation of MAPK. Epistasis analyses supported synergistic Brap and Lis1 functions in controlling neural progenitor proliferation and differentiation.\",\n      \"method\": \"Genetic epistasis analysis (double mutant), co-immunoprecipitation (Lis1-Brap interaction), MAPK activation assays in vivo, mouse CNS developmental phenotype analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus direct protein interaction, single lab, in vivo CNS context\",\n      \"pmids\": [\"23673330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Brap2 is a novel Nedd8-binding protein that interacts with the SCF ubiquitin ligase complex and is involved in NF-κB nuclear translocation following TNF-α stimulation. A putative neddylation site in Brap2 is associated with NF-κB activity. Brap2 modulates temporal control of NF-κB nuclear translocation mediated by inflammatory response.\",\n      \"method\": \"Co-immunoprecipitation, Nedd8 binding assay, TNF-α stimulation assay, NF-κB localization assay, neddylation site mutant analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding and functional assays, single lab, corroborates prior NF-κB findings\",\n      \"pmids\": [\"23554956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BRAP2 inhibits nuclear import of specific viral proteins (SV40 large T antigen and HCMV ppUL44) in a manner dependent on phosphorylation sites flanking their nuclear localization signals. Substitution of CDK phosphorylation site T124 of T-ag with Ala prevented BRAP2 inhibition, while Asp (phosphomimetic) enhanced it. Direct high-affinity binding of BRAP2(442-592) to T-ag(111-135) was strictly dependent on negative charge at T124 and the NLS, demonstrated by pulldown/AlphaScreen assays. No effect of BRAP2 was observed on HSV-1 pUL30 (which lacks a phosphorylation site near its NLS) or HIV-1 Tat.\",\n      \"method\": \"Ectopic expression in COS-7 and HL-60 cells, nuclear import quantification, site-directed mutagenesis, pulldown/AlphaScreen binding assay\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro binding with mutagenesis, cellular localization assays, multiple orthogonal methods, phosphorylation-dependence established\",\n      \"pmids\": [\"20040518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BRAP2 acts as a cytoplasmic retention factor for testicular nuclear proteins HMG20A and NuMA1, and prevents nuclear envelope accumulation of SYNE2. Co-immunoprecipitation confirmed association of BRAP2 with HMG20A, NuMA1, and SYNE2 in testis. Ectopic expression of BRAP2 inhibited nuclear localization of HMG20A and NuMA1, and prevented nuclear envelope accumulation of SYNE2 in cultured cells.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation from testis tissue, quantitative confocal microscopy of ectopic BRAP2 expression\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP from tissue plus quantitative imaging, single lab\",\n      \"pmids\": [\"23707952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss of Brap in mouse neural progenitor cells results in premature G1/S phase transition due to elevated Skp2 (SCF ubiquitin ligase component), which increases p27Kip1 destruction. Brap-mediated polyubiquitination of Skp2 was identified as a key regulatory step. Loss of Brap led to elevated Skp2, shortened G1 phase, premature S phase entry, hindered S phase progression, increased G2 arrest, impeded neuronal differentiation, and microcephaly.\",\n      \"method\": \"Conditional Brap mouse knockout, cell cycle analysis, ubiquitination assays for Skp2, p27 protein levels, neuronal differentiation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined cellular/molecular phenotype, polyubiquitination assay identifying Skp2 as substrate, multiple readouts in vivo and in vitro\",\n      \"pmids\": [\"28768199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In C. elegans, BRAP-2 promotes DNA damage-induced germline apoptosis by attenuating pro-survival signals of AKT-1 and PMK-1/SKN-1. Loss of brap-2 reduces germline apoptosis after DNA damage and increases skn-1 mRNA. The interaction between BRAP-2 and the AKT-1 phosphatase (C. elegans homolog of PHLPP1/2) is conserved. SKN-1 RNAi or loss of pmk-1 in brap-2 mutants restored apoptosis to wild-type levels.\",\n      \"method\": \"C. elegans brap-2 deletion mutant, germline apoptosis assays, genetic epistasis with brc-1/akt-1/pmk-1/skn-1, mRNA quantification, co-immunoprecipitation of BRAP-2 with AKT-1 phosphatase\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple alleles plus protein interaction, C. elegans model, single lab\",\n      \"pmids\": [\"29358669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In C. elegans, developmental arrest of brap-2 deletion mutants under oxidative stress is dependent on brc-1 (BRCA1 ortholog) and requires enhanced expression of the cell cycle inhibitor cki-1 through brc-1. Loss of brap-2 sensitizes animals to paraquat-induced larval arrest at the L1 stage.\",\n      \"method\": \"C. elegans genetic analysis, paraquat exposure, double mutant epistasis with brc-1, cki-1 expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in C. elegans model with molecular readout (cki-1 expression), single lab\",\n      \"pmids\": [\"20207739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BRAP overexpression in human bronchial epithelial cells inhibited both basal and inducible NF-κB transcriptional activity, while BRAP knockdown had the opposite effect. BRAP regulates NF-κB activity by enhancing histone deacetylase (HDAC) activity, mediated through its putative C-terminal domain.\",\n      \"method\": \"Gene transfer overexpression, siRNA knockdown, NF-κB reporter assay, HDAC activity assay, domain truncation analysis\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, NF-κB reporter and HDAC assay but limited mechanistic dissection; C-terminal domain inference is partial\",\n      \"pmids\": [\"26460487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Deletion of Brap in mouse brain causes persistent DNA double-strand breaks and elevation of histone H2A mono- and poly-ubiquitination (H2Aub), leading to cellular senescence, proteasome-mediated histone H2A proteolysis, neuroinflammation, impaired proteostasis, accelerated neurodegeneration, and shortened lifespan. H2Aub elevation also occurs in human Alzheimer's disease brain tissue, suggesting H2Aub chromatin aberrations act as a nexus linking multiple aging hallmarks.\",\n      \"method\": \"Conditional Brap mouse brain knockout, DNA damage assays, H2A ubiquitination assays, proteasome activity assays, lifespan analysis, human AD brain tissue immunostaining\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple molecular readouts including ubiquitination and DNA damage, single lab with in vivo and human tissue validation\",\n      \"pmids\": [\"35754718\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BRAP (also known as BRAP2, RNF52, IMP) is a Ras-responsive RING-domain E3 ubiquitin ligase that acts as a threshold modulator of the Ras-Raf-MEK-ERK MAP kinase cascade by targeting KSR1 to inhibit its homo-oligomerization and its scaffolding of Raf-MEK complexes; upon Ras activation, BRAP undergoes auto-polyubiquitination and is degraded, relieving this inhibition. Beyond MAPK regulation, BRAP functions as a cytoplasmic retention factor for nuclear proteins (including p21/CDKN1A) by binding their NLS in a phosphorylation-dependent manner, ubiquitinates Skp2 to control G1/S phase timing in neural progenitors, interacts with the IKK signalosome components IκBβ and IKKβ as well as Nedd8-SCF complexes to regulate NF-κB nuclear translocation, and promotes DNA damage-induced apoptosis by attenuating AKT-1 and PMK-1/SKN-1 pro-survival signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BRAP (also IMP, BRAP2, RNF52) is a cytoplasmic RING-domain E3 ubiquitin ligase that sets activation thresholds for mitogenic and stress-signaling cascades [#0]. Its founding function is as a Ras-responsive brake on the Raf-MEK-ERK pathway: BRAP inhibits the scaffold KSR1 by disrupting KSR1 homo-oligomerization and B-Raf/c-Raf hetero-oligomerization, thereby limiting MEK recruitment and c-Raf activation and acting as a threshold modulator rather than altering response timing [#0, #2]. Ras activation drives BRAP auto-polyubiquitination and autodegradation, relieving this inhibition and permitting productive Raf-MEK assembly [#0, #3]; BRAP stability is in turn opposed by the deubiquitylases USP15 and USP4, which counter its autoubiquitination [#6]. In the developing CNS, BRAP partners with the Nde1-Lis1 complex to tune MAPK thresholds during neural progenitor proliferation and differentiation [#7], and BRAP-mediated polyubiquitination of Skp2 restrains G1/S transition, with its loss causing premature S-phase entry and microcephaly [#11]. Independently of catalysis-driven signaling, BRAP serves as a cytoplasmic retention factor that binds nuclear-localization signals in a phosphorylation-dependent manner to sequester nuclear proteins including p21/CDKN1A, HMG20A, NuMA1, and certain viral cargoes such as SV40 large T antigen [#1, #9, #10]. BRAP also restrains NF-\\u03baB nuclear translocation through interaction with IKK signalosome components I\\u03baB\\u03b2 and IKK\\u03b2 and with Nedd8/SCF complexes [#5, #8], and its loss in mouse brain produces persistent DNA double-strand breaks and elevated histone H2A ubiquitination linked to senescence and neurodegeneration [#15]. BRAP variants are genetically associated with myocardial infarction [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established BRAP/IMP as a Ras-responsive E3 ligase that sets the activation threshold of the MAP kinase cascade by inhibiting the KSR scaffold, answering how mitogenic signal amplitude is gated.\",\n      \"evidence\": \"siRNA depletion, ubiquitination assays, Ras epistasis and MEK activation readouts in mammalian cells\",\n      \"pmids\": [\"14724641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular target of KSR inhibition at the oligomerization level\", \"Direct ubiquitination substrate within the Raf-MEK module not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed BRAP2 binds the p21 NLS and retains p21 in the cytoplasm, revealing a ubiquitination-independent role as a nuclear-protein sequestration factor.\",\n      \"evidence\": \"Reciprocal Co-IP and co-transfection localization assays during monocytic differentiation\",\n      \"pmids\": [\"15340083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Physiological signal triggering p21 release not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the mechanism of KSR inhibition, showing IMP disrupts KSR1 homo-oligomerization and Raf hetero-oligomerization to impair MEK recruitment and c-Raf activation.\",\n      \"evidence\": \"Co-IP, oligomerization and kinase activity assays with IMP expression/depletion\",\n      \"pmids\": [\"18332145\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Structural basis of the IMP-KSR interaction not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that Ras controls IMP levels through induction of autoubiquitination/autodegradation, establishing the feedback that licenses signal propagation.\",\n      \"evidence\": \"Ubiquitination assays, Ras activation experiments, functional rescue\",\n      \"pmids\": [\"19091743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of any cofactor enabling auto-degradation not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended cytoplasmic retention to phosphorylation-gated NLS recognition, showing BRAP2 blocks nuclear import of cargo whose NLS-flanking residues are phosphorylated.\",\n      \"evidence\": \"Nuclear import quantification, site-directed mutagenesis of CDK site T124, pulldown/AlphaScreen binding using SV40 T-ag and HCMV ppUL44\",\n      \"pmids\": [\"20040518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of phospho-NLS recognition across endogenous substrates not mapped\", \"Kinase responsible for substrate priming not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked BRAP to cardiovascular disease and NF-\\u03baB control, showing BRAP is a galectin-2 binding protein whose knockdown suppresses NF-\\u03baB in endothelial cells.\",\n      \"evidence\": \"Galectin-2 pulldown, siRNA knockdown, NF-\\u03baB activation assay; BRAP SNP-MI association\",\n      \"pmids\": [\"19198608\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting galectin-2 binding to NF-\\u03baB not established\", \"SNP association does not establish causal mechanism\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed BRAP in an oxidative-stress checkpoint, showing brap-2 loss sensitizes C. elegans to paraquat via brc-1-dependent cki-1 induction.\",\n      \"evidence\": \"C. elegans genetic epistasis with brc-1, paraquat exposure, cki-1 expression analysis\",\n      \"pmids\": [\"20207739\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between BRAP-2 and brc-1/cki-1 not defined\", \"Mammalian conservation untested here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapped BRAP onto the IKK signalosome, showing it interacts with I\\u03baB\\u03b2 and IKK\\u03b2 and is required for NF-\\u03baB nuclear translocation and inflammatory cytokine output.\",\n      \"evidence\": \"siRNA knockdown, reciprocal Co-IP, NF-\\u03baB translocation assay, cytokine ELISA in aortic smooth muscle cells\",\n      \"pmids\": [\"21670849\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether BRAP ubiquitinates IKK components not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified USP15/USP4 as deubiquitylases that stabilize BRAP, defining a ubiquitin-cycle regulatory loop affecting MAPK amplitude.\",\n      \"evidence\": \"Co-IP, domain mapping, ubiquitination and proteasomal degradation rescue, EGF/PDGF signaling assays\",\n      \"pmids\": [\"23105109\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"In vivo relevance of the USP15-BRAP axis not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected BRAP to neurodevelopmental MAPK threshold control via a Nde1-Lis1-Brap complex acting on KSR.\",\n      \"evidence\": \"Genetic epistasis (double mutant), Co-IP of Lis1-Brap, in vivo MAPK activation assays in mouse CNS\",\n      \"pmids\": [\"23673330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical role of Lis1 in BRAP catalysis not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Broadened the cytoplasmic-retention substrate set, showing BRAP2 sequesters HMG20A and NuMA1 and limits SYNE2 nuclear-envelope accumulation in testis.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP from testis tissue, quantitative confocal imaging of ectopic BRAP2\",\n      \"pmids\": [\"23707952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of retention in spermatogenesis not defined\", \"Phospho-dependence of these substrates not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Implicated BRAP2 in neddylation-coupled NF-\\u03baB timing, showing it binds Nedd8 and the SCF complex to modulate TNF-\\u03b1-induced nuclear translocation.\",\n      \"evidence\": \"Co-IP, Nedd8 binding assay, TNF-\\u03b1 stimulation, NF-\\u03baB localization, neddylation-site mutant analysis\",\n      \"pmids\": [\"23554956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether BRAP2 is itself neddylated functionally unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified Skp2 as a BRAP ubiquitination substrate controlling G1/S timing, explaining how Brap loss causes premature S-phase entry and microcephaly.\",\n      \"evidence\": \"Conditional mouse knockout, cell cycle analysis, Skp2 ubiquitination assays, p27 levels, differentiation assays\",\n      \"pmids\": [\"28768199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ubiquitin linkage type on Skp2 not specified\", \"Relationship to BRAP's MAPK role in the same cells not integrated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established a pro-apoptotic role for BRAP in DNA-damage response, showing BRAP-2 attenuates AKT-1 and PMK-1/SKN-1 survival signaling to permit germline apoptosis.\",\n      \"evidence\": \"C. elegans deletion mutant, germline apoptosis assays, epistasis with akt-1/pmk-1/skn-1, Co-IP of BRAP-2 with AKT-1 phosphatase\",\n      \"pmids\": [\"29358669\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian conservation of the apoptotic axis not demonstrated\", \"Mechanism of AKT-1 phosphatase regulation by BRAP-2 not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked Brap loss to chromatin and aging pathology, showing brain Brap deletion causes persistent DNA breaks, elevated H2A ubiquitination, senescence and neurodegeneration, with H2Aub also raised in human AD tissue.\",\n      \"evidence\": \"Conditional mouse brain knockout, DNA damage and H2Aub assays, proteasome and lifespan analysis, human AD brain immunostaining\",\n      \"pmids\": [\"35754718\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether elevated H2Aub is a direct or indirect consequence of BRAP loss not resolved\", \"Causal versus correlative role in human AD undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How BRAP's distinct activities — KSR/MAPK gating, Skp2 ubiquitination, cytoplasmic NLS retention, NF-\\u03baB control and chromatin/H2Aub regulation — are coordinated within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating ligase activity with non-catalytic retention function\", \"Structural basis of substrate selection unknown\", \"Whether disease associations reflect MAPK, NF-\\u03baB, or chromatin roles unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 3, 11]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [1, 9, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 9, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 9, 10]}\n    ],\n    \"complexes\": [\"Nde1-Lis1-Brap complex\", \"IKK signalosome\", \"SCF/Nedd8 complex\"],\n    \"partners\": [\"KSR1\", \"USP15\", \"USP4\", \"Lis1\", \"IKBKB\", \"Skp2\", \"NUMA1\", \"HMG20A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}