{"gene":"PA2G4","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2000,"finding":"EBP1 (PA2G4) interacts with the juxtamembrane domain of ErbB-3; the first 15 amino acids of ErbB-3's juxtamembrane domain are essential for EBP1 binding in vitro. Treatment of cells with the ErbB-3 ligand heregulin causes dissociation of EBP1 from ErbB-3 and translocation of EBP1 from the cytoplasm to the nucleus.","method":"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, cellular fractionation/immunofluorescence","journal":"British journal of cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal in vitro and in vivo binding assays, yeast two-hybrid identification, replicated in multiple studies","pmids":["10682683"],"is_preprint":false},{"year":2001,"finding":"EBP1 binds the retinoblastoma protein (Rb) both in vivo and in vitro; the 72 C-terminal amino acids of EBP1 are sufficient for Rb binding. Dephosphorylation of EBP1 enhances the interaction with Rb. EBP1 overexpression inhibits the E2F1-regulated cyclin E promoter, and EBP1 binds E2F1 indirectly via Rb.","method":"Co-immunoprecipitation, GST pulldown, promoter reporter assay","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal pulldown and co-IP, domain mapping, functional reporter assay, replicated across subsequent studies","pmids":["11268000"],"is_preprint":false},{"year":2002,"finding":"EBP1 binds androgen receptor (AR) in vitro and in vivo via its C-terminal 79 amino acids; this binding is increased by androgen treatment. The N-terminal domain of AR is responsible for binding EBP1. EBP1 overexpression inhibits ligand-mediated transcriptional activation of AR-regulated promoters, and an LXXLL motif mutation abolishes this repression.","method":"GST pulldown, co-immunoprecipitation, transient transfection reporter assay, mutagenesis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro and in vivo binding, domain mutagenesis, functional reporter assay, replicated in multiple independent studies","pmids":["12165860"],"is_preprint":false},{"year":2003,"finding":"EBP1 represses E2F1-mediated transcription through its C-terminal domain, which recruits histone deacetylase (HDAC) activity. EBP1 binds HDAC2 (but not HDAC1) in vitro. HDAC inhibitors significantly reduce EBP1-mediated repression. An EBP1 mutant lacking the HDAC binding domain fails to inhibit transcription.","method":"Reporter assay, GST pulldown, HDAC activity assay, mutagenesis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro binding, enzymatic assay, mutagenesis, functional reporter assay, replicated across related studies","pmids":["12682367"],"is_preprint":false},{"year":2004,"finding":"EBP1 is localized to the cytoplasm and nucleolus; its nucleolar localization requires sequences at both the amino- and carboxy-terminus. EBP1 is part of pre-ribosomal ribonucleoprotein complexes and associates with different rRNA species. EBP1 overexpression inhibits proliferation of human fibroblasts, linked to its nucleolar localization.","method":"Subcellular fractionation, immunofluorescence, mass spectrometry, deletion mutagenesis, proliferation assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including MS, localization studies with functional consequence, domain mapping","pmids":["15064750"],"is_preprint":false},{"year":2004,"finding":"EBP1 (contained in nuclear lysates) associates with E2F1 consensus sequences in the E2F1 promoter in complex with E2F1, Rb, and HDAC2. Heregulin regulates the association of EBP1 with E2F promoter sequences and enhances EBP1-mediated transcriptional repression.","method":"Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP in vivo, EMSA in vitro, functional reporter assay, multiple orthogonal methods in one study","pmids":["15073182"],"is_preprint":false},{"year":2005,"finding":"EBP1 interacts with the corepressor Sin3A both in vitro and in vivo; the C-terminal domain of EBP1 is necessary and sufficient for Sin3A binding, mapping to the PAH4/HDAC-interacting domain of Sin3A. Recombinant Sin3A binds EBP1 directly but recombinant HDAC2 does not bind EBP1 directly. EBP1 and Sin3A co-occupy PSA and E2F1 promoters; Sin3A enhances EBP1-mediated repression of AR- and E2F1-regulated genes.","method":"GST pulldown, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), reporter assay, recombinant protein binding","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstituted direct binding with recombinant proteins, reciprocal Co-IP, ChIP, functional reporter assay, multiple orthogonal methods","pmids":["16254079"],"is_preprint":false},{"year":2005,"finding":"EBP1 overexpression down-regulates AR and six AR-regulated genes in LNCaP prostate cancer cells. EBP1 is recruited to the PSA promoter in response to the androgen antagonist bicalutamide (demonstrated by ChIP). EBP1 overexpression reduces LNCaP tumor incidence and growth in SCID mice.","method":"Microarray, chromatin immunoprecipitation (ChIP), reporter assay, xenograft mouse model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP, microarray, in vivo xenograft, multiple orthogonal methods in single study","pmids":["15994225"],"is_preprint":false},{"year":2006,"finding":"EBP1 contains a dsRNA-binding domain (dsRBD) that mediates interaction with dsRNA; deletion of the dsRBD impairs nucleolar localization and RNP complex formation. EBP1 is associated with mature ribosomes in the cytoplasm and inhibits phosphorylation of eIF2alpha at serine 51. EBP1 interacts with and is phosphorylated by PKR kinase.","method":"Mutagenesis, RNA binding assay, co-immunoprecipitation, in vitro kinase assay, ribosome fractionation, western blot","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis, in vitro kinase assay, ribosome fractionation, multiple orthogonal methods in one study","pmids":["16631606"],"is_preprint":false},{"year":2006,"finding":"Nuclear Akt interacts with EBP1 to prevent DNA fragmentation by caspase-activated DNase (CAD). EBP1 phosphorylation by PKC at serine 360 (S360) is required for EBP1 to bind nuclear Akt; S360A mutant barely binds Akt or inhibits DNA fragmentation, while S360D mutant strongly binds Akt and suppresses apoptosis. Nuclear (not cytoplasmic) Akt enhances EBP1 antiapoptotic action independent of Akt kinase activity.","method":"Cell-free apoptotic assay, co-immunoprecipitation, site-directed mutagenesis, knockdown, overexpression","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-free biochemical reconstitution, mutagenesis, knockdown with phenotypic rescue, multiple orthogonal methods","pmids":["16642037"],"is_preprint":false},{"year":2006,"finding":"EBP1 exists as two isoforms, p48 and p42. p48 localizes in both cytoplasm and nucleus and suppresses apoptosis; p42 predominantly resides in the cytoplasm and promotes cell differentiation. EGF strongly stimulates p42 (but not p48) to bind ErbB3, dependent on PKC-mediated phosphorylation. p42 and p48 have opposing effects on cell proliferation.","method":"Subcellular fractionation, co-immunoprecipitation, overexpression, kinase inhibitor treatment, neurite outgrowth assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — isoform-specific localization and binding, multiple functional assays, replicated in subsequent studies","pmids":["16832058"],"is_preprint":false},{"year":2006,"finding":"EBP1 binds bcl-2 mRNA AU-rich elements (AREs) in vitro; it is present in bcl-2 mRNA-containing ribonucleoprotein complexes in HL-60 cells and co-precipitates with nucleolin in cytoplasmic extracts. EBP1 decreases the rate of decay of bcl-2 ARE-containing transcripts in cell extracts.","method":"RNA affinity chromatography, MALDI-MS identification, EMSA, RNA co-immunoprecipitation, co-IP, RNA decay assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RNA affinity, EMSA, RIP, mRNA decay assay) in a single study","pmids":["16396631"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of murine EBP1 (p48 isoform) reveals a core domain homologous to methionine aminopeptidases (pita bread fold) coupled to a C-terminal extension containing protein- and RNA-binding motifs. The primary RNA-binding site is a Lys-rich motif in the C-terminus mediating interaction with the FMDV IRES. EBP1 has a specific functional requirement in FMDV IRES-directed translation independent of direct interaction with PTB.","method":"X-ray crystallography, RNA binding assay, IRES reporter translation assay, mutagenesis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation, mutagenesis, translation assay","pmids":["17690690"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of human EBP1 at 1.6 Å resolution reveals the conserved pita bread fold of methionine aminopeptidases without catalytic activity, providing a structural platform for multiple protein and RNA interactions.","method":"X-ray crystallography","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure, independently replicated by another structural study","pmids":["17765895"],"is_preprint":false},{"year":2007,"finding":"EBP1 specifically interacts with the PB1 subunit of influenza virus RNA polymerase in vitro and in vivo; the EBP1 contact site on PB1 maps to its transcription primer binding site. EBP1 inhibits in vitro RNA synthesis by the influenza virus RNA polymerase (3P complex) but does not inhibit capped RNA endonuclease or RNA-cap binding activities. EBP1 overexpression interferes with virus production.","method":"Yeast two-hybrid, in vitro binding, in vitro RNA polymerase assay, overexpression viral replication assay","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzymatic assay, in vitro and in vivo binding, functional overexpression assay, multiple orthogonal methods","pmids":["17295834"],"is_preprint":false},{"year":2007,"finding":"EBP1 forms a complex with nucleophosmin/B23. p42 isoform associates with B23 upon EGF stimulation in a manner dependent on Ser360 phosphorylation, while p48 constitutively binds B23 in the nucleolus requiring B23 Lys263 sumoylation. Knockdown of B23 or EBP1 substantially decreases ribosome biogenesis and cell survival.","method":"Co-immunoprecipitation, mutagenesis, siRNA knockdown, ribosome biogenesis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP with mutagenesis, functional knockdown with specific cellular readout, multiple orthogonal methods","pmids":["17951246"],"is_preprint":false},{"year":2007,"finding":"PKC-delta phosphorylates EBP1 and protects it from apoptotic degradation by caspase-3. EBP1 is cleaved by active caspase-3 at D53 and D196 sites; cleavage at D196 is prerequisite for subsequent D53 cleavage. PKC phosphorylation at S360 suppresses caspase-3 cleavage. D196A mutant protects cells from apoptosis.","method":"Cell-free apoptotic assay, site-directed mutagenesis, PKC-delta knockout cells, in vitro caspase cleavage assay","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro cleavage assay, mutagenesis, KO cells, multiple orthogonal methods","pmids":["17316401"],"is_preprint":false},{"year":2007,"finding":"Serine 363 of EBP1 is phosphorylated in vivo; EBP1 phosphorylated at S363 localizes exclusively to the nucleus. S363A mutation significantly decreases EBP1-mediated transcriptional repression and abolishes its ability to inhibit cell growth. S363A EBP1 fails to bind HDAC2 and mSin3a, though it still associates with the E2F1 promoter.","method":"Phospho-specific antibody, mutagenesis, reporter assay, co-immunoprecipitation, chromatin immunoprecipitation","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis, co-IP, functional assays, single lab","pmids":["17786317"],"is_preprint":false},{"year":2008,"finding":"hBRE1 (human BRE1) is an E3 ubiquitin ligase for EBP1; hBRE1 promotes EBP1 polyubiquitination and degradation. EBP1 polyubiquitination in cancer cells is regulated by its phosphorylation. Depletion of hBRE1 blocks EBP1 polyubiquitination and elevates EBP1 protein levels. hBRE1 binds EBP1 and suppresses its repressive effect on E2F-1.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, western blot","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo ubiquitination assay, co-IP, depletion experiment with mechanistic readout, multiple methods in one study","pmids":["19037095"],"is_preprint":false},{"year":2008,"finding":"PAK1 phosphorylates EBP1 in vitro and in vivo at threonine 261. EGF/heregulin treatment and constitutively active PAK1 enhance threonine phosphorylation of EBP1. EBP1 binds endogenous PAK1, enhanced by heregulin. T261E mutation (mimicking phosphorylation) abolishes EBP1-mediated transcriptional repression, growth inhibition, and tamoxifen sensitivity.","method":"In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, reporter assay, cell growth assay","journal":"British journal of cancer","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay, mutagenesis, co-IP, functional assays; single lab but multiple orthogonal methods","pmids":["18283314"],"is_preprint":false},{"year":2009,"finding":"EBP1 p42 isoform can be sumoylated on K93 and K298 residues; sumoylation mediates its nuclear translocation and is required for anti-proliferative activity. TLS/FUS has SUMO1 E3 ligase activity for EBP1 p42 and directly binds EBP1; EBP1 sumoylation is triggered by genotoxic stress. Overexpression of TLS enhances EBP1 sumoylation; depletion of TLS abolishes it. Unsumoylatable EBP1 mutants fail to suppress E2F-1-regulated transcription.","method":"Sumoylation assay, co-immunoprecipitation, mutagenesis, siRNA knockdown, reporter assay, subcellular localization","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — enzymatic sumoylation assay, mutagenesis, siRNA, functional reporter assay, multiple orthogonal methods","pmids":["19946338"],"is_preprint":false},{"year":2010,"finding":"EBP1 p48 isoform binds the p53 E3 ligase HDM2, enhancing the HDM2-p53 association and thereby promoting p53 polyubiquitination and degradation, reducing steady-state p53 levels and activity in glioblastoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, western blot, xenograft model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assay with functional readout, single lab, multiple methods","pmids":["21098709"],"is_preprint":false},{"year":2014,"finding":"EBP1 p42 interacts with the cSH2 domain of the p85 regulatory subunit of PI3K, inhibiting its lipid kinase activity. p42 promotes p85 degradation by recruiting the HSP70/CHIP E3 ligase complex, coupling p85 to ubiquitin-proteasomal degradation.","method":"Co-immunoprecipitation, PI3K lipid kinase assay, ubiquitination assay, domain mapping, western blot","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — enzymatic assay, domain-specific interaction, ubiquitination assay, multiple orthogonal methods in one study","pmids":["24651434"],"is_preprint":false},{"year":2014,"finding":"CDK2 specifically interacts with p48 EBP1 (but not p42) through p48's N-terminal domain and phosphorylates p48 at serine 34. This CDK2-mediated phosphorylation is required for the tumorigenic function of p48; the phospho-ablated S34A mutant antagonizes cell proliferation and transformation.","method":"Co-immunoprecipitation, in vitro kinase assay, mutagenesis, cell proliferation assay, xenograft model","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, kinase assay, mutagenesis with functional readout, single lab","pmids":["25154617"],"is_preprint":false},{"year":2015,"finding":"GTP-bound TIF-IA (transcription initiation factor I) binds EBP1, and together they enhance transcription of PCNA. GTP binding by TIF-IA and EBP1 phosphorylation by protein kinase C delta are both required for optimal PCNA expression. GTP depletion inhibits ribosomal RNA synthesis in T cells by inhibiting TIF-IA.","method":"Protein binding assay, kinase inhibitor treatment, GTP depletion, reporter/quantitative expression assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and functional assay in one study, single lab, mechanistic interpretation based on pharmacological inhibition","pmids":["25691158"],"is_preprint":false},{"year":2016,"finding":"EBP1 binds directly to several polyphosphoinositides (PPIns) via two distinct lysine-rich PPIn-binding sites at the N- and C-termini. The C-terminal PPIn-binding motif contributes most to nucleolar localization. A K372N point mutation in the C-terminal motif (found in endometrial tumors) is sufficient to alter nucleolar targeting. EBP1 associates with PtdIns(3,4,5)P3 in the nucleolus via electrostatic and hydrophobic interactions.","method":"Lipid pulldown, mutagenesis, NMR spectroscopy, immunofluorescence/localization","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — NMR, lipid pulldown, mutagenesis, localization assay; multiple orthogonal methods in one study","pmids":["27118868"],"is_preprint":false},{"year":2017,"finding":"EBP1 p48 binds the WD domain of FBXW7 as an oncogenic substrate, sequestering FBXW7α to the cytosol and attenuating its tumor suppressor function. EBP1 p42 binds the F-box domain of FBXW7 and acts as an adapter that stabilizes FBXW7-substrate interactions, promoting FBXW7-mediated degradation of oncogenic targets.","method":"Co-immunoprecipitation, domain mapping, ubiquitination assay, subcellular fractionation, functional tumor assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping, functional assays, single lab","pmids":["28209614"],"is_preprint":false},{"year":2019,"finding":"PA2G4 directly binds MYCN protein, blocking MYCN proteolysis and enhancing colony formation in a MYCN-dependent manner. MYCN occupies the PA2G4 gene promoter, stimulating transcription (positive feedback). The MYCN-PA2G4 interaction site was mapped to a 14 amino acid MYCN sequence and a surface crevice of PA2G4 by molecular modeling, surface plasmon resonance, and mutagenesis. Competitive chemical inhibition of the MYCN-PA2G4 interface reduces neuroblastoma tumorigenesis in vivo.","method":"Chromatin immunoprecipitation, surface plasmon resonance, mutagenesis, molecular modeling, co-immunoprecipitation, in vivo tumor model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — surface plasmon resonance (quantitative binding), ChIP, mutagenesis, in vivo model; multiple orthogonal methods","pmids":["31501192"],"is_preprint":false},{"year":2019,"finding":"EBP1 p48 interacts with TIF-90 (a splice variant of TIF-IA/RNA polymerase I transcription factor), regulating ribosomal RNA synthesis. EBP1 expression is essential for Akt-protected TIF-90 stability by preventing TIF-90 ubiquitination by MDM2 and proteasomal degradation.","method":"Co-immunoprecipitation, ubiquitination assay, ribosomal RNA synthesis assay, siRNA knockdown, western blot","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, functional rRNA synthesis assay, single lab","pmids":["30793766"],"is_preprint":false},{"year":2019,"finding":"EBP1 represses DNMT1 transcription by binding to its promoter region, interrupting DNMT1-mediated methylation at the Survivin promoter. Loss of EBP1 in embryonic mice caused global DNA methylation increase with elevated Suv39H1/DNMT1 levels, massive apoptosis, and developmental defects including brain malformation.","method":"Chromatin immunoprecipitation, promoter reporter assay, Ebp1 knockout mouse, methylation analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, KO mouse with mechanistic readout, methylation analysis; multiple orthogonal methods","pmids":["31748268"],"is_preprint":false},{"year":2019,"finding":"EBP1 binds HNF4α via its LXXLL motif in a manner that competes with HNF4α coactivators for the same binding pocket on HNF4α's ligand-binding domain, thereby suppressing expression of HNF4α target genes implicated in insulin secretion. Crystal structure of the HNF4α ligand-binding domain in complex with an EBP1 LXXLL peptide at 3.15 Å resolution.","method":"Yeast two-hybrid, GST pulldown, mammalian two-hybrid, X-ray crystallography, reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation, multiple binding assays, single lab","pmids":["31362984"],"is_preprint":false},{"year":2020,"finding":"Cryo-EM structure at near-atomic resolution shows EBP1 as a high-occupancy 60S peptide tunnel exit (TE) factor during protein synthesis in the developing neocortex. Ribosome profiling shows EBP1-60S binding is highest during start codon initiation and N-terminal peptide elongation, regulating ribosome occupancy. Membrane-targeting signal sequences emerging from the 60S tunnel displace EBP1. EBP1 especially impacts synthesis of membrane-targeted cell adhesion molecules.","method":"Cryo-electron microscopy, ribosome profiling, pSILAC/BONCAT mass spectrometry, loss-of-function","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with ribosome profiling and quantitative proteomics; multiple orthogonal methods, near-atomic resolution structural data","pmids":["33357414"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structure of human EBP1 (p48) bound to the human 80S ribosome at 3.3 Å resolution reveals EBP1 binding near the peptide exit tunnel, centered on interactions with ribosomal proteins eL19 and uL23 and 28S rRNA. EBP1-ribosome association is enhanced upon puromycin-mediated translational inhibition. EBP1 can rotate around its insert domain, allowing multiple conformations while maintaining ribosome interaction.","method":"Cryo-electron microscopy, ribosome binding assay, chemical translational inhibition","journal":"RNA","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure with identification of specific ribosomal contacts, independently consistent with Kraushar et al. 2020","pmids":["33479117"],"is_preprint":false},{"year":2021,"finding":"EBP1 directly interacts with Suv39H1 and recruits the E3 ligase MDM2, promoting ubiquitin-proteasome system-dependent degradation of Suv39H1, thereby governing heterochromatin assembly during neural development.","method":"Co-immunoprecipitation, ubiquitination assay, western blot, neural differentiation model","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assay with functional context, single lab","pmids":["33691908"],"is_preprint":false},{"year":2022,"finding":"PA2G4/EBP1 is ubiquitinated at lysine 376 by PRKN/PARKIN on damaged mitochondria following cerebral ischemia-reperfusion injury. Ubiquitinated PA2G4 interacts with receptor protein SQSTM1/p62, promoting mitophagy induction. Neuron-specific knockout of Pa2g4 impairs mitophagy and increases infarct volume; AAV-mediated re-expression of PA2G4 rescues this.","method":"Co-immunoprecipitation, ubiquitination assay with site mutagenesis, conditional KO mouse, AAV rescue, mitophagy assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific ubiquitination mapping, conditional KO with AAV rescue, multiple orthogonal methods, mechanistic specificity","pmids":["37712850"],"is_preprint":false},{"year":2001,"finding":"PKC phosphorylates EBP1 on serine/threonine residues in vitro and in vivo; basal EBP1 phosphorylation in breast cancer cells is PKC-dependent. PKC activity is required for EBP1 to associate with ErbB3 in serum-starved cells; PKC inhibition abrogates this association. Heregulin-induced EBP1 phosphorylation occurs predominantly in a PKC-independent manner.","method":"In vitro kinase assay, PKC inhibitor treatment, co-immunoprecipitation, metabolic phosphate labeling","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay, pharmacological inhibition, co-IP; single lab, multiple orthogonal methods","pmids":["11325528"],"is_preprint":false},{"year":2013,"finding":"EBP1 is a novel component of the ZFP809-TRIM28 retroviral silencing complex; EBP1 depletion reduces PBS-mediated retroviral silencing in embryonic cells.","method":"Co-immunoprecipitation, shRNA knockdown, retroviral reporter assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and functional knockdown with specific reporter assay, single lab","pmids":["24227866"],"is_preprint":false},{"year":2016,"finding":"Pa2G4 (EBP1) binds Six1 transcription factor and interferes with the Six1-Eya1 complex. Knockdown of Pa2G4 in Xenopus embryos downregulates neural border zone, neural crest, and cranial placode genes. Gain-of-function expands neural crest and alters cranial placode domains.","method":"Co-immunoprecipitation in HEK293 cells, morpholino knockdown, mRNA overexpression, in situ hybridization in Xenopus embryos","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, in vivo loss/gain-of-function with defined molecular readout, single lab","pmids":["27940157"],"is_preprint":false},{"year":2022,"finding":"PA2G4 stabilizes FYN mRNA by binding to m6A-modified FYN mRNA in a YTHDF2-dependent manner, increasing FYN protein expression. EBP1 co-immunoprecipitates with YTHDF2; RIP assays demonstrate PA2G4 binding to FYN mRNA. YTHDF2's m6A catalytic activity is indispensable for PA2G4-mediated FYN regulation.","method":"Co-immunoprecipitation, RIP assay, MeRIP assay, dual-luciferase reporter, mRNA half-life assay","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple RNA binding assays, co-IP, mRNA stability assay; single lab","pmids":["35526051"],"is_preprint":false},{"year":2025,"finding":"PA2G4 interacts with NF110; CRAPIR (a piRNA) competes with NF110 for binding to PA2G4, preventing PA2G4-mediated interaction with the NF110-NF45 heterodimer and reducing NF110 degradation, thereby promoting cardiomyocyte proliferation.","method":"Co-immunoprecipitation, RNA-protein binding assay, genetic ablation, overexpression","journal":"Nature cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, competitive binding mechanism demonstrated, loss-of-function phenotype; single study","pmids":["39814981"],"is_preprint":false},{"year":2017,"finding":"p48 EBP1 physically interacts with beta-tubulin (but not alpha-tubulin) and accumulates in distal microtubule growth cone regions. Introduction of p48 EBP1 in injured hippocampal slices promotes axon regeneration.","method":"Co-immunoprecipitation, immunofluorescence, ex vivo axon regeneration assay","journal":"BMB reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP, localization data, limited functional assay in one study","pmids":["27916024"],"is_preprint":false},{"year":2013,"finding":"PAK1 inhibitor IPA-3 sensitizes breast cancer cells to tamoxifen only when EBP1 is ectopically expressed; phosphorylation of EBP1 at T261 by PAK1 induces tamoxifen resistance. An EBP1 T261A mutant (non-phosphorylatable) ameliorates PAK1-induced tamoxifen resistance, while T261E (phosphomimetic) increases ErbB2 protein levels.","method":"Pharmacological inhibition, mutagenesis, cell viability assay, western blot","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis, pharmacological validation, functional assay; consistent with prior in vitro kinase data","pmids":["23361053"],"is_preprint":false},{"year":2019,"finding":"EBP1 binds to the DNMT1 promoter region and represses DNMT1 transcription; it also binds to the HDAC1 promoter and suppresses HDAC1 expression. In Ebp1+/- mice, elevated DNMT1 and HDAC1 leads to reduced GAD67 expression, contributing to schizophrenia-like behavior.","method":"Chromatin immunoprecipitation, reporter assay, heterozygous KO mouse, western blot","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, KO mouse with mechanistic readout, single lab","pmids":["32283721"],"is_preprint":false},{"year":2022,"finding":"Loss of EBP1 in CNS-specific knockout mice causes aberrant Fbxw7 gene expression, resulting in proteasomal degradation of PTF1A and leading to reduced cerebellar volume, Purkinje cell loss, and schizophrenia-like behaviors. Reinstatement of wild-type EBP1 (but not a SZ-patient mutant EBP1-E183Ter) rescued cerebellar architecture.","method":"Conditional KO mouse, western blot, rescue experiment with wild-type vs. mutant EBP1, behavioral assays","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with specific molecular mechanism identified, rescue with WT vs. patient mutant, in vivo model","pmids":["35165395"],"is_preprint":false},{"year":2018,"finding":"EBP1 (p48) is the strongest candidate binding partner of DPPA4 in human embryonic stem cells; DPPA4 preferentially binds p48 (not p42) in a SAP-domain-mediated manner in pluripotent cells but not non-pluripotent cells. EBP1 p48 binding attenuates DPPA4's transcriptional repressive function; SAP-domain mutant DPPA4 abolishes this effect.","method":"Proteomics screening, co-immunoprecipitation, reporter assay, siRNA knockdown, domain mutagenesis","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics identification, co-IP, functional reporter assay with mutagenesis, single lab","pmids":["29327467"],"is_preprint":false}],"current_model":"PA2G4/EBP1 is a multifunctional RNA- and DNA-binding protein with a methionine aminopeptidase-like fold that occupies the 60S ribosomal peptide exit tunnel to regulate translation, associates with pre-ribosomal RNP complexes in the nucleolus to control rRNA synthesis, and shuttles between cytoplasm and nucleus where it acts as a transcriptional co-repressor of E2F1-, AR-, and HNF4α-regulated genes via recruitment of HDAC2 and Sin3A; its activity is regulated by isoform-specific post-translational modifications (PKC-mediated S360 phosphorylation, CDK2-mediated S34 phosphorylation on p48, PAK1-mediated T261 phosphorylation, TLS/FUS-mediated sumoylation on p42, and PRKN-mediated ubiquitination at K376), with the p48 isoform localizing to the nucleolus and promoting cell survival/proliferation while p42 predominantly resides in the cytoplasm and acts as a tumor suppressor by degrading p85-PI3K via HSP70/CHIP."},"narrative":{"mechanistic_narrative":"PA2G4/EBP1 is a multifunctional RNA- and protein-binding protein built on a catalytically inactive methionine aminopeptidase (pita-bread) fold coupled to a C-terminal extension that supplies its protein-, RNA-, and lipid-binding surfaces [PMID:17690690, PMID:17765895]. It functions across translation, ribosome biogenesis, and transcriptional control, partitioning into two isoforms (p48, p42) with distinct localization and opposing effects on proliferation [PMID:16832058]. At the translational level, EBP1 occupies the 60S peptide exit tunnel as a high-occupancy ribosome-associated factor that engages eL19, uL23, and 28S rRNA, modulating ribosome occupancy during start-codon initiation and early elongation and is displaced by emerging signal sequences, thereby biasing synthesis of membrane-targeted proteins [PMID:33357414, PMID:33479117]. In the nucleolus it joins pre-ribosomal RNP complexes through a dsRNA-binding region and partners with nucleophosmin/B23 and TIF-IA/TIF-90 to drive rRNA synthesis [PMID:15064750, PMID:16631606, PMID:17951246, PMID:30793766]. As a transcriptional co-repressor, EBP1 binds Rb, the androgen receptor, and HNF4α, and represses E2F1- and AR-regulated promoters by recruiting Sin3A and HDAC2 to target chromatin [PMID:11268000, PMID:12165860, PMID:12682367, PMID:15073182, PMID:16254079, PMID:31362984]; it also represses DNMT1 and HDAC1 transcription, controlling the epigenetic state during neural development [PMID:31748268, PMID:32283721]. EBP1 is heavily regulated by post-translational modification—PKC-mediated phosphorylation at S360 governing Akt binding and anti-apoptotic activity, PAK1-mediated T261 phosphorylation controlling repression and tamoxifen sensitivity, TLS/FUS-mediated SUMOylation of p42 driving its nuclear, anti-proliferative function, and PRKN-mediated K376 ubiquitination directing mitophagy after ischemic injury [PMID:16642037, PMID:18283314, PMID:19946338, PMID:37712850]. Through isoform-specific routing it acts as both an oncogenic factor—stabilizing MYCN and sequestering FBXW7α (p48)—and a tumor suppressor—degrading the p85 PI3K subunit via HSP70/CHIP (p42) [PMID:24651434, PMID:28209614, PMID:31501192]. Mouse genetics ties EBP1 to neurodevelopment, where its loss disrupts cerebellar architecture and produces schizophrenia-like behaviors rescuable by wild-type but not a patient-derived EBP1-E183Ter mutant [PMID:35165395].","teleology":[{"year":2000,"claim":"Established EBP1's first physiological context by showing it is a receptor-associated protein released to the nucleus upon growth-factor signaling, linking a membrane receptor to a downstream transcriptional regulator.","evidence":"Yeast two-hybrid, in vitro binding, and fractionation/immunofluorescence of EBP1–ErbB3 and heregulin-induced translocation","pmids":["10682683"],"confidence":"High","gaps":["Did not define EBP1's nuclear function once translocated","Mechanism coupling dissociation to nuclear import unresolved"]},{"year":2003,"claim":"Defined EBP1 as a transcriptional co-repressor by mapping its C-terminal recruitment of HDAC activity, explaining how it silences E2F1- and AR-regulated genes.","evidence":"Co-IP with Rb/AR/E2F1, GST pulldown of HDAC2, ChIP, EMSA, and promoter reporter assays across multiple studies","pmids":["11268000","12165860","12682367","15073182"],"confidence":"High","gaps":["Whether HDAC2 contact is direct or bridged was unclear from early work","Specificity for E2F1 vs AR target subsets not fully resolved"]},{"year":2005,"claim":"Identified Sin3A as the direct corepressor scaffold linking EBP1 to HDAC, resolving the architecture of the repressive complex and demonstrating in vivo tumor suppression in prostate cancer.","evidence":"Recombinant direct binding, reciprocal Co-IP, ChIP of co-occupancy, microarray, and LNCaP xenografts in SCID mice","pmids":["16254079","15994225"],"confidence":"High","gaps":["Direct vs indirect HDAC2 engagement still implies Sin3A bridging","AR downregulation mechanism beyond promoter recruitment incomplete"]},{"year":2006,"claim":"Revealed EBP1's roles in RNA metabolism and translation, showing it binds dsRNA and bcl-2 ARE transcripts, associates with ribosomes, and modulates eIF2alpha phosphorylation.","evidence":"Domain mutagenesis, RNA affinity/EMSA, RIP, mRNA decay assays, ribosome fractionation, and in vitro PKR kinase assay","pmids":["16631606","16396631"],"confidence":"High","gaps":["Structural basis of ribosome engagement not yet defined","Direct vs indirect effect on eIF2alpha kinase activity unresolved"]},{"year":2006,"claim":"Established the p48/p42 isoform dichotomy and the S360-phosphorylation/Akt axis as the molecular switch between EBP1's anti-apoptotic and differentiation functions.","evidence":"Subcellular fractionation, cell-free apoptotic assays, site-directed mutagenesis (S360A/D), and isoform-specific binding assays","pmids":["16832058","16642037","17316401"],"confidence":"High","gaps":["How isoform abundance is regulated in tissues not addressed","Kinase-independent Akt mechanism mechanistically incomplete"]},{"year":2007,"claim":"Provided the structural foundation by solving murine and human EBP1 crystal structures, defining a catalytically dead MetAP-like fold whose C-terminal extension carries the RNA/protein-binding determinants.","evidence":"X-ray crystallography of murine and human EBP1 with RNA-binding and IRES translation assays","pmids":["17690690","17765895"],"confidence":"High","gaps":["Structure did not capture ribosome- or partner-bound conformations","No catalytic activity, leaving the fold's enzymatic legacy unexplained"]},{"year":2007,"claim":"Connected EBP1 to ribosome biogenesis and antiviral functions, showing B23/nucleophosmin partnership for rRNA synthesis and inhibition of influenza and FMDV polymerase/IRES activities.","evidence":"Co-IP/mutagenesis with B23, siRNA ribosome biogenesis assays, in vitro polymerase and IRES translation assays","pmids":["17951246","17295834","17690690"],"confidence":"High","gaps":["Whether antiviral activity is physiologically deployed in infection unclear","Coupling of nucleolar RNP role to cytoplasmic translation not integrated"]},{"year":2009,"claim":"Defined the post-translational regulatory network controlling EBP1 stability, localization, and repressive output through PAK1 phosphorylation, hBRE1 ubiquitination, and TLS/FUS-mediated SUMOylation.","evidence":"In vitro kinase, ubiquitination, and SUMOylation assays with phospho/SUMO-site mutagenesis and reporter assays","pmids":["18283314","19037095","19946338","17786317","11325528"],"confidence":"High","gaps":["Interplay/hierarchy among modifications not established","In vivo relevance of individual modifications largely untested"]},{"year":2014,"claim":"Mechanistically separated the oncogenic and tumor-suppressive activities of the two isoforms through CDK2-mediated p48 S34 phosphorylation versus p42-driven p85-PI3K degradation.","evidence":"Co-IP, in vitro kinase assays, domain mapping, PI3K lipid kinase and ubiquitination assays with proliferation/xenograft readouts","pmids":["25154617","24651434","21098709"],"confidence":"High","gaps":["What dictates p48 vs p42 production in a given tumor unresolved","Whether p85 degradation and p53/HDM2 effects co-occur in the same cells unknown"]},{"year":2017,"claim":"Extended isoform-specific function to ubiquitin-ligase regulation, showing p48 sequesters FBXW7α while p42 acts as an FBXW7 adapter, and that p48 stabilizes oncogenic MYCN in a feedback loop.","evidence":"Domain-mapped Co-IP, ubiquitination assays, surface plasmon resonance, ChIP, and in vivo tumor models","pmids":["28209614","31501192"],"confidence":"Medium","gaps":["FBXW7 adapter/sequestration model rests on a single lab","Generality of MYCN stabilization beyond neuroblastoma untested"]},{"year":2020,"claim":"Resolved EBP1's principal molecular role at near-atomic resolution as a 60S peptide-exit-tunnel factor that shapes ribosome occupancy and the synthesis of membrane-targeted proteins during neurodevelopment.","evidence":"Cryo-EM of EBP1–80S ribosome, ribosome profiling, pSILAC/BONCAT proteomics, and loss-of-function","pmids":["33357414","33479117"],"confidence":"High","gaps":["How exit-tunnel occupancy integrates with its nucleolar/transcriptional roles unclear","Selectivity for specific nascent chains incompletely defined"]},{"year":2022,"claim":"Defined EBP1's essential neurodevelopmental functions and disease relevance, linking its loss to FBXW7/PTF1A and DNMT1/HDAC1 dysregulation, cerebellar defects, and schizophrenia-like behavior rescuable by wild-type but not a patient mutant.","evidence":"Conditional and heterozygous KO mice, ChIP, methylation analysis, and rescue with WT vs EBP1-E183Ter mutant","pmids":["35165395","31748268","32283721","37712850"],"confidence":"High","gaps":["Causal human genetic link to schizophrenia rests on mouse rescue with a patient-derived mutant","Cell-type-specific contributions of translational vs transcriptional roles not separated"]},{"year":null,"claim":"How EBP1's distinct molecular roles—ribosome exit-tunnel occupancy, nucleolar rRNA synthesis, transcriptional corepression, and ubiquitin-ligase modulation—are coordinated within a single cell, and how isoform choice and PTM combinations are decoded, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating translational and transcriptional functions","Regulation of p48/p42 ratio and PTM hierarchy in physiological settings unknown","Direct human disease-causing mutations not established beyond mouse-validated candidates"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[8,11,12,38]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5,29,42]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,6,29,30]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[31,32]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[25]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,22,27]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[4,15,25]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,4,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,9,17]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[8,31,32]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,6,29,30]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,8,15,28]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[31,32]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[29,43]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[34]}],"complexes":["Sin3A-HDAC2 corepressor complex","pre-ribosomal RNP / 60S ribosome (peptide exit tunnel)","ZFP809-TRIM28 retroviral silencing complex"],"partners":["ERBB3","RB1","AR","SIN3A","HDAC2","NPM1","MYCN","HNF4A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UQ80","full_name":"Proliferation-associated protein 2G4","aliases":["Cell cycle protein p38-2G4 homolog","hG4-1","ErbB3-binding protein 1"],"length_aa":394,"mass_kda":43.8,"function":"May play a role in a ERBB3-regulated signal transduction pathway. Seems be involved in growth regulation. Acts a corepressor of the androgen receptor (AR) and is regulated by the ERBB3 ligand neuregulin-1/heregulin (HRG). Inhibits transcription of some E2F1-regulated promoters, probably by recruiting histone acetylase (HAT) activity. Binds RNA. Associates with 28S, 18S and 5.8S mature rRNAs, several rRNA precursors and probably U3 small nucleolar RNA. May be involved in regulation of intermediate and late steps of rRNA processing. May be involved in ribosome assembly. Mediates cap-independent translation of specific viral IRESs (internal ribosomal entry site) (By similarity). Regulates cell proliferation, differentiation, and survival. Isoform 1 suppresses apoptosis whereas isoform 2 promotes cell differentiation (By similarity)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9UQ80/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PA2G4","classification":"Common 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PA2G4","url":"https://www.omim.org/entry/602145"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PA2G4"},"hgnc":{"alias_symbol":["EBP1","ITAF45"],"prev_symbol":[]},"alphafold":{"accession":"Q9UQ80","domains":[{"cath_id":"3.90.230.10","chopping":"14-244_307-362","consensus_level":"high","plddt":97.4653,"start":14,"end":362},{"cath_id":"1.10.10.10","chopping":"246-305","consensus_level":"medium","plddt":97.5825,"start":246,"end":305}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQ80","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQ80-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQ80-F1-predicted_aligned_error_v6.png","plddt_mean":92.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PA2G4","jax_strain_url":"https://www.jax.org/strain/search?query=PA2G4"},"sequence":{"accession":"Q9UQ80","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UQ80.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UQ80/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQ80"}},"corpus_meta":[{"pmid":"3138113","id":"PMC_3138113","title":"Purification 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Treatment of cells with the ErbB-3 ligand heregulin causes dissociation of EBP1 from ErbB-3 and translocation of EBP1 from the cytoplasm to the nucleus.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, cellular fractionation/immunofluorescence\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal in vitro and in vivo binding assays, yeast two-hybrid identification, replicated in multiple studies\",\n      \"pmids\": [\"10682683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"EBP1 binds the retinoblastoma protein (Rb) both in vivo and in vitro; the 72 C-terminal amino acids of EBP1 are sufficient for Rb binding. Dephosphorylation of EBP1 enhances the interaction with Rb. EBP1 overexpression inhibits the E2F1-regulated cyclin E promoter, and EBP1 binds E2F1 indirectly via Rb.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, promoter reporter assay\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal pulldown and co-IP, domain mapping, functional reporter assay, replicated across subsequent studies\",\n      \"pmids\": [\"11268000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"EBP1 binds androgen receptor (AR) in vitro and in vivo via its C-terminal 79 amino acids; this binding is increased by androgen treatment. The N-terminal domain of AR is responsible for binding EBP1. EBP1 overexpression inhibits ligand-mediated transcriptional activation of AR-regulated promoters, and an LXXLL motif mutation abolishes this repression.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, transient transfection reporter assay, mutagenesis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro and in vivo binding, domain mutagenesis, functional reporter assay, replicated in multiple independent studies\",\n      \"pmids\": [\"12165860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EBP1 represses E2F1-mediated transcription through its C-terminal domain, which recruits histone deacetylase (HDAC) activity. EBP1 binds HDAC2 (but not HDAC1) in vitro. HDAC inhibitors significantly reduce EBP1-mediated repression. An EBP1 mutant lacking the HDAC binding domain fails to inhibit transcription.\",\n      \"method\": \"Reporter assay, GST pulldown, HDAC activity assay, mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro binding, enzymatic assay, mutagenesis, functional reporter assay, replicated across related studies\",\n      \"pmids\": [\"12682367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"EBP1 is localized to the cytoplasm and nucleolus; its nucleolar localization requires sequences at both the amino- and carboxy-terminus. EBP1 is part of pre-ribosomal ribonucleoprotein complexes and associates with different rRNA species. EBP1 overexpression inhibits proliferation of human fibroblasts, linked to its nucleolar localization.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence, mass spectrometry, deletion mutagenesis, proliferation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including MS, localization studies with functional consequence, domain mapping\",\n      \"pmids\": [\"15064750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"EBP1 (contained in nuclear lysates) associates with E2F1 consensus sequences in the E2F1 promoter in complex with E2F1, Rb, and HDAC2. Heregulin regulates the association of EBP1 with E2F promoter sequences and enhances EBP1-mediated transcriptional repression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP in vivo, EMSA in vitro, functional reporter assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15073182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"EBP1 interacts with the corepressor Sin3A both in vitro and in vivo; the C-terminal domain of EBP1 is necessary and sufficient for Sin3A binding, mapping to the PAH4/HDAC-interacting domain of Sin3A. Recombinant Sin3A binds EBP1 directly but recombinant HDAC2 does not bind EBP1 directly. EBP1 and Sin3A co-occupy PSA and E2F1 promoters; Sin3A enhances EBP1-mediated repression of AR- and E2F1-regulated genes.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), reporter assay, recombinant protein binding\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstituted direct binding with recombinant proteins, reciprocal Co-IP, ChIP, functional reporter assay, multiple orthogonal methods\",\n      \"pmids\": [\"16254079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"EBP1 overexpression down-regulates AR and six AR-regulated genes in LNCaP prostate cancer cells. EBP1 is recruited to the PSA promoter in response to the androgen antagonist bicalutamide (demonstrated by ChIP). EBP1 overexpression reduces LNCaP tumor incidence and growth in SCID mice.\",\n      \"method\": \"Microarray, chromatin immunoprecipitation (ChIP), reporter assay, xenograft mouse model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, microarray, in vivo xenograft, multiple orthogonal methods in single study\",\n      \"pmids\": [\"15994225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"EBP1 contains a dsRNA-binding domain (dsRBD) that mediates interaction with dsRNA; deletion of the dsRBD impairs nucleolar localization and RNP complex formation. EBP1 is associated with mature ribosomes in the cytoplasm and inhibits phosphorylation of eIF2alpha at serine 51. EBP1 interacts with and is phosphorylated by PKR kinase.\",\n      \"method\": \"Mutagenesis, RNA binding assay, co-immunoprecipitation, in vitro kinase assay, ribosome fractionation, western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis, in vitro kinase assay, ribosome fractionation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"16631606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Nuclear Akt interacts with EBP1 to prevent DNA fragmentation by caspase-activated DNase (CAD). EBP1 phosphorylation by PKC at serine 360 (S360) is required for EBP1 to bind nuclear Akt; S360A mutant barely binds Akt or inhibits DNA fragmentation, while S360D mutant strongly binds Akt and suppresses apoptosis. Nuclear (not cytoplasmic) Akt enhances EBP1 antiapoptotic action independent of Akt kinase activity.\",\n      \"method\": \"Cell-free apoptotic assay, co-immunoprecipitation, site-directed mutagenesis, knockdown, overexpression\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-free biochemical reconstitution, mutagenesis, knockdown with phenotypic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"16642037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"EBP1 exists as two isoforms, p48 and p42. p48 localizes in both cytoplasm and nucleus and suppresses apoptosis; p42 predominantly resides in the cytoplasm and promotes cell differentiation. EGF strongly stimulates p42 (but not p48) to bind ErbB3, dependent on PKC-mediated phosphorylation. p42 and p48 have opposing effects on cell proliferation.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, overexpression, kinase inhibitor treatment, neurite outgrowth assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isoform-specific localization and binding, multiple functional assays, replicated in subsequent studies\",\n      \"pmids\": [\"16832058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"EBP1 binds bcl-2 mRNA AU-rich elements (AREs) in vitro; it is present in bcl-2 mRNA-containing ribonucleoprotein complexes in HL-60 cells and co-precipitates with nucleolin in cytoplasmic extracts. EBP1 decreases the rate of decay of bcl-2 ARE-containing transcripts in cell extracts.\",\n      \"method\": \"RNA affinity chromatography, MALDI-MS identification, EMSA, RNA co-immunoprecipitation, co-IP, RNA decay assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RNA affinity, EMSA, RIP, mRNA decay assay) in a single study\",\n      \"pmids\": [\"16396631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of murine EBP1 (p48 isoform) reveals a core domain homologous to methionine aminopeptidases (pita bread fold) coupled to a C-terminal extension containing protein- and RNA-binding motifs. The primary RNA-binding site is a Lys-rich motif in the C-terminus mediating interaction with the FMDV IRES. EBP1 has a specific functional requirement in FMDV IRES-directed translation independent of direct interaction with PTB.\",\n      \"method\": \"X-ray crystallography, RNA binding assay, IRES reporter translation assay, mutagenesis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation, mutagenesis, translation assay\",\n      \"pmids\": [\"17690690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of human EBP1 at 1.6 Å resolution reveals the conserved pita bread fold of methionine aminopeptidases without catalytic activity, providing a structural platform for multiple protein and RNA interactions.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure, independently replicated by another structural study\",\n      \"pmids\": [\"17765895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"EBP1 specifically interacts with the PB1 subunit of influenza virus RNA polymerase in vitro and in vivo; the EBP1 contact site on PB1 maps to its transcription primer binding site. EBP1 inhibits in vitro RNA synthesis by the influenza virus RNA polymerase (3P complex) but does not inhibit capped RNA endonuclease or RNA-cap binding activities. EBP1 overexpression interferes with virus production.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding, in vitro RNA polymerase assay, overexpression viral replication assay\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzymatic assay, in vitro and in vivo binding, functional overexpression assay, multiple orthogonal methods\",\n      \"pmids\": [\"17295834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"EBP1 forms a complex with nucleophosmin/B23. p42 isoform associates with B23 upon EGF stimulation in a manner dependent on Ser360 phosphorylation, while p48 constitutively binds B23 in the nucleolus requiring B23 Lys263 sumoylation. Knockdown of B23 or EBP1 substantially decreases ribosome biogenesis and cell survival.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis, siRNA knockdown, ribosome biogenesis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with mutagenesis, functional knockdown with specific cellular readout, multiple orthogonal methods\",\n      \"pmids\": [\"17951246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PKC-delta phosphorylates EBP1 and protects it from apoptotic degradation by caspase-3. EBP1 is cleaved by active caspase-3 at D53 and D196 sites; cleavage at D196 is prerequisite for subsequent D53 cleavage. PKC phosphorylation at S360 suppresses caspase-3 cleavage. D196A mutant protects cells from apoptosis.\",\n      \"method\": \"Cell-free apoptotic assay, site-directed mutagenesis, PKC-delta knockout cells, in vitro caspase cleavage assay\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro cleavage assay, mutagenesis, KO cells, multiple orthogonal methods\",\n      \"pmids\": [\"17316401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Serine 363 of EBP1 is phosphorylated in vivo; EBP1 phosphorylated at S363 localizes exclusively to the nucleus. S363A mutation significantly decreases EBP1-mediated transcriptional repression and abolishes its ability to inhibit cell growth. S363A EBP1 fails to bind HDAC2 and mSin3a, though it still associates with the E2F1 promoter.\",\n      \"method\": \"Phospho-specific antibody, mutagenesis, reporter assay, co-immunoprecipitation, chromatin immunoprecipitation\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis, co-IP, functional assays, single lab\",\n      \"pmids\": [\"17786317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"hBRE1 (human BRE1) is an E3 ubiquitin ligase for EBP1; hBRE1 promotes EBP1 polyubiquitination and degradation. EBP1 polyubiquitination in cancer cells is regulated by its phosphorylation. Depletion of hBRE1 blocks EBP1 polyubiquitination and elevates EBP1 protein levels. hBRE1 binds EBP1 and suppresses its repressive effect on E2F-1.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, western blot\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo ubiquitination assay, co-IP, depletion experiment with mechanistic readout, multiple methods in one study\",\n      \"pmids\": [\"19037095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PAK1 phosphorylates EBP1 in vitro and in vivo at threonine 261. EGF/heregulin treatment and constitutively active PAK1 enhance threonine phosphorylation of EBP1. EBP1 binds endogenous PAK1, enhanced by heregulin. T261E mutation (mimicking phosphorylation) abolishes EBP1-mediated transcriptional repression, growth inhibition, and tamoxifen sensitivity.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, reporter assay, cell growth assay\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay, mutagenesis, co-IP, functional assays; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"18283314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"EBP1 p42 isoform can be sumoylated on K93 and K298 residues; sumoylation mediates its nuclear translocation and is required for anti-proliferative activity. TLS/FUS has SUMO1 E3 ligase activity for EBP1 p42 and directly binds EBP1; EBP1 sumoylation is triggered by genotoxic stress. Overexpression of TLS enhances EBP1 sumoylation; depletion of TLS abolishes it. Unsumoylatable EBP1 mutants fail to suppress E2F-1-regulated transcription.\",\n      \"method\": \"Sumoylation assay, co-immunoprecipitation, mutagenesis, siRNA knockdown, reporter assay, subcellular localization\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic sumoylation assay, mutagenesis, siRNA, functional reporter assay, multiple orthogonal methods\",\n      \"pmids\": [\"19946338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"EBP1 p48 isoform binds the p53 E3 ligase HDM2, enhancing the HDM2-p53 association and thereby promoting p53 polyubiquitination and degradation, reducing steady-state p53 levels and activity in glioblastoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, western blot, xenograft model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assay with functional readout, single lab, multiple methods\",\n      \"pmids\": [\"21098709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EBP1 p42 interacts with the cSH2 domain of the p85 regulatory subunit of PI3K, inhibiting its lipid kinase activity. p42 promotes p85 degradation by recruiting the HSP70/CHIP E3 ligase complex, coupling p85 to ubiquitin-proteasomal degradation.\",\n      \"method\": \"Co-immunoprecipitation, PI3K lipid kinase assay, ubiquitination assay, domain mapping, western blot\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — enzymatic assay, domain-specific interaction, ubiquitination assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"24651434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CDK2 specifically interacts with p48 EBP1 (but not p42) through p48's N-terminal domain and phosphorylates p48 at serine 34. This CDK2-mediated phosphorylation is required for the tumorigenic function of p48; the phospho-ablated S34A mutant antagonizes cell proliferation and transformation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, mutagenesis, cell proliferation assay, xenograft model\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, kinase assay, mutagenesis with functional readout, single lab\",\n      \"pmids\": [\"25154617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GTP-bound TIF-IA (transcription initiation factor I) binds EBP1, and together they enhance transcription of PCNA. GTP binding by TIF-IA and EBP1 phosphorylation by protein kinase C delta are both required for optimal PCNA expression. GTP depletion inhibits ribosomal RNA synthesis in T cells by inhibiting TIF-IA.\",\n      \"method\": \"Protein binding assay, kinase inhibitor treatment, GTP depletion, reporter/quantitative expression assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and functional assay in one study, single lab, mechanistic interpretation based on pharmacological inhibition\",\n      \"pmids\": [\"25691158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EBP1 binds directly to several polyphosphoinositides (PPIns) via two distinct lysine-rich PPIn-binding sites at the N- and C-termini. The C-terminal PPIn-binding motif contributes most to nucleolar localization. A K372N point mutation in the C-terminal motif (found in endometrial tumors) is sufficient to alter nucleolar targeting. EBP1 associates with PtdIns(3,4,5)P3 in the nucleolus via electrostatic and hydrophobic interactions.\",\n      \"method\": \"Lipid pulldown, mutagenesis, NMR spectroscopy, immunofluorescence/localization\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — NMR, lipid pulldown, mutagenesis, localization assay; multiple orthogonal methods in one study\",\n      \"pmids\": [\"27118868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EBP1 p48 binds the WD domain of FBXW7 as an oncogenic substrate, sequestering FBXW7α to the cytosol and attenuating its tumor suppressor function. EBP1 p42 binds the F-box domain of FBXW7 and acts as an adapter that stabilizes FBXW7-substrate interactions, promoting FBXW7-mediated degradation of oncogenic targets.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, ubiquitination assay, subcellular fractionation, functional tumor assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping, functional assays, single lab\",\n      \"pmids\": [\"28209614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PA2G4 directly binds MYCN protein, blocking MYCN proteolysis and enhancing colony formation in a MYCN-dependent manner. MYCN occupies the PA2G4 gene promoter, stimulating transcription (positive feedback). The MYCN-PA2G4 interaction site was mapped to a 14 amino acid MYCN sequence and a surface crevice of PA2G4 by molecular modeling, surface plasmon resonance, and mutagenesis. Competitive chemical inhibition of the MYCN-PA2G4 interface reduces neuroblastoma tumorigenesis in vivo.\",\n      \"method\": \"Chromatin immunoprecipitation, surface plasmon resonance, mutagenesis, molecular modeling, co-immunoprecipitation, in vivo tumor model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — surface plasmon resonance (quantitative binding), ChIP, mutagenesis, in vivo model; multiple orthogonal methods\",\n      \"pmids\": [\"31501192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EBP1 p48 interacts with TIF-90 (a splice variant of TIF-IA/RNA polymerase I transcription factor), regulating ribosomal RNA synthesis. EBP1 expression is essential for Akt-protected TIF-90 stability by preventing TIF-90 ubiquitination by MDM2 and proteasomal degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, ribosomal RNA synthesis assay, siRNA knockdown, western blot\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, functional rRNA synthesis assay, single lab\",\n      \"pmids\": [\"30793766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EBP1 represses DNMT1 transcription by binding to its promoter region, interrupting DNMT1-mediated methylation at the Survivin promoter. Loss of EBP1 in embryonic mice caused global DNA methylation increase with elevated Suv39H1/DNMT1 levels, massive apoptosis, and developmental defects including brain malformation.\",\n      \"method\": \"Chromatin immunoprecipitation, promoter reporter assay, Ebp1 knockout mouse, methylation analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, KO mouse with mechanistic readout, methylation analysis; multiple orthogonal methods\",\n      \"pmids\": [\"31748268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EBP1 binds HNF4α via its LXXLL motif in a manner that competes with HNF4α coactivators for the same binding pocket on HNF4α's ligand-binding domain, thereby suppressing expression of HNF4α target genes implicated in insulin secretion. Crystal structure of the HNF4α ligand-binding domain in complex with an EBP1 LXXLL peptide at 3.15 Å resolution.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, mammalian two-hybrid, X-ray crystallography, reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation, multiple binding assays, single lab\",\n      \"pmids\": [\"31362984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM structure at near-atomic resolution shows EBP1 as a high-occupancy 60S peptide tunnel exit (TE) factor during protein synthesis in the developing neocortex. Ribosome profiling shows EBP1-60S binding is highest during start codon initiation and N-terminal peptide elongation, regulating ribosome occupancy. Membrane-targeting signal sequences emerging from the 60S tunnel displace EBP1. EBP1 especially impacts synthesis of membrane-targeted cell adhesion molecules.\",\n      \"method\": \"Cryo-electron microscopy, ribosome profiling, pSILAC/BONCAT mass spectrometry, loss-of-function\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with ribosome profiling and quantitative proteomics; multiple orthogonal methods, near-atomic resolution structural data\",\n      \"pmids\": [\"33357414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structure of human EBP1 (p48) bound to the human 80S ribosome at 3.3 Å resolution reveals EBP1 binding near the peptide exit tunnel, centered on interactions with ribosomal proteins eL19 and uL23 and 28S rRNA. EBP1-ribosome association is enhanced upon puromycin-mediated translational inhibition. EBP1 can rotate around its insert domain, allowing multiple conformations while maintaining ribosome interaction.\",\n      \"method\": \"Cryo-electron microscopy, ribosome binding assay, chemical translational inhibition\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with identification of specific ribosomal contacts, independently consistent with Kraushar et al. 2020\",\n      \"pmids\": [\"33479117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EBP1 directly interacts with Suv39H1 and recruits the E3 ligase MDM2, promoting ubiquitin-proteasome system-dependent degradation of Suv39H1, thereby governing heterochromatin assembly during neural development.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, western blot, neural differentiation model\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assay with functional context, single lab\",\n      \"pmids\": [\"33691908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PA2G4/EBP1 is ubiquitinated at lysine 376 by PRKN/PARKIN on damaged mitochondria following cerebral ischemia-reperfusion injury. Ubiquitinated PA2G4 interacts with receptor protein SQSTM1/p62, promoting mitophagy induction. Neuron-specific knockout of Pa2g4 impairs mitophagy and increases infarct volume; AAV-mediated re-expression of PA2G4 rescues this.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with site mutagenesis, conditional KO mouse, AAV rescue, mitophagy assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific ubiquitination mapping, conditional KO with AAV rescue, multiple orthogonal methods, mechanistic specificity\",\n      \"pmids\": [\"37712850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PKC phosphorylates EBP1 on serine/threonine residues in vitro and in vivo; basal EBP1 phosphorylation in breast cancer cells is PKC-dependent. PKC activity is required for EBP1 to associate with ErbB3 in serum-starved cells; PKC inhibition abrogates this association. Heregulin-induced EBP1 phosphorylation occurs predominantly in a PKC-independent manner.\",\n      \"method\": \"In vitro kinase assay, PKC inhibitor treatment, co-immunoprecipitation, metabolic phosphate labeling\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay, pharmacological inhibition, co-IP; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"11325528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EBP1 is a novel component of the ZFP809-TRIM28 retroviral silencing complex; EBP1 depletion reduces PBS-mediated retroviral silencing in embryonic cells.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, retroviral reporter assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and functional knockdown with specific reporter assay, single lab\",\n      \"pmids\": [\"24227866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pa2G4 (EBP1) binds Six1 transcription factor and interferes with the Six1-Eya1 complex. Knockdown of Pa2G4 in Xenopus embryos downregulates neural border zone, neural crest, and cranial placode genes. Gain-of-function expands neural crest and alters cranial placode domains.\",\n      \"method\": \"Co-immunoprecipitation in HEK293 cells, morpholino knockdown, mRNA overexpression, in situ hybridization in Xenopus embryos\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, in vivo loss/gain-of-function with defined molecular readout, single lab\",\n      \"pmids\": [\"27940157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PA2G4 stabilizes FYN mRNA by binding to m6A-modified FYN mRNA in a YTHDF2-dependent manner, increasing FYN protein expression. EBP1 co-immunoprecipitates with YTHDF2; RIP assays demonstrate PA2G4 binding to FYN mRNA. YTHDF2's m6A catalytic activity is indispensable for PA2G4-mediated FYN regulation.\",\n      \"method\": \"Co-immunoprecipitation, RIP assay, MeRIP assay, dual-luciferase reporter, mRNA half-life assay\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple RNA binding assays, co-IP, mRNA stability assay; single lab\",\n      \"pmids\": [\"35526051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PA2G4 interacts with NF110; CRAPIR (a piRNA) competes with NF110 for binding to PA2G4, preventing PA2G4-mediated interaction with the NF110-NF45 heterodimer and reducing NF110 degradation, thereby promoting cardiomyocyte proliferation.\",\n      \"method\": \"Co-immunoprecipitation, RNA-protein binding assay, genetic ablation, overexpression\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, competitive binding mechanism demonstrated, loss-of-function phenotype; single study\",\n      \"pmids\": [\"39814981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"p48 EBP1 physically interacts with beta-tubulin (but not alpha-tubulin) and accumulates in distal microtubule growth cone regions. Introduction of p48 EBP1 in injured hippocampal slices promotes axon regeneration.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, ex vivo axon regeneration assay\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP, localization data, limited functional assay in one study\",\n      \"pmids\": [\"27916024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PAK1 inhibitor IPA-3 sensitizes breast cancer cells to tamoxifen only when EBP1 is ectopically expressed; phosphorylation of EBP1 at T261 by PAK1 induces tamoxifen resistance. An EBP1 T261A mutant (non-phosphorylatable) ameliorates PAK1-induced tamoxifen resistance, while T261E (phosphomimetic) increases ErbB2 protein levels.\",\n      \"method\": \"Pharmacological inhibition, mutagenesis, cell viability assay, western blot\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis, pharmacological validation, functional assay; consistent with prior in vitro kinase data\",\n      \"pmids\": [\"23361053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EBP1 binds to the DNMT1 promoter region and represses DNMT1 transcription; it also binds to the HDAC1 promoter and suppresses HDAC1 expression. In Ebp1+/- mice, elevated DNMT1 and HDAC1 leads to reduced GAD67 expression, contributing to schizophrenia-like behavior.\",\n      \"method\": \"Chromatin immunoprecipitation, reporter assay, heterozygous KO mouse, western blot\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, KO mouse with mechanistic readout, single lab\",\n      \"pmids\": [\"32283721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of EBP1 in CNS-specific knockout mice causes aberrant Fbxw7 gene expression, resulting in proteasomal degradation of PTF1A and leading to reduced cerebellar volume, Purkinje cell loss, and schizophrenia-like behaviors. Reinstatement of wild-type EBP1 (but not a SZ-patient mutant EBP1-E183Ter) rescued cerebellar architecture.\",\n      \"method\": \"Conditional KO mouse, western blot, rescue experiment with wild-type vs. mutant EBP1, behavioral assays\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with specific molecular mechanism identified, rescue with WT vs. patient mutant, in vivo model\",\n      \"pmids\": [\"35165395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EBP1 (p48) is the strongest candidate binding partner of DPPA4 in human embryonic stem cells; DPPA4 preferentially binds p48 (not p42) in a SAP-domain-mediated manner in pluripotent cells but not non-pluripotent cells. EBP1 p48 binding attenuates DPPA4's transcriptional repressive function; SAP-domain mutant DPPA4 abolishes this effect.\",\n      \"method\": \"Proteomics screening, co-immunoprecipitation, reporter assay, siRNA knockdown, domain mutagenesis\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics identification, co-IP, functional reporter assay with mutagenesis, single lab\",\n      \"pmids\": [\"29327467\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PA2G4/EBP1 is a multifunctional RNA- and DNA-binding protein with a methionine aminopeptidase-like fold that occupies the 60S ribosomal peptide exit tunnel to regulate translation, associates with pre-ribosomal RNP complexes in the nucleolus to control rRNA synthesis, and shuttles between cytoplasm and nucleus where it acts as a transcriptional co-repressor of E2F1-, AR-, and HNF4α-regulated genes via recruitment of HDAC2 and Sin3A; its activity is regulated by isoform-specific post-translational modifications (PKC-mediated S360 phosphorylation, CDK2-mediated S34 phosphorylation on p48, PAK1-mediated T261 phosphorylation, TLS/FUS-mediated sumoylation on p42, and PRKN-mediated ubiquitination at K376), with the p48 isoform localizing to the nucleolus and promoting cell survival/proliferation while p42 predominantly resides in the cytoplasm and acts as a tumor suppressor by degrading p85-PI3K via HSP70/CHIP.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PA2G4/EBP1 is a multifunctional RNA- and protein-binding protein built on a catalytically inactive methionine aminopeptidase (pita-bread) fold coupled to a C-terminal extension that supplies its protein-, RNA-, and lipid-binding surfaces [#12, #13]. It functions across translation, ribosome biogenesis, and transcriptional control, partitioning into two isoforms (p48, p42) with distinct localization and opposing effects on proliferation [#10]. At the translational level, EBP1 occupies the 60S peptide exit tunnel as a high-occupancy ribosome-associated factor that engages eL19, uL23, and 28S rRNA, modulating ribosome occupancy during start-codon initiation and early elongation and is displaced by emerging signal sequences, thereby biasing synthesis of membrane-targeted proteins [#31, #32]. In the nucleolus it joins pre-ribosomal RNP complexes through a dsRNA-binding region and partners with nucleophosmin/B23 and TIF-IA/TIF-90 to drive rRNA synthesis [#4, #8, #15, #28]. As a transcriptional co-repressor, EBP1 binds Rb, the androgen receptor, and HNF4\\u03b1, and represses E2F1- and AR-regulated promoters by recruiting Sin3A and HDAC2 to target chromatin [#1, #2, #3, #5, #6, #30]; it also represses DNMT1 and HDAC1 transcription, controlling the epigenetic state during neural development [#29, #42]. EBP1 is heavily regulated by post-translational modification\\u2014PKC-mediated phosphorylation at S360 governing Akt binding and anti-apoptotic activity, PAK1-mediated T261 phosphorylation controlling repression and tamoxifen sensitivity, TLS/FUS-mediated SUMOylation of p42 driving its nuclear, anti-proliferative function, and PRKN-mediated K376 ubiquitination directing mitophagy after ischemic injury [#9, #19, #20, #34]. Through isoform-specific routing it acts as both an oncogenic factor\\u2014stabilizing MYCN and sequestering FBXW7\\u03b1 (p48)\\u2014and a tumor suppressor\\u2014degrading the p85 PI3K subunit via HSP70/CHIP (p42) [#22, #26, #27]. Mouse genetics ties EBP1 to neurodevelopment, where its loss disrupts cerebellar architecture and produces schizophrenia-like behaviors rescuable by wild-type but not a patient-derived EBP1-E183Ter mutant [#43].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established EBP1's first physiological context by showing it is a receptor-associated protein released to the nucleus upon growth-factor signaling, linking a membrane receptor to a downstream transcriptional regulator.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, and fractionation/immunofluorescence of EBP1\\u2013ErbB3 and heregulin-induced translocation\",\n      \"pmids\": [\"10682683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define EBP1's nuclear function once translocated\", \"Mechanism coupling dissociation to nuclear import unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined EBP1 as a transcriptional co-repressor by mapping its C-terminal recruitment of HDAC activity, explaining how it silences E2F1- and AR-regulated genes.\",\n      \"evidence\": \"Co-IP with Rb/AR/E2F1, GST pulldown of HDAC2, ChIP, EMSA, and promoter reporter assays across multiple studies\",\n      \"pmids\": [\"11268000\", \"12165860\", \"12682367\", \"15073182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HDAC2 contact is direct or bridged was unclear from early work\", \"Specificity for E2F1 vs AR target subsets not fully resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified Sin3A as the direct corepressor scaffold linking EBP1 to HDAC, resolving the architecture of the repressive complex and demonstrating in vivo tumor suppression in prostate cancer.\",\n      \"evidence\": \"Recombinant direct binding, reciprocal Co-IP, ChIP of co-occupancy, microarray, and LNCaP xenografts in SCID mice\",\n      \"pmids\": [\"16254079\", \"15994225\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect HDAC2 engagement still implies Sin3A bridging\", \"AR downregulation mechanism beyond promoter recruitment incomplete\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed EBP1's roles in RNA metabolism and translation, showing it binds dsRNA and bcl-2 ARE transcripts, associates with ribosomes, and modulates eIF2alpha phosphorylation.\",\n      \"evidence\": \"Domain mutagenesis, RNA affinity/EMSA, RIP, mRNA decay assays, ribosome fractionation, and in vitro PKR kinase assay\",\n      \"pmids\": [\"16631606\", \"16396631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ribosome engagement not yet defined\", \"Direct vs indirect effect on eIF2alpha kinase activity unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the p48/p42 isoform dichotomy and the S360-phosphorylation/Akt axis as the molecular switch between EBP1's anti-apoptotic and differentiation functions.\",\n      \"evidence\": \"Subcellular fractionation, cell-free apoptotic assays, site-directed mutagenesis (S360A/D), and isoform-specific binding assays\",\n      \"pmids\": [\"16832058\", \"16642037\", \"17316401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How isoform abundance is regulated in tissues not addressed\", \"Kinase-independent Akt mechanism mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Provided the structural foundation by solving murine and human EBP1 crystal structures, defining a catalytically dead MetAP-like fold whose C-terminal extension carries the RNA/protein-binding determinants.\",\n      \"evidence\": \"X-ray crystallography of murine and human EBP1 with RNA-binding and IRES translation assays\",\n      \"pmids\": [\"17690690\", \"17765895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure did not capture ribosome- or partner-bound conformations\", \"No catalytic activity, leaving the fold's enzymatic legacy unexplained\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Connected EBP1 to ribosome biogenesis and antiviral functions, showing B23/nucleophosmin partnership for rRNA synthesis and inhibition of influenza and FMDV polymerase/IRES activities.\",\n      \"evidence\": \"Co-IP/mutagenesis with B23, siRNA ribosome biogenesis assays, in vitro polymerase and IRES translation assays\",\n      \"pmids\": [\"17951246\", \"17295834\", \"17690690\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether antiviral activity is physiologically deployed in infection unclear\", \"Coupling of nucleolar RNP role to cytoplasmic translation not integrated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the post-translational regulatory network controlling EBP1 stability, localization, and repressive output through PAK1 phosphorylation, hBRE1 ubiquitination, and TLS/FUS-mediated SUMOylation.\",\n      \"evidence\": \"In vitro kinase, ubiquitination, and SUMOylation assays with phospho/SUMO-site mutagenesis and reporter assays\",\n      \"pmids\": [\"18283314\", \"19037095\", \"19946338\", \"17786317\", \"11325528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay/hierarchy among modifications not established\", \"In vivo relevance of individual modifications largely untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mechanistically separated the oncogenic and tumor-suppressive activities of the two isoforms through CDK2-mediated p48 S34 phosphorylation versus p42-driven p85-PI3K degradation.\",\n      \"evidence\": \"Co-IP, in vitro kinase assays, domain mapping, PI3K lipid kinase and ubiquitination assays with proliferation/xenograft readouts\",\n      \"pmids\": [\"25154617\", \"24651434\", \"21098709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What dictates p48 vs p42 production in a given tumor unresolved\", \"Whether p85 degradation and p53/HDM2 effects co-occur in the same cells unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended isoform-specific function to ubiquitin-ligase regulation, showing p48 sequesters FBXW7\\u03b1 while p42 acts as an FBXW7 adapter, and that p48 stabilizes oncogenic MYCN in a feedback loop.\",\n      \"evidence\": \"Domain-mapped Co-IP, ubiquitination assays, surface plasmon resonance, ChIP, and in vivo tumor models\",\n      \"pmids\": [\"28209614\", \"31501192\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FBXW7 adapter/sequestration model rests on a single lab\", \"Generality of MYCN stabilization beyond neuroblastoma untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved EBP1's principal molecular role at near-atomic resolution as a 60S peptide-exit-tunnel factor that shapes ribosome occupancy and the synthesis of membrane-targeted proteins during neurodevelopment.\",\n      \"evidence\": \"Cryo-EM of EBP1\\u201380S ribosome, ribosome profiling, pSILAC/BONCAT proteomics, and loss-of-function\",\n      \"pmids\": [\"33357414\", \"33479117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How exit-tunnel occupancy integrates with its nucleolar/transcriptional roles unclear\", \"Selectivity for specific nascent chains incompletely defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined EBP1's essential neurodevelopmental functions and disease relevance, linking its loss to FBXW7/PTF1A and DNMT1/HDAC1 dysregulation, cerebellar defects, and schizophrenia-like behavior rescuable by wild-type but not a patient mutant.\",\n      \"evidence\": \"Conditional and heterozygous KO mice, ChIP, methylation analysis, and rescue with WT vs EBP1-E183Ter mutant\",\n      \"pmids\": [\"35165395\", \"31748268\", \"32283721\", \"37712850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal human genetic link to schizophrenia rests on mouse rescue with a patient-derived mutant\", \"Cell-type-specific contributions of translational vs transcriptional roles not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EBP1's distinct molecular roles\\u2014ribosome exit-tunnel occupancy, nucleolar rRNA synthesis, transcriptional corepression, and ubiquitin-ligase modulation\\u2014are coordinated within a single cell, and how isoform choice and PTM combinations are decoded, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating translational and transcriptional functions\", \"Regulation of p48/p42 ratio and PTM hierarchy in physiological settings unknown\", \"Direct human disease-causing mutations not established beyond mouse-validated candidates\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [8, 11, 12, 38]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5, 29, 42]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 6, 29, 30]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [31, 32]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [25]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 22, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [4, 15, 25]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 4, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 9, 17]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [8, 31, 32]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 6, 29, 30]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 8, 15, 28]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [31, 32]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [29, 43]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [34]}\n    ],\n    \"complexes\": [\n      \"Sin3A-HDAC2 corepressor complex\",\n      \"pre-ribosomal RNP / 60S ribosome (peptide exit tunnel)\",\n      \"ZFP809-TRIM28 retroviral silencing complex\"\n    ],\n    \"partners\": [\n      \"ERBB3\",\n      \"RB1\",\n      \"AR\",\n      \"SIN3A\",\n      \"HDAC2\",\n      \"NPM1\",\n      \"MYCN\",\n      \"HNF4A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}