{"gene":"PA2G4","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2000,"finding":"Ebp1 (PA2G4) interacts with the juxtamembrane domain of ErbB-3, with the first 15 amino acids of the juxtamembrane domain essential for binding in vitro; heregulin treatment 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, subcellular fractionation/immunofluorescence","journal":"British journal of cancer","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and in vitro binding with domain mapping, replicated across labs","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 binding to Rb; Ebp1 inhibits E2F1-regulated cyclin-E promoter activity and binds E2F1 indirectly via Rb.","method":"Co-immunoprecipitation, GST pulldown, reporter gene assay, confocal immunofluorescence","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro GST pulldown with domain mapping plus in vivo Co-IP and functional reporter assay","pmids":["11268000"],"is_preprint":false},{"year":2003,"finding":"Ebp1 represses E2F-regulated transcription via its C-terminal domain, which binds HDAC activity; Ebp1 binds HDAC2 (but not HDAC1) in vitro; HDAC inhibitors reduce Ebp1-mediated repression; an Ebp1 mutant lacking the HDAC-binding domain fails to repress transcription.","method":"Reporter gene assay, GST pulldown, HDAC activity assay, co-immunoprecipitation, mutagenesis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro binding with domain mutagenesis plus functional assays with inhibitors and deletion mutants","pmids":["12682367"],"is_preprint":false},{"year":2002,"finding":"Ebp1 binds the androgen receptor (AR) in vitro and in vivo; binding is increased by androgen treatment; the C-terminal 79 amino acids of Ebp1 are sufficient to bind AR via its N-terminal domain; Ebp1 inhibits ligand-mediated AR transcriptional activation; an LXXLL motif in Ebp1 is required for this inhibition.","method":"Co-immunoprecipitation, GST pulldown, transient transfection reporter assay, mutagenesis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal Co-IP, in vitro binding with domain mapping, functional reporter assays with mutants","pmids":["12165860"],"is_preprint":false},{"year":2004,"finding":"Ebp1 is localized to the cytoplasm and nucleolus; nucleolar localization requires sequences at both N- and C-termini; Ebp1 overexpression inhibits proliferation linked to its nucleolar localization; Ebp1 is part of ribonucleoprotein complexes and associates with different rRNA species.","method":"Confocal immunofluorescence, subcellular fractionation, mass spectrometry, cell proliferation assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (localization, MS interactome, functional KO) in single study","pmids":["15064750"],"is_preprint":false},{"year":2004,"finding":"Heregulin regulates the association of Ebp1 with E2F1 promoter elements; Ebp1 binds E2F consensus sequences in nuclear lysates together with E2F1, Rb, and HDAC2; chromatin immunoprecipitation shows Ebp1 is recruited to the E2F1 promoter in vivo; HRG enhances Ebp1-mediated transcriptional repression.","method":"DNA affinity pulldown, chromatin immunoprecipitation (ChIP), reporter gene assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — ChIP plus in vitro DNA binding and functional reporter, moderate evidence","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 binds Sin3A (via PAD4/HDAC-interacting domain of Sin3A); Ebp1 and Sin3A associate at PSA and E2F1 promoters in vivo; Sin3A enhances Ebp1-mediated repression of AR- and E2F1-regulated genes.","method":"GST pulldown, co-immunoprecipitation, ChIP, DNA affinity precipitation, reporter gene assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted direct binding (recombinant Sin3A + Ebp1), reciprocal Co-IP, ChIP, functional assays","pmids":["16254079"],"is_preprint":false},{"year":2005,"finding":"Ebp1 overexpression down-regulates AR and AR-regulated genes (including PSA); Ebp1 is recruited to the PSA promoter in response to the androgen antagonist bicalutamide as shown by ChIP; androgens fail to stimulate growth of ebp1 transfectants.","method":"Chromatin immunoprecipitation, microarray, reporter gene assay, in vivo xenograft","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — ChIP with multiple functional assays and in vivo validation","pmids":["15994225"],"is_preprint":false},{"year":2006,"finding":"Nuclear Akt interacts with PKC-phosphorylated Ebp1 (at S360) to prevent DNA fragmentation by caspase-activated DNase (CAD); phospho-mimetic S360D mutant strongly binds nuclear Akt and suppresses apoptosis, while S360A mutant barely binds Akt or inhibits DNA fragmentation; nuclear (not cytoplasmic) Akt enhances Ebp1 antiapoptotic action independent of Akt kinase activity.","method":"Cell-free apoptotic assay, nuclear extract purification, Co-IP, site-directed mutagenesis, siRNA knockdown, overexpression","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical reconstitution with mutagenesis, multiple orthogonal methods","pmids":["16642037"],"is_preprint":false},{"year":2006,"finding":"Ebp1 has two isoforms, p48 and p42: p48 localizes to both cytoplasm and nucleus and suppresses apoptosis; p42 predominantly resides in cytoplasm and promotes differentiation; EGF stimulates p42 to bind ErbB3 in a PKC-phosphorylation-dependent manner; p48 does not bind ErbB3 regardless of EGF; p48 promotes cell proliferation while p42 inhibits it.","method":"Subcellular fractionation, co-immunoprecipitation, overexpression, siRNA knockdown, flow cytometry","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods distinguishing isoform-specific functions, replicated in multiple cell types","pmids":["16832058"],"is_preprint":false},{"year":2006,"finding":"Ebp1 contains a dsRNA-binding domain (dsRBD); this domain mediates interaction with dsRNA, is required for nucleolar localization, and for forming RNP complexes; in the cytoplasm, Ebp1 associates with mature ribosomes; Ebp1 inhibits phosphorylation of eIF2α at S51 and interacts with and is phosphorylated by PKR kinase.","method":"dsRNA-binding assay, co-immunoprecipitation, sucrose gradient fractionation, in vitro kinase assay, deletion mutagenesis, immunofluorescence","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro binding assay with domain mapping, in vitro kinase assay, ribosome fractionation","pmids":["16631606"],"is_preprint":false},{"year":2006,"finding":"Ebp1 is identified as a component of cytoplasmic bcl-2 mRNP complexes; recombinant Ebp1 binds bcl-2 ARE RNA but not GM-CSF ARE in vitro; Ebp1 co-precipitates with nucleolin from HL-60 cytoplasmic extracts in an RNA-dependent manner; Ebp1 decreases the rate of decay of bcl-2 ARE-containing transcripts in cell extracts.","method":"RNA affinity chromatography, MALDI-MS, EMSA, RNA co-immunoprecipitation, RNA decay assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical methods including reconstituted RNA-binding and mRNA stability assay","pmids":["16396631"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of murine Ebp1 (p48) reveals a core domain homologous to methionine aminopeptidases (pita bread fold), coupled to a C-terminal extension; the primary RNA-binding site is formed by a Lys-rich motif in the C-terminus mediating FMDV IRES interaction; the structure explains conformational differences between p42 and p48 isoforms and disposition of the LKALL protein-interacting motif.","method":"X-ray crystallography, mutagenesis, IRES translation assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis and functional validation in single study","pmids":["17690690"],"is_preprint":false},{"year":2007,"finding":"Human Ebp1 crystal structure at 1.6 Å resolution reveals a conserved pita bread fold homologous to methionine aminopeptidases but without catalytic activity; the structure reveals how Ebp1 may discriminate between protein and RNA interaction partners.","method":"X-ray crystallography","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure","pmids":["17765895"],"is_preprint":false},{"year":2007,"finding":"Ebp1 specifically interacts with the PB1 subunit of influenza virus RNA polymerase at PB1's transcription primer binding site; Ebp1 inhibits in vitro RNA synthesis by the influenza virus RNA polymerase complex but not capped RNA endonuclease or RNA-cap binding activities; overexpression of Ebp1 interferes with influenza virus production.","method":"Yeast two-hybrid, in vitro Co-IP, in vitro RNA synthesis assay, overexpression","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro enzymatic assay plus Co-IP and in vivo overexpression","pmids":["17295834"],"is_preprint":false},{"year":2007,"finding":"Ebp1 forms a complex with nucleophosmin/B23; p48 constitutively binds B23 in the nucleolus requiring B23 K263 sumoylation; p42 selectively binds unsumoylated B23 upon EGF stimulation, dependent on Ser360 phosphorylation; knockdown of B23 or Ebp1 substantially decreases ribosome biogenesis and cell survival.","method":"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, ribosome biogenesis assay, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with mutagenesis defining interaction requirements and functional knockdown","pmids":["17951246"],"is_preprint":false},{"year":2007,"finding":"Protein kinase C-delta phosphorylates Ebp1 at S360, protecting it from caspase-3 cleavage at D196 and D53 sites; PKCδ-deficient cells show robust Ebp1 cleavage; S360 phosphorylation suppresses caspase-3-mediated degradation; D196A mutant markedly protects cells from apoptosis.","method":"In vitro kinase assay, cell-free apoptotic assay, site-directed mutagenesis, PKCδ knockout cells","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase assay with mutagenesis plus genetic KO cells","pmids":["17316401"],"is_preprint":false},{"year":2008,"finding":"Human Bre1 acts as an E3 ubiquitin ligase for Ebp1, promoting its polyubiquitination and proteasomal degradation; Ebp1 polyubiquitination is regulated by its phosphorylation; depletion of hBre1 blocks Ebp1 polyubiquitination and elevates Ebp1 protein level; hBre1 suppresses Ebp1's repressive effect on E2F-1.","method":"In vitro ubiquitination assay, co-immunoprecipitation, siRNA knockdown, Western blot","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro ubiquitination reconstitution plus Co-IP and functional assays","pmids":["19037095"],"is_preprint":false},{"year":2009,"finding":"Ebp1 p42 isoform is sumoylated on K93 and K298, which mediate its nuclear translocation and are required for anti-proliferative activity; TLS/FUS acts as a SUMO1 E3 ligase for Ebp1 p42; Ebp1 directly binds TLS/FUS; genotoxic stress-triggered phosphorylation of Ebp1 regulates this interaction; unsumoylated Ebp1 mutants fail to suppress E2F-1 transcription.","method":"Co-immunoprecipitation, in vitro sumoylation assay, site-directed mutagenesis, siRNA knockdown, reporter gene assay, subcellular fractionation","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro sumoylation assay with mutagenesis, reciprocal Co-IP, functional reporter assays","pmids":["19946338"],"is_preprint":false},{"year":2010,"finding":"p48 isoform of Ebp1 binds HDM2 (MDM2), enhancing HDM2-p53 association and promoting p53 polyubiquitination and degradation, thereby reducing steady-state p53 levels and activity in glioblastoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, Western blot, overexpression/knockdown","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with ubiquitination assay and functional p53 level measurement","pmids":["21098709"],"is_preprint":false},{"year":2001,"finding":"PKC phosphorylates Ebp1 on serine/threonine residues in vitro; basal Ebp1 phosphorylation in vivo is PKC-dependent; heregulin-induced phosphorylation is predominantly PKC-independent; PKC inhibition abrogates Ebp1 association with ErbB3.","method":"In vitro kinase assay, metabolic labeling/phosphorylation analysis, PKC inhibitor treatment, co-immunoprecipitation","journal":"Molecular and cellular endocrinology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase assay plus pharmacological inhibitor with functional Co-IP readout","pmids":["11325528"],"is_preprint":false},{"year":2007,"finding":"Ebp1 serine 363 is phosphorylated in vivo; phospho-S363 Ebp1 localizes exclusively to the nucleus; S363A mutation decreases transcriptional repression and abrogates cell growth inhibition; S363A mutant fails to bind HDAC2 and mSin3a despite associating with E2F1 promoter elements.","method":"Phospho-specific antibody, immunofluorescence, reporter gene assay, co-immunoprecipitation, ChIP","journal":"International journal of oncology","confidence":"High","confidence_rationale":"Tier 2 — phospho-specific detection with mutagenesis and multiple functional readouts","pmids":["17786317"],"is_preprint":false},{"year":2008,"finding":"PAK1 phosphorylates Ebp1 in vitro at threonine 261; HRG treatment and constitutively active PAK1 enhance threonine phosphorylation of Ebp1 in MCF-7 cells; endogenous Ebp1 binds PAK1 and association is enhanced by HRG; a phospho-mimetic T261E mutation abolishes Ebp1's ability to repress transcription, inhibit growth, and contribute to tamoxifen sensitivity.","method":"In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis, reporter gene assay, cell growth assay","journal":"British journal of cancer","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase assay with phosphosite mapping and mutagenesis, functional validation","pmids":["18283314"],"is_preprint":false},{"year":2014,"finding":"p42 Ebp1 interacts with the cSH2 domain of p85 (PI3K regulatory subunit), leading to inhibition of PI3K lipid kinase activity; p42 induces proteasomal degradation of p85 by recruiting the HSP70/CHIP E3 ligase complex, which ubiquitinates p85.","method":"Co-immunoprecipitation, in vitro PI3K activity assay, ubiquitination assay, Western blot, in vivo xenograft","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase activity assay, ubiquitination assay with complex identification, in vivo validation","pmids":["24651434"],"is_preprint":false},{"year":2014,"finding":"p48 Ebp1 interacts with CDK2 through its N-terminal domain; CDK2 specifically phosphorylates p48 at serine 34 (not p42); phospho-ablated S34A mutant antagonizes cell proliferation and transformation; CDK2-mediated S34 phosphorylation is required for p48's oncogenic function.","method":"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, cell proliferation assay, mouse xenograft","journal":"Molecular carcinogenesis","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase assay with domain mapping and mutagenesis, in vivo validation","pmids":["25154617"],"is_preprint":false},{"year":2015,"finding":"TIF-IA (a GTP-binding protein that recruits RNA Pol I to ribosomal DNA promoter) binds EBP1; together they enhance transcription of PCNA; GTP binding by TIF-IA and PKCδ-mediated EBP1 phosphorylation are both required for optimal PCNA expression and ribosomal RNA synthesis in T cells.","method":"Co-immunoprecipitation, reporter gene assay, kinase assay, pharmacological inhibition","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with functional assays but single lab","pmids":["25691158"],"is_preprint":false},{"year":2016,"finding":"EBP1 binds directly to multiple polyphosphoinositides (PPIns) via two lysine-rich motifs at N- and C-termini; the C-terminal PPIn-binding motif is the major contributor to nucleolar localization; a K372N mutation (found in endometrial tumors) within the C-terminal motif alters nucleolar targeting; EBP1 associates with PtdIns(3,4,5)P3 in the nucleolus via electrostatic and hydrophobic interactions as shown by NMR.","method":"Lipid pulldown, mutagenesis, immunofluorescence, NMR","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — NMR structural data plus mutagenesis and cell-based localization, multiple methods","pmids":["27118868"],"is_preprint":false},{"year":2017,"finding":"EBP1 P48 binds to the WD domain of FBXW7 as an oncogenic substrate and sequesters FBXW7α to the cytosol; EBP1 P42 binds to both the F-box domain of FBXW7 and FBXW7 substrates, acting as an adapter to promote FBXW7-mediated degradation of oncogenic targets.","method":"Co-immunoprecipitation, subcellular fractionation, ubiquitination assay, domain mapping","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with domain-specific binding analysis and functional ubiquitination assay","pmids":["28209614"],"is_preprint":false},{"year":2019,"finding":"MYCN directly occupies the PA2G4 gene promoter stimulating its transcription; PA2G4 directly binds MYCN protein protecting it from proteolysis; the MYCN-PA2G4 interaction site was mapped to a 14 amino acid MYCN sequence and a surface crevice of PA2G4; competitive chemical inhibition of this interface reduces MYCN and PA2G4 levels and inhibits neuroblastoma tumorigenesis in vivo.","method":"ChIP, surface plasmon resonance, mutagenesis, molecular modeling, in vivo tumor model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 — biophysical binding (SPR) with mutagenesis, ChIP, and in vivo validation","pmids":["31501192"],"is_preprint":false},{"year":2019,"finding":"circERBB2 regulates nucleolar localization of PA2G4, forming a circERBB2-PA2G4-TIFIA regulatory axis to modulate ribosomal DNA transcription and cancer cell proliferation.","method":"RNA pulldown, RNA immunoprecipitation, FISH, knockdown, in vivo xenograft","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 — RNA-protein interaction assays with functional knockdown, single lab","pmids":["31752867"],"is_preprint":false},{"year":2019,"finding":"EBP1 directly interacts with Suv39H1 and recruits the E3 ligase MDM2, promoting ubiquitin-proteasome-dependent degradation of Suv39H1 to regulate heterochromatin assembly during neural development; EBP1 also binds to the DNMT1 promoter, repressing DNA methylation.","method":"Co-immunoprecipitation, ChIP, ubiquitination assay, Western blot, KO mouse model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — Co-IP identifying ternary complex, ubiquitination assay, ChIP, in vivo genetic model","pmids":["31748268"],"is_preprint":false},{"year":2019,"finding":"EBP1 binds HNF4α in a LXXLL motif-mediated manner; EBP1 suppresses expression of HNF4α target genes involved in insulin secretion; crystal structure of HNF4α ligand-binding domain in complex with EBP1 LXXLL peptide at 3.15 Å shows EBP1's LXXLL motif competes with HNF4α coactivators for the same binding pocket.","method":"Yeast two-hybrid, mammalian two-hybrid, GST pulldown, X-ray crystallography, reporter gene assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus biochemical binding assays and functional gene expression readout","pmids":["31362984"],"is_preprint":false},{"year":2019,"finding":"Ebp1 p48 interacts with TIF-90 (a splice variant of TIF-IA) to regulate ribosomal RNA synthesis; Ebp1 promotes Akt-mediated protection of TIF-90 stability by preventing TIF-90 ubiquitination by Mdm2 and its proteasomal degradation.","method":"Co-immunoprecipitation, ubiquitination assay, rRNA synthesis assay, knockdown/overexpression","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with ubiquitination assay, single lab","pmids":["30793766"],"is_preprint":false},{"year":2020,"finding":"Cryo-EM structure of human Ebp1 (p48) bound to the human 80S ribosome at 3.3 Å reveals Ebp1 binds in the vicinity of the peptide exit tunnel, interacting with ribosomal proteins eL19 and uL23 and 28S rRNA; Ebp1-80S binding is enhanced upon puromycin-mediated translational inhibition; Ebp1 can rotate around its insert domain; membrane-targeting domains emerging from the 60S tunnel displace Ebp1.","method":"Cryo-EM, ribosome profiling, pSILAC/BONCAT mass spectrometry","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — near-atomic resolution cryo-EM structure with ribosome profiling and MS validation","pmids":["33357414"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structure of human Ebp1 (p48 isoform) bound to the human 80S ribosome at 3.3 Å: Ebp1 binds near the peptide exit tunnel via interactions with eL19, uL23, and 28S rRNA; binding is enhanced by puromycin-induced translational arrest; Ebp1 can rotate around its insert domain providing conformational flexibility at the ribosome.","method":"Cryo-EM, sucrose gradient ribosome fractionation","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 — independent cryo-EM structural study confirming ribosome interaction site","pmids":["33479117"],"is_preprint":false},{"year":2021,"finding":"EBP1 promotes UPS-dependent degradation of Suv39H1 by directly interacting with it and recruiting E3 ligase MDM2; this mechanism governs heterochromatin assembly and neural development.","method":"Co-immunoprecipitation, ubiquitination assay, Western blot","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and ubiquitination assay, single lab, replicates prior finding from same group","pmids":["33691908"],"is_preprint":false},{"year":2023,"finding":"PA2G4/EBP1 is ubiquitinated at lysine 376 by PRKN/PARKIN on damaged mitochondria; ubiquitinated PA2G4 interacts with the mitophagy receptor SQSTM1/p62 to induce mitophagy, promoting neuroprotection during cerebral ischemia-reperfusion injury; neuron-specific Ebp1 KO increases infarct volume and impairs mitophagy.","method":"Co-immunoprecipitation, ubiquitination mapping, neuron-specific KO mouse, AAV rescue, mitophagy assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — site-specific ubiquitination mapping, Co-IP, genetic KO with phenotypic rescue","pmids":["37712850"],"is_preprint":false},{"year":2022,"finding":"PA2G4 promotes HCC metastasis by stabilizing FYN mRNA through interaction with the m6A reader YTHDF2; FYN mRNA is m6A-modified and bound by both PA2G4 and YTHDF2; YTHDF2's m6A catalytic activity is indispensable for PA2G4-mediated regulation of FYN.","method":"Co-immunoprecipitation, RIP, MeRIP, RNA half-life assay, dual luciferase reporter, in vivo lung metastasis model","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple RNA-protein interaction methods, single lab","pmids":["35526051"],"is_preprint":false},{"year":2025,"finding":"PA2G4 binds the NF110-NF45 heterodimer and prevents NF110 degradation; CRAPIR (a PIWI-interacting RNA) competes with NF110 for binding to PA2G4, thereby preventing PA2G4-NF110 interaction, reducing NF110 degradation, and promoting cardiomyocyte proliferation and heart regeneration.","method":"Co-immunoprecipitation, RNA pulldown, CRISPR knockout, antagomir knockdown, AAV overexpression, in vivo cardiac injury model","journal":"Nature cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP defining ternary complex, RNA pulldown, in vivo genetic models with phenotypic rescue","pmids":["39814981"],"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 of Moloney murine leukemia virus in embryonic cells.","method":"Co-immunoprecipitation (complex identification), siRNA knockdown, retroviral reporter assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP identifying complex component plus functional knockdown, single lab","pmids":["24227866"],"is_preprint":false},{"year":2016,"finding":"Pa2G4 (EBP1) binds to Six1 in human embryonic kidney cells and interferes with the Six1-Eya1 complex; in Xenopus, knockdown of Pa2G4 downregulates neural border zone, neural crest and cranial placode genes while expanding neural plate genes, demonstrating a role in neural crest and otic development.","method":"Co-immunoprecipitation (mammalian cells), morpholino knockdown in Xenopus, in situ hybridization","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with in vivo loss-of-function phenotype, single lab","pmids":["27940157"],"is_preprint":false},{"year":2018,"finding":"DPPA4 preferentially binds EBP1 p48 isoform in pluripotent cells via DPPA4's SAP domain; DPPA4 transcriptional repressive function is increased by p48 knockdown; this effect is abolished with an interaction-deficient DPPA4 ΔSAP mutant.","method":"Proteomics screen, co-immunoprecipitation, siRNA knockdown, reporter gene assay, mutagenesis","journal":"Stem cells (Dayton, Ohio)","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with domain mapping and functional reporter, single lab","pmids":["29327467"],"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 in neurons; introduction of p48 Ebp1 promotes axon regeneration in injured hippocampal slices.","method":"Co-immunoprecipitation, immunofluorescence, ex vivo axon regeneration assay","journal":"BMB reports","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP with localization and ex vivo functional assay, single lab, limited mechanistic detail","pmids":["27916024"],"is_preprint":false},{"year":2011,"finding":"EBP1 inhibits translation of androgen receptor mRNA in castration-resistant prostate cancer cells without altering AR mRNA steady-state levels or stability; heregulin further diminishes AR translation in EBP1-transfected cells.","method":"Polysome fractionation, Western blot, quantitative PCR, mRNA stability assay","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 2 — polysome profiling distinguishing translational from transcriptional regulation, single lab","pmids":["21965718"],"is_preprint":false},{"year":2012,"finding":"EBP1 decreases ErbB2 mRNA primarily through a transcriptional mechanism; EBP1 binds both distal and proximal endogenous ErbB2 promoters in vivo; Sin3A-interaction mutants of EBP1 have reduced ability to decrease ErbB2 promoter activity; EBP1 overexpression or ablation does not alter ErbB2 mRNA stability.","method":"ChIP, reporter gene assay, mRNA stability assay, site-directed mutagenesis, shRNA knockdown","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP with multiple controls, distinguishes transcriptional vs. post-transcriptional mechanism","pmids":["23242156"],"is_preprint":false}],"current_model":"PA2G4/EBP1 is a multifunctional DNA/RNA-binding protein with a methionine aminopeptidase-like (pita-bread) fold that operates as a context-dependent regulator of transcription and translation: it binds ErbB3 at the juxtamembrane domain (dissociating upon heregulin/PKC phosphorylation) and translocates to the nucleus, where the p48 isoform recruits HDAC2 and Sin3A to repress E2F1- and androgen receptor-regulated promoters via its C-terminal domain; it also binds Rb, HDM2/p53, and nuclear Akt (requiring PKCδ-mediated S360 phosphorylation) to modulate cell survival; the p42 isoform undergoes TLS/FUS-mediated sumoylation at K93/K298 to facilitate nuclear translocation and transcriptional repression, and promotes proteasomal degradation of the PI3K p85 subunit by recruiting HSP70/CHIP; in the cytoplasm, both isoforms associate with the 60S ribosome exit tunnel (contacting eL19, uL23, and 28S rRNA) to regulate translation, inhibit eIF2α phosphorylation, and stabilize bcl-2 mRNA; p48 additionally interacts with MYCN to protect it from proteolysis, while ubiquitination of PA2G4 at K376 by PARKIN recruits SQSTM1/p62 to trigger mitophagy for neuroprotection."},"narrative":{"teleology":[{"year":2000,"claim":"Identifying EBP1 as an ErbB3-interacting protein established it as a signaling-responsive factor: heregulin dissociates EBP1 from ErbB3 and triggers its nuclear translocation, linking receptor tyrosine kinase signaling to nuclear function.","evidence":"Yeast two-hybrid, Co-IP, in vitro binding with domain mapping, subcellular fractionation in breast cancer cells","pmids":["10682683"],"confidence":"High","gaps":["Direct structural basis of ErbB3–EBP1 interaction unresolved","Downstream nuclear targets upon translocation unknown at this stage"]},{"year":2001,"claim":"Demonstrating that EBP1 binds Rb and represses E2F1-regulated cyclin E promoter activity established a nuclear transcriptional repressor function, while PKC-dependent phosphorylation was shown to regulate ErbB3 association, revealing the first post-translational control mechanism.","evidence":"Co-IP, GST pulldown with domain mapping, reporter assays (Rb binding); in vitro kinase assay with PKC inhibitors (phosphorylation)","pmids":["11268000","11325528"],"confidence":"High","gaps":["Identity of recruited chromatin-modifying complexes not yet known","Phosphorylation sites on EBP1 not yet mapped"]},{"year":2003,"claim":"Showing that EBP1 recruits HDAC2 (but not HDAC1) through its C-terminal domain to mediate transcriptional repression resolved how EBP1 silences E2F targets at the chromatin level.","evidence":"GST pulldown, HDAC activity assay, HDAC inhibitor treatment, deletion mutagenesis, reporter assays","pmids":["12682367"],"confidence":"High","gaps":["Whether HDAC2 recruitment is sufficient or requires additional corepressors not addressed"]},{"year":2002,"claim":"Identification of EBP1 as an androgen receptor corepressor via an LXXLL motif extended its transcriptional repressor function beyond E2F to nuclear hormone receptor signaling.","evidence":"Co-IP, GST pulldown with domain mapping, reporter assays with LXXLL mutagenesis in prostate cancer cells","pmids":["12165860"],"confidence":"High","gaps":["Whether AR repression involves HDAC recruitment not yet tested"]},{"year":2004,"claim":"Establishing that EBP1 localizes to the nucleolus, associates with rRNP complexes, and inhibits proliferation linked this protein to ribosome biogenesis and demonstrated that nucleolar targeting requires both N- and C-terminal sequences.","evidence":"Confocal immunofluorescence, mass spectrometry, subcellular fractionation, proliferation assays","pmids":["15064750"],"confidence":"High","gaps":["Specific rRNA processing steps regulated by EBP1 not identified"]},{"year":2005,"claim":"ChIP showing EBP1 occupancy at the E2F1 promoter together with Rb and HDAC2, and identification of Sin3A as a direct EBP1-binding corepressor, completed the model of a ternary repressive complex at E2F- and AR-regulated genes.","evidence":"ChIP, DNA affinity pulldown, GST pulldown with domain mapping for Sin3A, reporter assays","pmids":["15073182","16254079","15994225"],"confidence":"High","gaps":["Genome-wide target spectrum of this repressive complex not defined"]},{"year":2006,"claim":"Discovery of two functionally distinct isoforms (p48 and p42), PKCδ-mediated S360 phosphorylation protecting EBP1 from caspase-3 cleavage, nuclear Akt interaction, dsRNA binding mediating ribosome association and eIF2α regulation, and bcl-2 mRNA stabilization collectively revealed EBP1 as a multifunctional regulator of translation, survival, and differentiation.","evidence":"Multiple orthogonal methods across four studies: subcellular fractionation, Co-IP, in vitro kinase assays, mutagenesis, dsRNA binding assays, ribosome fractionation, RNA affinity chromatography, mRNA decay assays","pmids":["16832058","16642037","17316401","16631606","16396631"],"confidence":"High","gaps":["Structural basis for isoform-specific localization and partner selection unknown","Precise mechanism of eIF2α phosphorylation inhibition not resolved"]},{"year":2007,"claim":"Crystal structures of murine and human EBP1 revealed a catalytically inactive methionine aminopeptidase fold with a C-terminal RNA-binding extension, while functional studies identified nucleophosmin/B23 interaction required for ribosome biogenesis and S363 phosphorylation controlling HDAC2/Sin3A recruitment.","evidence":"X-ray crystallography (1.6–2.0 Å), mutagenesis, IRES translation assay, Co-IP with B23, ribosome biogenesis assay, phospho-specific antibodies, ChIP","pmids":["17690690","17765895","17951246","17786317"],"confidence":"High","gaps":["No co-crystal with RNA or protein partners at this time","How B23 sumoylation state toggles isoform-specific binding not structurally resolved"]},{"year":2008,"claim":"Identification of PAK1-mediated T261 phosphorylation as a switch that inactivates EBP1 transcriptional repression, and hBre1 as an E3 ligase promoting EBP1 proteasomal degradation, established kinase and ubiquitin-mediated layers of EBP1 regulation.","evidence":"In vitro kinase assay with site mapping, Co-IP, reporter assays (PAK1); in vitro ubiquitination reconstitution, siRNA (hBre1)","pmids":["18283314","19037095"],"confidence":"High","gaps":["Whether PAK1 and PKCδ phosphorylation are coordinated is unknown","Full ubiquitin chain topology on EBP1 not defined"]},{"year":2009,"claim":"Demonstrating TLS/FUS-mediated sumoylation of p42 at K93/K298 as required for nuclear translocation and E2F1 repression explained how the cytoplasmic p42 isoform gains nuclear repressor function under genotoxic stress.","evidence":"In vitro sumoylation assay, Co-IP, mutagenesis, reporter assays, subcellular fractionation","pmids":["19946338"],"confidence":"High","gaps":["Desumoylation enzymes acting on EBP1 not identified","Genotoxic stress signals upstream of TLS/FUS not fully mapped"]},{"year":2010,"claim":"Showing that p48 enhances HDM2-mediated p53 polyubiquitination and degradation established EBP1 as a modulator of the p53 tumor suppressor pathway in glioblastoma.","evidence":"Co-IP, ubiquitination assay, p53 protein level measurement in glioblastoma cells","pmids":["21098709"],"confidence":"High","gaps":["Whether this function is isoform-specific to p48 not fully dissected","Physiological triggers for EBP1-HDM2 complex formation unclear"]},{"year":2014,"claim":"Two parallel discoveries showed that p42 promotes PI3K p85 degradation by recruiting HSP70/CHIP, directly inhibiting PI3K signaling, while CDK2 phosphorylates p48 at S34 to enable its oncogenic function—delineating isoform-specific oncogenic versus tumor-suppressive activities.","evidence":"Co-IP, in vitro PI3K activity assay, ubiquitination assay, in vitro kinase assay, mutagenesis, xenograft models","pmids":["24651434","25154617"],"confidence":"High","gaps":["Whether CDK2 phosphorylation of p48 affects ribosome binding unknown","How HSP70/CHIP is specifically recruited by p42 but not p48 not resolved structurally"]},{"year":2016,"claim":"Identification of polyphosphoinositide binding via lysine-rich motifs, with the C-terminal motif governing nucleolar targeting and a cancer-associated K372N mutation disrupting it, established a lipid-signaling input for EBP1 localization.","evidence":"Lipid pulldown, NMR, mutagenesis, immunofluorescence","pmids":["27918868"],"confidence":"High","gaps":["Whether PPIn binding competes with RNA binding at overlapping motifs not tested","Functional consequence of K372N in tumorigenesis not demonstrated in vivo"]},{"year":2017,"claim":"Discovery that p48 and p42 differentially interact with FBXW7 E3 ligase—p48 as an oncogenic substrate sequestering FBXW7α, p42 as an adapter promoting FBXW7-mediated degradation of oncoproteins—provided a unified framework for the opposing roles of the two isoforms.","evidence":"Co-IP, subcellular fractionation, ubiquitination assay, domain mapping","pmids":["28209614"],"confidence":"High","gaps":["Identity of all FBXW7 substrates whose turnover is modulated by p42 not catalogued","In vivo validation in genetic models lacking"]},{"year":2019,"claim":"Multiple 2019 studies revealed new EBP1 functions: direct binding and stabilization of MYCN in neuroblastoma; interaction with HNF4α via the LXXLL motif (co-crystal at 3.15 Å); promotion of Suv39H1 degradation via MDM2 recruitment to regulate heterochromatin in neural development; and regulation of rDNA transcription through a circERBB2–PA2G4–TIFIA axis.","evidence":"SPR and mutagenesis with in vivo tumor models (MYCN); X-ray crystallography and reporter assays (HNF4α); Co-IP, ubiquitination assay, KO mouse (Suv39H1); RNA pulldown and RIP with xenograft (circERBB2)","pmids":["31501192","31362984","31748268","31752867"],"confidence":"High","gaps":["Structural basis of full-length MYCN–PA2G4 complex not determined","Whether Suv39H1 degradation is isoform-specific is unclear","circERBB2 finding from single lab"]},{"year":2020,"claim":"Cryo-EM structures of EBP1 bound to the human 80S ribosome at the peptide exit tunnel resolved how EBP1 contacts eL19, uL23, and 28S rRNA, and showed that translational arrest enhances binding while emerging signal sequences displace it, establishing EBP1 as a ribosome-associated factor sensing translational state.","evidence":"Cryo-EM at 3.3 Å, ribosome profiling, pSILAC/BONCAT mass spectrometry; independently confirmed by a second cryo-EM study","pmids":["33357414","33479117"],"confidence":"High","gaps":["Functional consequence of EBP1 at the exit tunnel on nascent chain folding or targeting not demonstrated","Whether p42 binds ribosomes similarly to p48 not structurally addressed"]},{"year":2023,"claim":"Demonstration that PARKIN ubiquitinates PA2G4 at K376 on damaged mitochondria, enabling SQSTM1/p62 recruitment and mitophagy, with neuron-specific KO increasing ischemic infarct volume, established a neuroprotective mitophagy role for PA2G4.","evidence":"Ubiquitination site mapping, Co-IP, neuron-specific KO mouse, AAV rescue, mitophagy assays","pmids":["37712850"],"confidence":"High","gaps":["Whether mitophagy function is isoform-specific not determined","How PA2G4 is recruited to damaged mitochondria upstream of PARKIN ubiquitination is unclear"]},{"year":2025,"claim":"Identification of PA2G4 as a stabilizer of NF110 (in an NF110-NF45 heterodimer) that is competitively displaced by the piRNA CRAPIR to promote cardiomyocyte proliferation extended PA2G4 function to cardiac regeneration.","evidence":"Reciprocal Co-IP, RNA pulldown, CRISPR KO, AAV overexpression, in vivo cardiac injury model","pmids":["39814981"],"confidence":"High","gaps":["Whether NF110 stabilization depends on EBP1 isoform identity not examined","Mechanism by which NF110 degradation promotes cardiomyocyte cell cycle re-entry not fully resolved"]},{"year":null,"claim":"Key unresolved questions include: how PA2G4 toggles between ribosomal, nuclear transcriptional, and mitochondrial functions in the same cell; what determines isoform-specific partner selection at the structural level; and whether EBP1's exit-tunnel binding directly regulates nascent polypeptide fate.","evidence":"","pmids":[],"confidence":"Low","gaps":["No integrative model of isoform-specific subcellular trafficking","No co-structure of EBP1 with full-length nuclear partners (AR, Rb, MYCN)","Genome-wide or translatome-wide target specificity not comprehensively profiled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[10,11,12,26,29,37]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,3,5,6,7,31,44]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[19,23,27,28,38]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[26]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[30]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[23,27]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[4,15,26,29]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5,8,9,18,21]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9,10,33]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[10,33,34]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[36]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,3,5,6,7,31,44]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[30,35]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8,9,20,23]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[8,16,19]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[36]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[10,33,34]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,24]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[30,40]}],"complexes":["EBP1-Sin3A-HDAC2 corepressor complex","80S ribosome (exit tunnel-associated)","ZFP809-TRIM28 retroviral silencing complex"],"partners":["ERBB3","RB1","HDAC2","SIN3A","AKT1","MYCN","MDM2","NPM1"],"other_free_text":[]},"mechanistic_narrative":"PA2G4 (EBP1) is a multifunctional RNA- and DNA-binding protein with a catalytically inactive methionine aminopeptidase (pita-bread) fold that acts as a context-dependent regulator of transcription, translation, ribosome biogenesis, and mitophagy. In the nucleus, the p48 isoform recruits HDAC2 and the corepressor Sin3A via its C-terminal domain to repress E2F1- and androgen receptor-regulated promoters, while the p42 isoform undergoes TLS/FUS-mediated sumoylation at K93/K298 for nuclear translocation and additionally promotes proteasomal degradation of the PI3K p85 subunit through recruitment of the HSP70/CHIP E3 ligase [PMID:12682367, PMID:16254079, PMID:19946338, PMID:24651434]. In the cytoplasm, PA2G4 binds the 60S ribosomal subunit at the peptide exit tunnel—contacting eL19, uL23, and 28S rRNA—to regulate co-translational events, inhibits eIF2α phosphorylation via its dsRNA-binding domain, and stabilizes bcl-2 mRNA [PMID:33357414, PMID:16631606, PMID:16396631]. PA2G4 also participates in cell survival signaling through PKCδ-dependent S360 phosphorylation enabling nuclear Akt interaction, protects MYCN from proteolysis in neuroblastoma, and is ubiquitinated at K376 by PARKIN on damaged mitochondria to recruit SQSTM1/p62 and trigger neuroprotective mitophagy [PMID:16642037, PMID:31501192, PMID:37712850]."},"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 Essential","n_dependent_lines":591,"n_total_lines":1208,"dependency_fraction":0.48923841059602646},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RPL4","stoichiometry":4.0},{"gene":"ARHGAP35","stoichiometry":0.2},{"gene":"CAPRIN1","stoichiometry":0.2},{"gene":"CTCF","stoichiometry":0.2},{"gene":"EIF2S3","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2},{"gene":"RBM42","stoichiometry":0.2},{"gene":"RBM8A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PA2G4","total_profiled":1310},"omim":[{"mim_id":"617048","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 21; DNAJC21","url":"https://www.omim.org/entry/617048"},{"mim_id":"602145","title":"PROLIFERATION-ASSOCIATED 2G4, 38-KD; 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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2000,\n      \"finding\": \"Ebp1 (PA2G4) interacts with the juxtamembrane domain of ErbB-3, with the first 15 amino acids of the juxtamembrane domain essential for binding in vitro; heregulin treatment 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, subcellular fractionation/immunofluorescence\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and in vitro binding with domain mapping, replicated across labs\",\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 binding to Rb; Ebp1 inhibits E2F1-regulated cyclin-E promoter activity and binds E2F1 indirectly via Rb.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, reporter gene assay, confocal immunofluorescence\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro GST pulldown with domain mapping plus in vivo Co-IP and functional reporter assay\",\n      \"pmids\": [\"11268000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Ebp1 represses E2F-regulated transcription via its C-terminal domain, which binds HDAC activity; Ebp1 binds HDAC2 (but not HDAC1) in vitro; HDAC inhibitors reduce Ebp1-mediated repression; an Ebp1 mutant lacking the HDAC-binding domain fails to repress transcription.\",\n      \"method\": \"Reporter gene assay, GST pulldown, HDAC activity assay, co-immunoprecipitation, mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro binding with domain mutagenesis plus functional assays with inhibitors and deletion mutants\",\n      \"pmids\": [\"12682367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Ebp1 binds the androgen receptor (AR) in vitro and in vivo; binding is increased by androgen treatment; the C-terminal 79 amino acids of Ebp1 are sufficient to bind AR via its N-terminal domain; Ebp1 inhibits ligand-mediated AR transcriptional activation; an LXXLL motif in Ebp1 is required for this inhibition.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, transient transfection reporter assay, mutagenesis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal Co-IP, in vitro binding with domain mapping, functional reporter assays with mutants\",\n      \"pmids\": [\"12165860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Ebp1 is localized to the cytoplasm and nucleolus; nucleolar localization requires sequences at both N- and C-termini; Ebp1 overexpression inhibits proliferation linked to its nucleolar localization; Ebp1 is part of ribonucleoprotein complexes and associates with different rRNA species.\",\n      \"method\": \"Confocal immunofluorescence, subcellular fractionation, mass spectrometry, cell proliferation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (localization, MS interactome, functional KO) in single study\",\n      \"pmids\": [\"15064750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Heregulin regulates the association of Ebp1 with E2F1 promoter elements; Ebp1 binds E2F consensus sequences in nuclear lysates together with E2F1, Rb, and HDAC2; chromatin immunoprecipitation shows Ebp1 is recruited to the E2F1 promoter in vivo; HRG enhances Ebp1-mediated transcriptional repression.\",\n      \"method\": \"DNA affinity pulldown, chromatin immunoprecipitation (ChIP), reporter gene assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus in vitro DNA binding and functional reporter, moderate evidence\",\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 binds Sin3A (via PAD4/HDAC-interacting domain of Sin3A); Ebp1 and Sin3A associate at PSA and E2F1 promoters in vivo; Sin3A enhances Ebp1-mediated repression of AR- and E2F1-regulated genes.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, ChIP, DNA affinity precipitation, reporter gene assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted direct binding (recombinant Sin3A + Ebp1), reciprocal Co-IP, ChIP, functional assays\",\n      \"pmids\": [\"16254079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Ebp1 overexpression down-regulates AR and AR-regulated genes (including PSA); Ebp1 is recruited to the PSA promoter in response to the androgen antagonist bicalutamide as shown by ChIP; androgens fail to stimulate growth of ebp1 transfectants.\",\n      \"method\": \"Chromatin immunoprecipitation, microarray, reporter gene assay, in vivo xenograft\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP with multiple functional assays and in vivo validation\",\n      \"pmids\": [\"15994225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Nuclear Akt interacts with PKC-phosphorylated Ebp1 (at S360) to prevent DNA fragmentation by caspase-activated DNase (CAD); phospho-mimetic S360D mutant strongly binds nuclear Akt and suppresses apoptosis, while S360A mutant barely binds Akt or inhibits DNA fragmentation; nuclear (not cytoplasmic) Akt enhances Ebp1 antiapoptotic action independent of Akt kinase activity.\",\n      \"method\": \"Cell-free apoptotic assay, nuclear extract purification, Co-IP, site-directed mutagenesis, siRNA knockdown, overexpression\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical reconstitution with mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"16642037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Ebp1 has two isoforms, p48 and p42: p48 localizes to both cytoplasm and nucleus and suppresses apoptosis; p42 predominantly resides in cytoplasm and promotes differentiation; EGF stimulates p42 to bind ErbB3 in a PKC-phosphorylation-dependent manner; p48 does not bind ErbB3 regardless of EGF; p48 promotes cell proliferation while p42 inhibits it.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, overexpression, siRNA knockdown, flow cytometry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods distinguishing isoform-specific functions, replicated in multiple cell types\",\n      \"pmids\": [\"16832058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Ebp1 contains a dsRNA-binding domain (dsRBD); this domain mediates interaction with dsRNA, is required for nucleolar localization, and for forming RNP complexes; in the cytoplasm, Ebp1 associates with mature ribosomes; Ebp1 inhibits phosphorylation of eIF2α at S51 and interacts with and is phosphorylated by PKR kinase.\",\n      \"method\": \"dsRNA-binding assay, co-immunoprecipitation, sucrose gradient fractionation, in vitro kinase assay, deletion mutagenesis, immunofluorescence\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro binding assay with domain mapping, in vitro kinase assay, ribosome fractionation\",\n      \"pmids\": [\"16631606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Ebp1 is identified as a component of cytoplasmic bcl-2 mRNP complexes; recombinant Ebp1 binds bcl-2 ARE RNA but not GM-CSF ARE in vitro; Ebp1 co-precipitates with nucleolin from HL-60 cytoplasmic extracts in an RNA-dependent manner; Ebp1 decreases the rate of decay of bcl-2 ARE-containing transcripts in cell extracts.\",\n      \"method\": \"RNA affinity chromatography, MALDI-MS, EMSA, RNA co-immunoprecipitation, RNA decay assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical methods including reconstituted RNA-binding and mRNA stability assay\",\n      \"pmids\": [\"16396631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of murine Ebp1 (p48) reveals a core domain homologous to methionine aminopeptidases (pita bread fold), coupled to a C-terminal extension; the primary RNA-binding site is formed by a Lys-rich motif in the C-terminus mediating FMDV IRES interaction; the structure explains conformational differences between p42 and p48 isoforms and disposition of the LKALL protein-interacting motif.\",\n      \"method\": \"X-ray crystallography, mutagenesis, IRES translation assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis and functional validation in single study\",\n      \"pmids\": [\"17690690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human Ebp1 crystal structure at 1.6 Å resolution reveals a conserved pita bread fold homologous to methionine aminopeptidases but without catalytic activity; the structure reveals how Ebp1 may discriminate between protein and RNA interaction partners.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure\",\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 at PB1's transcription primer binding site; Ebp1 inhibits in vitro RNA synthesis by the influenza virus RNA polymerase complex but not capped RNA endonuclease or RNA-cap binding activities; overexpression of Ebp1 interferes with influenza virus production.\",\n      \"method\": \"Yeast two-hybrid, in vitro Co-IP, in vitro RNA synthesis assay, overexpression\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro enzymatic assay plus Co-IP and in vivo overexpression\",\n      \"pmids\": [\"17295834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Ebp1 forms a complex with nucleophosmin/B23; p48 constitutively binds B23 in the nucleolus requiring B23 K263 sumoylation; p42 selectively binds unsumoylated B23 upon EGF stimulation, dependent on Ser360 phosphorylation; knockdown of B23 or Ebp1 substantially decreases ribosome biogenesis and cell survival.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, ribosome biogenesis assay, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with mutagenesis defining interaction requirements and functional knockdown\",\n      \"pmids\": [\"17951246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Protein kinase C-delta phosphorylates Ebp1 at S360, protecting it from caspase-3 cleavage at D196 and D53 sites; PKCδ-deficient cells show robust Ebp1 cleavage; S360 phosphorylation suppresses caspase-3-mediated degradation; D196A mutant markedly protects cells from apoptosis.\",\n      \"method\": \"In vitro kinase assay, cell-free apoptotic assay, site-directed mutagenesis, PKCδ knockout cells\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay with mutagenesis plus genetic KO cells\",\n      \"pmids\": [\"17316401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Human Bre1 acts as an E3 ubiquitin ligase for Ebp1, promoting its polyubiquitination and proteasomal degradation; Ebp1 polyubiquitination is regulated by its phosphorylation; depletion of hBre1 blocks Ebp1 polyubiquitination and elevates Ebp1 protein level; hBre1 suppresses Ebp1's repressive effect on E2F-1.\",\n      \"method\": \"In vitro ubiquitination assay, co-immunoprecipitation, siRNA knockdown, Western blot\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro ubiquitination reconstitution plus Co-IP and functional assays\",\n      \"pmids\": [\"19037095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Ebp1 p42 isoform is sumoylated on K93 and K298, which mediate its nuclear translocation and are required for anti-proliferative activity; TLS/FUS acts as a SUMO1 E3 ligase for Ebp1 p42; Ebp1 directly binds TLS/FUS; genotoxic stress-triggered phosphorylation of Ebp1 regulates this interaction; unsumoylated Ebp1 mutants fail to suppress E2F-1 transcription.\",\n      \"method\": \"Co-immunoprecipitation, in vitro sumoylation assay, site-directed mutagenesis, siRNA knockdown, reporter gene assay, subcellular fractionation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro sumoylation assay with mutagenesis, reciprocal Co-IP, functional reporter assays\",\n      \"pmids\": [\"19946338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"p48 isoform of Ebp1 binds HDM2 (MDM2), enhancing HDM2-p53 association and promoting p53 polyubiquitination and degradation, thereby reducing steady-state p53 levels and activity in glioblastoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Western blot, overexpression/knockdown\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with ubiquitination assay and functional p53 level measurement\",\n      \"pmids\": [\"21098709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PKC phosphorylates Ebp1 on serine/threonine residues in vitro; basal Ebp1 phosphorylation in vivo is PKC-dependent; heregulin-induced phosphorylation is predominantly PKC-independent; PKC inhibition abrogates Ebp1 association with ErbB3.\",\n      \"method\": \"In vitro kinase assay, metabolic labeling/phosphorylation analysis, PKC inhibitor treatment, co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay plus pharmacological inhibitor with functional Co-IP readout\",\n      \"pmids\": [\"11325528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Ebp1 serine 363 is phosphorylated in vivo; phospho-S363 Ebp1 localizes exclusively to the nucleus; S363A mutation decreases transcriptional repression and abrogates cell growth inhibition; S363A mutant fails to bind HDAC2 and mSin3a despite associating with E2F1 promoter elements.\",\n      \"method\": \"Phospho-specific antibody, immunofluorescence, reporter gene assay, co-immunoprecipitation, ChIP\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — phospho-specific detection with mutagenesis and multiple functional readouts\",\n      \"pmids\": [\"17786317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PAK1 phosphorylates Ebp1 in vitro at threonine 261; HRG treatment and constitutively active PAK1 enhance threonine phosphorylation of Ebp1 in MCF-7 cells; endogenous Ebp1 binds PAK1 and association is enhanced by HRG; a phospho-mimetic T261E mutation abolishes Ebp1's ability to repress transcription, inhibit growth, and contribute to tamoxifen sensitivity.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis, reporter gene assay, cell growth assay\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay with phosphosite mapping and mutagenesis, functional validation\",\n      \"pmids\": [\"18283314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"p42 Ebp1 interacts with the cSH2 domain of p85 (PI3K regulatory subunit), leading to inhibition of PI3K lipid kinase activity; p42 induces proteasomal degradation of p85 by recruiting the HSP70/CHIP E3 ligase complex, which ubiquitinates p85.\",\n      \"method\": \"Co-immunoprecipitation, in vitro PI3K activity assay, ubiquitination assay, Western blot, in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase activity assay, ubiquitination assay with complex identification, in vivo validation\",\n      \"pmids\": [\"24651434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"p48 Ebp1 interacts with CDK2 through its N-terminal domain; CDK2 specifically phosphorylates p48 at serine 34 (not p42); phospho-ablated S34A mutant antagonizes cell proliferation and transformation; CDK2-mediated S34 phosphorylation is required for p48's oncogenic function.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, cell proliferation assay, mouse xenograft\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay with domain mapping and mutagenesis, in vivo validation\",\n      \"pmids\": [\"25154617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TIF-IA (a GTP-binding protein that recruits RNA Pol I to ribosomal DNA promoter) binds EBP1; together they enhance transcription of PCNA; GTP binding by TIF-IA and PKCδ-mediated EBP1 phosphorylation are both required for optimal PCNA expression and ribosomal RNA synthesis in T cells.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene assay, kinase assay, pharmacological inhibition\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with functional assays but single lab\",\n      \"pmids\": [\"25691158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EBP1 binds directly to multiple polyphosphoinositides (PPIns) via two lysine-rich motifs at N- and C-termini; the C-terminal PPIn-binding motif is the major contributor to nucleolar localization; a K372N mutation (found in endometrial tumors) within the C-terminal motif alters nucleolar targeting; EBP1 associates with PtdIns(3,4,5)P3 in the nucleolus via electrostatic and hydrophobic interactions as shown by NMR.\",\n      \"method\": \"Lipid pulldown, mutagenesis, immunofluorescence, NMR\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structural data plus mutagenesis and cell-based localization, multiple methods\",\n      \"pmids\": [\"27118868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EBP1 P48 binds to the WD domain of FBXW7 as an oncogenic substrate and sequesters FBXW7α to the cytosol; EBP1 P42 binds to both the F-box domain of FBXW7 and FBXW7 substrates, acting as an adapter to promote FBXW7-mediated degradation of oncogenic targets.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, ubiquitination assay, domain mapping\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with domain-specific binding analysis and functional ubiquitination assay\",\n      \"pmids\": [\"28209614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MYCN directly occupies the PA2G4 gene promoter stimulating its transcription; PA2G4 directly binds MYCN protein protecting it from proteolysis; the MYCN-PA2G4 interaction site was mapped to a 14 amino acid MYCN sequence and a surface crevice of PA2G4; competitive chemical inhibition of this interface reduces MYCN and PA2G4 levels and inhibits neuroblastoma tumorigenesis in vivo.\",\n      \"method\": \"ChIP, surface plasmon resonance, mutagenesis, molecular modeling, in vivo tumor model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biophysical binding (SPR) with mutagenesis, ChIP, and in vivo validation\",\n      \"pmids\": [\"31501192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"circERBB2 regulates nucleolar localization of PA2G4, forming a circERBB2-PA2G4-TIFIA regulatory axis to modulate ribosomal DNA transcription and cancer cell proliferation.\",\n      \"method\": \"RNA pulldown, RNA immunoprecipitation, FISH, knockdown, in vivo xenograft\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RNA-protein interaction assays with functional knockdown, single lab\",\n      \"pmids\": [\"31752867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EBP1 directly interacts with Suv39H1 and recruits the E3 ligase MDM2, promoting ubiquitin-proteasome-dependent degradation of Suv39H1 to regulate heterochromatin assembly during neural development; EBP1 also binds to the DNMT1 promoter, repressing DNA methylation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, ubiquitination assay, Western blot, KO 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 — Co-IP identifying ternary complex, ubiquitination assay, ChIP, in vivo genetic model\",\n      \"pmids\": [\"31748268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EBP1 binds HNF4α in a LXXLL motif-mediated manner; EBP1 suppresses expression of HNF4α target genes involved in insulin secretion; crystal structure of HNF4α ligand-binding domain in complex with EBP1 LXXLL peptide at 3.15 Å shows EBP1's LXXLL motif competes with HNF4α coactivators for the same binding pocket.\",\n      \"method\": \"Yeast two-hybrid, mammalian two-hybrid, GST pulldown, X-ray crystallography, reporter gene assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus biochemical binding assays and functional gene expression readout\",\n      \"pmids\": [\"31362984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Ebp1 p48 interacts with TIF-90 (a splice variant of TIF-IA) to regulate ribosomal RNA synthesis; Ebp1 promotes Akt-mediated protection of TIF-90 stability by preventing TIF-90 ubiquitination by Mdm2 and its proteasomal degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, rRNA synthesis assay, knockdown/overexpression\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with ubiquitination assay, single lab\",\n      \"pmids\": [\"30793766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM structure of human Ebp1 (p48) bound to the human 80S ribosome at 3.3 Å reveals Ebp1 binds in the vicinity of the peptide exit tunnel, interacting with ribosomal proteins eL19 and uL23 and 28S rRNA; Ebp1-80S binding is enhanced upon puromycin-mediated translational inhibition; Ebp1 can rotate around its insert domain; membrane-targeting domains emerging from the 60S tunnel displace Ebp1.\",\n      \"method\": \"Cryo-EM, ribosome profiling, pSILAC/BONCAT mass spectrometry\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — near-atomic resolution cryo-EM structure with ribosome profiling and MS validation\",\n      \"pmids\": [\"33357414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structure of human Ebp1 (p48 isoform) bound to the human 80S ribosome at 3.3 Å: Ebp1 binds near the peptide exit tunnel via interactions with eL19, uL23, and 28S rRNA; binding is enhanced by puromycin-induced translational arrest; Ebp1 can rotate around its insert domain providing conformational flexibility at the ribosome.\",\n      \"method\": \"Cryo-EM, sucrose gradient ribosome fractionation\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — independent cryo-EM structural study confirming ribosome interaction site\",\n      \"pmids\": [\"33479117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EBP1 promotes UPS-dependent degradation of Suv39H1 by directly interacting with it and recruiting E3 ligase MDM2; this mechanism governs heterochromatin assembly and neural development.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Western blot\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and ubiquitination assay, single lab, replicates prior finding from same group\",\n      \"pmids\": [\"33691908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PA2G4/EBP1 is ubiquitinated at lysine 376 by PRKN/PARKIN on damaged mitochondria; ubiquitinated PA2G4 interacts with the mitophagy receptor SQSTM1/p62 to induce mitophagy, promoting neuroprotection during cerebral ischemia-reperfusion injury; neuron-specific Ebp1 KO increases infarct volume and impairs mitophagy.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination mapping, neuron-specific KO mouse, AAV rescue, mitophagy assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — site-specific ubiquitination mapping, Co-IP, genetic KO with phenotypic rescue\",\n      \"pmids\": [\"37712850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PA2G4 promotes HCC metastasis by stabilizing FYN mRNA through interaction with the m6A reader YTHDF2; FYN mRNA is m6A-modified and bound by both PA2G4 and YTHDF2; YTHDF2's m6A catalytic activity is indispensable for PA2G4-mediated regulation of FYN.\",\n      \"method\": \"Co-immunoprecipitation, RIP, MeRIP, RNA half-life assay, dual luciferase reporter, in vivo lung metastasis model\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple RNA-protein interaction methods, single lab\",\n      \"pmids\": [\"35526051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PA2G4 binds the NF110-NF45 heterodimer and prevents NF110 degradation; CRAPIR (a PIWI-interacting RNA) competes with NF110 for binding to PA2G4, thereby preventing PA2G4-NF110 interaction, reducing NF110 degradation, and promoting cardiomyocyte proliferation and heart regeneration.\",\n      \"method\": \"Co-immunoprecipitation, RNA pulldown, CRISPR knockout, antagomir knockdown, AAV overexpression, in vivo cardiac injury model\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP defining ternary complex, RNA pulldown, in vivo genetic models with phenotypic rescue\",\n      \"pmids\": [\"39814981\"],\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 of Moloney murine leukemia virus in embryonic cells.\",\n      \"method\": \"Co-immunoprecipitation (complex identification), siRNA knockdown, retroviral reporter assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP identifying complex component plus functional knockdown, single lab\",\n      \"pmids\": [\"24227866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pa2G4 (EBP1) binds to Six1 in human embryonic kidney cells and interferes with the Six1-Eya1 complex; in Xenopus, knockdown of Pa2G4 downregulates neural border zone, neural crest and cranial placode genes while expanding neural plate genes, demonstrating a role in neural crest and otic development.\",\n      \"method\": \"Co-immunoprecipitation (mammalian cells), morpholino knockdown in Xenopus, in situ hybridization\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with in vivo loss-of-function phenotype, single lab\",\n      \"pmids\": [\"27940157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DPPA4 preferentially binds EBP1 p48 isoform in pluripotent cells via DPPA4's SAP domain; DPPA4 transcriptional repressive function is increased by p48 knockdown; this effect is abolished with an interaction-deficient DPPA4 ΔSAP mutant.\",\n      \"method\": \"Proteomics screen, co-immunoprecipitation, siRNA knockdown, reporter gene assay, mutagenesis\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with domain mapping and functional reporter, single lab\",\n      \"pmids\": [\"29327467\"],\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 in neurons; introduction of p48 Ebp1 promotes axon regeneration in injured hippocampal slices.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, ex vivo axon regeneration assay\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with localization and ex vivo functional assay, single lab, limited mechanistic detail\",\n      \"pmids\": [\"27916024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EBP1 inhibits translation of androgen receptor mRNA in castration-resistant prostate cancer cells without altering AR mRNA steady-state levels or stability; heregulin further diminishes AR translation in EBP1-transfected cells.\",\n      \"method\": \"Polysome fractionation, Western blot, quantitative PCR, mRNA stability assay\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — polysome profiling distinguishing translational from transcriptional regulation, single lab\",\n      \"pmids\": [\"21965718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"EBP1 decreases ErbB2 mRNA primarily through a transcriptional mechanism; EBP1 binds both distal and proximal endogenous ErbB2 promoters in vivo; Sin3A-interaction mutants of EBP1 have reduced ability to decrease ErbB2 promoter activity; EBP1 overexpression or ablation does not alter ErbB2 mRNA stability.\",\n      \"method\": \"ChIP, reporter gene assay, mRNA stability assay, site-directed mutagenesis, shRNA knockdown\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP with multiple controls, distinguishes transcriptional vs. post-transcriptional mechanism\",\n      \"pmids\": [\"23242156\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PA2G4/EBP1 is a multifunctional DNA/RNA-binding protein with a methionine aminopeptidase-like (pita-bread) fold that operates as a context-dependent regulator of transcription and translation: it binds ErbB3 at the juxtamembrane domain (dissociating upon heregulin/PKC phosphorylation) and translocates to the nucleus, where the p48 isoform recruits HDAC2 and Sin3A to repress E2F1- and androgen receptor-regulated promoters via its C-terminal domain; it also binds Rb, HDM2/p53, and nuclear Akt (requiring PKCδ-mediated S360 phosphorylation) to modulate cell survival; the p42 isoform undergoes TLS/FUS-mediated sumoylation at K93/K298 to facilitate nuclear translocation and transcriptional repression, and promotes proteasomal degradation of the PI3K p85 subunit by recruiting HSP70/CHIP; in the cytoplasm, both isoforms associate with the 60S ribosome exit tunnel (contacting eL19, uL23, and 28S rRNA) to regulate translation, inhibit eIF2α phosphorylation, and stabilize bcl-2 mRNA; p48 additionally interacts with MYCN to protect it from proteolysis, while ubiquitination of PA2G4 at K376 by PARKIN recruits SQSTM1/p62 to trigger mitophagy for neuroprotection.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PA2G4 (EBP1) is a multifunctional RNA- and DNA-binding protein with a catalytically inactive methionine aminopeptidase (pita-bread) fold that acts as a context-dependent regulator of transcription, translation, ribosome biogenesis, and mitophagy. In the nucleus, the p48 isoform recruits HDAC2 and the corepressor Sin3A via its C-terminal domain to repress E2F1- and androgen receptor-regulated promoters, while the p42 isoform undergoes TLS/FUS-mediated sumoylation at K93/K298 for nuclear translocation and additionally promotes proteasomal degradation of the PI3K p85 subunit through recruitment of the HSP70/CHIP E3 ligase [PMID:12682367, PMID:16254079, PMID:19946338, PMID:24651434]. In the cytoplasm, PA2G4 binds the 60S ribosomal subunit at the peptide exit tunnel—contacting eL19, uL23, and 28S rRNA—to regulate co-translational events, inhibits eIF2α phosphorylation via its dsRNA-binding domain, and stabilizes bcl-2 mRNA [PMID:33357414, PMID:16631606, PMID:16396631]. PA2G4 also participates in cell survival signaling through PKCδ-dependent S360 phosphorylation enabling nuclear Akt interaction, protects MYCN from proteolysis in neuroblastoma, and is ubiquitinated at K376 by PARKIN on damaged mitochondria to recruit SQSTM1/p62 and trigger neuroprotective mitophagy [PMID:16642037, PMID:31501192, PMID:37712850].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying EBP1 as an ErbB3-interacting protein established it as a signaling-responsive factor: heregulin dissociates EBP1 from ErbB3 and triggers its nuclear translocation, linking receptor tyrosine kinase signaling to nuclear function.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, in vitro binding with domain mapping, subcellular fractionation in breast cancer cells\",\n      \"pmids\": [\"10682683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural basis of ErbB3–EBP1 interaction unresolved\", \"Downstream nuclear targets upon translocation unknown at this stage\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrating that EBP1 binds Rb and represses E2F1-regulated cyclin E promoter activity established a nuclear transcriptional repressor function, while PKC-dependent phosphorylation was shown to regulate ErbB3 association, revealing the first post-translational control mechanism.\",\n      \"evidence\": \"Co-IP, GST pulldown with domain mapping, reporter assays (Rb binding); in vitro kinase assay with PKC inhibitors (phosphorylation)\",\n      \"pmids\": [\"11268000\", \"11325528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of recruited chromatin-modifying complexes not yet known\", \"Phosphorylation sites on EBP1 not yet mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showing that EBP1 recruits HDAC2 (but not HDAC1) through its C-terminal domain to mediate transcriptional repression resolved how EBP1 silences E2F targets at the chromatin level.\",\n      \"evidence\": \"GST pulldown, HDAC activity assay, HDAC inhibitor treatment, deletion mutagenesis, reporter assays\",\n      \"pmids\": [\"12682367\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HDAC2 recruitment is sufficient or requires additional corepressors not addressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of EBP1 as an androgen receptor corepressor via an LXXLL motif extended its transcriptional repressor function beyond E2F to nuclear hormone receptor signaling.\",\n      \"evidence\": \"Co-IP, GST pulldown with domain mapping, reporter assays with LXXLL mutagenesis in prostate cancer cells\",\n      \"pmids\": [\"12165860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AR repression involves HDAC recruitment not yet tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that EBP1 localizes to the nucleolus, associates with rRNP complexes, and inhibits proliferation linked this protein to ribosome biogenesis and demonstrated that nucleolar targeting requires both N- and C-terminal sequences.\",\n      \"evidence\": \"Confocal immunofluorescence, mass spectrometry, subcellular fractionation, proliferation assays\",\n      \"pmids\": [\"15064750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific rRNA processing steps regulated by EBP1 not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"ChIP showing EBP1 occupancy at the E2F1 promoter together with Rb and HDAC2, and identification of Sin3A as a direct EBP1-binding corepressor, completed the model of a ternary repressive complex at E2F- and AR-regulated genes.\",\n      \"evidence\": \"ChIP, DNA affinity pulldown, GST pulldown with domain mapping for Sin3A, reporter assays\",\n      \"pmids\": [\"15073182\", \"16254079\", \"15994225\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide target spectrum of this repressive complex not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovery of two functionally distinct isoforms (p48 and p42), PKCδ-mediated S360 phosphorylation protecting EBP1 from caspase-3 cleavage, nuclear Akt interaction, dsRNA binding mediating ribosome association and eIF2α regulation, and bcl-2 mRNA stabilization collectively revealed EBP1 as a multifunctional regulator of translation, survival, and differentiation.\",\n      \"evidence\": \"Multiple orthogonal methods across four studies: subcellular fractionation, Co-IP, in vitro kinase assays, mutagenesis, dsRNA binding assays, ribosome fractionation, RNA affinity chromatography, mRNA decay assays\",\n      \"pmids\": [\"16832058\", \"16642037\", \"17316401\", \"16631606\", \"16396631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for isoform-specific localization and partner selection unknown\", \"Precise mechanism of eIF2α phosphorylation inhibition not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Crystal structures of murine and human EBP1 revealed a catalytically inactive methionine aminopeptidase fold with a C-terminal RNA-binding extension, while functional studies identified nucleophosmin/B23 interaction required for ribosome biogenesis and S363 phosphorylation controlling HDAC2/Sin3A recruitment.\",\n      \"evidence\": \"X-ray crystallography (1.6–2.0 Å), mutagenesis, IRES translation assay, Co-IP with B23, ribosome biogenesis assay, phospho-specific antibodies, ChIP\",\n      \"pmids\": [\"17690690\", \"17765895\", \"17951246\", \"17786317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal with RNA or protein partners at this time\", \"How B23 sumoylation state toggles isoform-specific binding not structurally resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of PAK1-mediated T261 phosphorylation as a switch that inactivates EBP1 transcriptional repression, and hBre1 as an E3 ligase promoting EBP1 proteasomal degradation, established kinase and ubiquitin-mediated layers of EBP1 regulation.\",\n      \"evidence\": \"In vitro kinase assay with site mapping, Co-IP, reporter assays (PAK1); in vitro ubiquitination reconstitution, siRNA (hBre1)\",\n      \"pmids\": [\"18283314\", \"19037095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PAK1 and PKCδ phosphorylation are coordinated is unknown\", \"Full ubiquitin chain topology on EBP1 not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating TLS/FUS-mediated sumoylation of p42 at K93/K298 as required for nuclear translocation and E2F1 repression explained how the cytoplasmic p42 isoform gains nuclear repressor function under genotoxic stress.\",\n      \"evidence\": \"In vitro sumoylation assay, Co-IP, mutagenesis, reporter assays, subcellular fractionation\",\n      \"pmids\": [\"19946338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Desumoylation enzymes acting on EBP1 not identified\", \"Genotoxic stress signals upstream of TLS/FUS not fully mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showing that p48 enhances HDM2-mediated p53 polyubiquitination and degradation established EBP1 as a modulator of the p53 tumor suppressor pathway in glioblastoma.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, p53 protein level measurement in glioblastoma cells\",\n      \"pmids\": [\"21098709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this function is isoform-specific to p48 not fully dissected\", \"Physiological triggers for EBP1-HDM2 complex formation unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Two parallel discoveries showed that p42 promotes PI3K p85 degradation by recruiting HSP70/CHIP, directly inhibiting PI3K signaling, while CDK2 phosphorylates p48 at S34 to enable its oncogenic function—delineating isoform-specific oncogenic versus tumor-suppressive activities.\",\n      \"evidence\": \"Co-IP, in vitro PI3K activity assay, ubiquitination assay, in vitro kinase assay, mutagenesis, xenograft models\",\n      \"pmids\": [\"24651434\", \"25154617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDK2 phosphorylation of p48 affects ribosome binding unknown\", \"How HSP70/CHIP is specifically recruited by p42 but not p48 not resolved structurally\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of polyphosphoinositide binding via lysine-rich motifs, with the C-terminal motif governing nucleolar targeting and a cancer-associated K372N mutation disrupting it, established a lipid-signaling input for EBP1 localization.\",\n      \"evidence\": \"Lipid pulldown, NMR, mutagenesis, immunofluorescence\",\n      \"pmids\": [\"27918868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PPIn binding competes with RNA binding at overlapping motifs not tested\", \"Functional consequence of K372N in tumorigenesis not demonstrated in vivo\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that p48 and p42 differentially interact with FBXW7 E3 ligase—p48 as an oncogenic substrate sequestering FBXW7α, p42 as an adapter promoting FBXW7-mediated degradation of oncoproteins—provided a unified framework for the opposing roles of the two isoforms.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, ubiquitination assay, domain mapping\",\n      \"pmids\": [\"28209614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of all FBXW7 substrates whose turnover is modulated by p42 not catalogued\", \"In vivo validation in genetic models lacking\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Multiple 2019 studies revealed new EBP1 functions: direct binding and stabilization of MYCN in neuroblastoma; interaction with HNF4α via the LXXLL motif (co-crystal at 3.15 Å); promotion of Suv39H1 degradation via MDM2 recruitment to regulate heterochromatin in neural development; and regulation of rDNA transcription through a circERBB2–PA2G4–TIFIA axis.\",\n      \"evidence\": \"SPR and mutagenesis with in vivo tumor models (MYCN); X-ray crystallography and reporter assays (HNF4α); Co-IP, ubiquitination assay, KO mouse (Suv39H1); RNA pulldown and RIP with xenograft (circERBB2)\",\n      \"pmids\": [\"31501192\", \"31362984\", \"31748268\", \"31752867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of full-length MYCN–PA2G4 complex not determined\", \"Whether Suv39H1 degradation is isoform-specific is unclear\", \"circERBB2 finding from single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cryo-EM structures of EBP1 bound to the human 80S ribosome at the peptide exit tunnel resolved how EBP1 contacts eL19, uL23, and 28S rRNA, and showed that translational arrest enhances binding while emerging signal sequences displace it, establishing EBP1 as a ribosome-associated factor sensing translational state.\",\n      \"evidence\": \"Cryo-EM at 3.3 Å, ribosome profiling, pSILAC/BONCAT mass spectrometry; independently confirmed by a second cryo-EM study\",\n      \"pmids\": [\"33357414\", \"33479117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of EBP1 at the exit tunnel on nascent chain folding or targeting not demonstrated\", \"Whether p42 binds ribosomes similarly to p48 not structurally addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstration that PARKIN ubiquitinates PA2G4 at K376 on damaged mitochondria, enabling SQSTM1/p62 recruitment and mitophagy, with neuron-specific KO increasing ischemic infarct volume, established a neuroprotective mitophagy role for PA2G4.\",\n      \"evidence\": \"Ubiquitination site mapping, Co-IP, neuron-specific KO mouse, AAV rescue, mitophagy assays\",\n      \"pmids\": [\"37712850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mitophagy function is isoform-specific not determined\", \"How PA2G4 is recruited to damaged mitochondria upstream of PARKIN ubiquitination is unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of PA2G4 as a stabilizer of NF110 (in an NF110-NF45 heterodimer) that is competitively displaced by the piRNA CRAPIR to promote cardiomyocyte proliferation extended PA2G4 function to cardiac regeneration.\",\n      \"evidence\": \"Reciprocal Co-IP, RNA pulldown, CRISPR KO, AAV overexpression, in vivo cardiac injury model\",\n      \"pmids\": [\"39814981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NF110 stabilization depends on EBP1 isoform identity not examined\", \"Mechanism by which NF110 degradation promotes cardiomyocyte cell cycle re-entry not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how PA2G4 toggles between ribosomal, nuclear transcriptional, and mitochondrial functions in the same cell; what determines isoform-specific partner selection at the structural level; and whether EBP1's exit-tunnel binding directly regulates nascent polypeptide fate.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No integrative model of isoform-specific subcellular trafficking\", \"No co-structure of EBP1 with full-length nuclear partners (AR, Rb, MYCN)\", \"Genome-wide or translatome-wide target specificity not comprehensively profiled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [10, 11, 12, 26, 29, 37]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 3, 5, 6, 7, 31, 44]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [19, 23, 27, 28, 38]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [26]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [30]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [23, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [4, 15, 26, 29]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5, 8, 9, 18, 21]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9, 10, 33]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [10, 33, 34]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [36]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 3, 5, 6, 7, 31, 44]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [30, 35]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 9, 20, 23]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [8, 16, 19]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [36]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 33, 34]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 24]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [30, 40]}\n    ],\n    \"complexes\": [\n      \"EBP1-Sin3A-HDAC2 corepressor complex\",\n      \"80S ribosome (exit tunnel-associated)\",\n      \"ZFP809-TRIM28 retroviral silencing complex\"\n    ],\n    \"partners\": [\n      \"ERBB3\",\n      \"RB1\",\n      \"HDAC2\",\n      \"SIN3A\",\n      \"AKT1\",\n      \"MYCN\",\n      \"MDM2\",\n      \"NPM1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}