{"gene":"JADE1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2002,"finding":"Jade-1 protein directly interacts with VHL protein (pVHL) as shown by yeast two-hybrid and co-immunoprecipitation; pVHL stabilizes Jade-1 protein by increasing its half-life up to 3-fold, identifying protein stabilization as a new VHL function. Jade-1 localizes to cytoplasm and nucleus (including speckles) where it partly colocalizes with VHL.","method":"Yeast two-hybrid screen, co-immunoprecipitation, metabolic labeling, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP and metabolic labeling, replicated across multiple cell lines and conditions","pmids":["12169691"],"is_preprint":false},{"year":2004,"finding":"VHL-mediated stabilization of Jade-1 requires the PHD-extended PHD module of Jade-1, not its PEST domain. Both the alpha and beta domains of VHL are required for Jade-1 stabilization, while the beta domain alone is sufficient for binding. VHL missense mutations associated with renal cancer (Leu118Pro, Arg167Trp) fail to stabilize Jade-1, whereas mutations without renal cancer risk (Tyr98His, Tyr112His) fully stabilize Jade-1.","method":"Co-immunoprecipitation, cotransfection with domain deletions/mutants, metabolic labeling","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple VHL mutants tested with domain mapping and metabolic labeling, multiple orthogonal methods","pmids":["14973063"],"is_preprint":false},{"year":2004,"finding":"Jade-1 is a transcriptional co-activator: Gal4-Jade-1 fusion activates transcription 5–6-fold at Gal4-responsive promoters. Jade-1 overexpression specifically increases acetylated histone H4 but not H3, and this requires the PHD fingers. TIP60 HAT physically associates with Jade-1 and augments its HAT activity.","method":"Gal4 reporter co-transfection, western blot for acetylated histones, co-immunoprecipitation with TIP60, PHD deletion mutants","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays and co-IP from single lab with domain mutant validation","pmids":["15502158"],"is_preprint":false},{"year":2005,"finding":"Jade-1 promotes apoptosis: overexpression increased apoptosis by 40–50% and decreased anti-apoptotic Bcl-2 levels; Jade-1 inhibited renal cancer cell growth, colony formation, and tumor formation in nude mice. Antisense Jade-1 confirmed these results.","method":"Overexpression and antisense knockdown in renal cancer cell lines, apoptosis assays, colony formation assay, nude mouse xenograft","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function experiments with multiple phenotypic readouts in a single lab","pmids":["16046545"],"is_preprint":false},{"year":2008,"finding":"Jade-1 is a component of the HBO1 HAT complex and acts as a critical co-factor: co-expression of Jade-1/1L and HBO1 synergistically increases acetylation of endogenous histone H4 in epithelial cells; siRNA depletion of Jade-1 reduces H4 acetylation; Jade-1/1L enhances HBO1-mediated H4 acetylation severalfold in vitro with reconstituted oligonucleosome substrates. The PHD fingers of Jade-1 are required for this activity but not for HBO1 binding.","method":"Co-expression, siRNA knockdown, in vitro HAT assay with reconstituted oligonucleosomes, PHD finger deletion mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with nucleosome substrates plus cell-based gain/loss-of-function and domain mutagenesis","pmids":["18684714"],"is_preprint":false},{"year":2008,"finding":"Jade-1 binds beta-catenin in Wnt-responsive fashion and functions as an E3 ubiquitin ligase that ubiquitylates both phosphorylated and non-phosphorylated beta-catenin, thereby destabilizing wild-type beta-catenin but not cancer-causing forms. pVHL downregulates beta-catenin in a Jade-1-dependent manner and inhibits Wnt signaling, directly linking pVHL to the Wnt pathway through Jade-1.","method":"Co-immunoprecipitation, ubiquitylation assays, siRNA knockdown, reporter assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical ubiquitylation assay, co-IP, genetic dependency (Jade-1-dependent pVHL effect), replicated across cell-based and biochemical systems","pmids":["18806787"],"is_preprint":false},{"year":2012,"finding":"Jade-1 colocalizes with NPHP1 at the transition zone of primary cilia and interacts with NPHP4. NPHP4 stabilizes Jade-1 protein levels and promotes translocation of Jade-1 to the nucleus; NPHP4 and Jade-1 additively inhibit canonical Wnt signaling, conserved in zebrafish.","method":"Co-immunoprecipitation, co-localization imaging, protein stability assays, Wnt reporter assays, zebrafish genetic experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus localization imaging and functional epistasis in zebrafish, single lab","pmids":["22654112"],"is_preprint":false},{"year":2012,"finding":"Full-length polycystin-1 (PC1) binds, stabilizes, and colocalizes with Jade-1 and inhibits Jade-1 ubiquitination. The PC1 cytoplasmic tail and PC1-CTF promote Jade-1 ubiquitination and degradation (dominant-negative mechanism). Jade-1 ubiquitination is mediated by the E3 ligase Siah-1 which binds PC1. ADPKD-associated PC1 mutants fail to regulate Jade-1.","method":"Co-immunoprecipitation, co-localization, ubiquitination assays, ADPKD mutant analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assays with domain variants and disease mutants, single lab","pmids":["23001567"],"is_preprint":false},{"year":2012,"finding":"JADE1S-HBO1 complex is required for cell proliferation: siRNA knockdown of JADE1 diminished DNA synthesis, decreased HBO1 protein expression, and prevented chromatin recruitment of replication factor Mcm7. In an acute kidney injury mouse model, JADE1S and JADE1L protein levels decrease after injury and recover during regeneration; JADE1S recovery correlated with histone H4 acetylation on K5 and K12 but not H3K14.","method":"siRNA knockdown, BrdU/DNA synthesis assay, chromatin immunoprecipitation (Mcm7), mouse ischemia-reperfusion injury model, western blot","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA with specific phenotypic readouts plus in vivo model, single lab","pmids":["23159946"],"is_preprint":false},{"year":2013,"finding":"Jade-1 binds and inhibits AKT1: Jade-1 overexpression increases phospho-AKT/AKT1 levels while silencing decreases them; pVHL reintroduction increases Jade-1 and suppresses phospho-AKT. The N-terminus of Jade-1 binds both the catalytic domain and C-terminal regulatory tail of AKT1, suppressing AKT kinase activity.","method":"Kinase arrays, co-immunoprecipitation, overexpression and siRNA silencing, domain mapping with AKT binding assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase arrays plus co-IP with domain mapping and cell-based phenotype, single lab","pmids":["23824745"],"is_preprint":false},{"year":2014,"finding":"Casein kinase 1α (CK1α) phosphorylates Jade-1 at a conserved SLS motif and reduces Jade-1's ability to inhibit β-catenin/Wnt signaling. A Jade-1 mutant lacking the SLS motif is more effective than wild-type at reducing β-catenin-induced secondary axis formation in Xenopus laevis embryos.","method":"In vitro kinase assay, site-directed mutagenesis of SLS motif, Xenopus secondary axis formation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — kinase assay plus in vivo Xenopus functional validation, single lab","pmids":["25100726"],"is_preprint":false},{"year":2014,"finding":"HBO1-JADE1S complex undergoes cell cycle-dependent chromatin shuttling: JADE1S is nuclear/chromatin-associated in interphase, dissociates from chromatin and enters cytoplasm at prophase, and re-associates with chromatin in telophase/early G1. Cytoplasmic JADE1S is phosphorylated at 6 residues (S89, T92, S102, S121, S392, T468). Aurora A kinase inhibitor prevents the JADE1S band shift and chromatin dissociation. Chromatin re-association parallels global histone H4 acetylation.","method":"Cell fractionation, immunofluorescence, mass spectrometry of phosphorylated residues, Aurora A kinase inhibitor, in vivo mouse kidney immunostaining","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (fractionation, MS, inhibitor, in vivo) from single lab","pmids":["24739512"],"is_preprint":false},{"year":2018,"finding":"JADE1 functions as a scaffolding protein that physically links HBO1 to its histone H3-H4 substrate. The N-terminal 21-residue domain of JADE1 binds both HBO1 and histones and increases HBO1 catalytic efficiency for H3-H4 acetylation ~5-fold. A second nearby domain in JADE1 also contacts the histone core. HBO1 contains an N-terminal histone-binding domain (HBD) that contacts H3-H4 independently of JADE1 but does not significantly contribute to HAT activity.","method":"In vitro reconstitution with recombinant proteins, HAT activity assays with histone substrates, JADE1 deletion mapping in vitro and in vivo","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with recombinant proteins plus domain deletion mapping both in vitro and in vivo, rigorous enzyme kinetics","pmids":["29382722"],"is_preprint":false},{"year":2021,"finding":"JADE1 protein co-immunoprecipitates with four-repeat tau (0N4R) from post-mortem human PART brain tissue. JADE1 protein localizes within tau aggregates containing 4R isoforms. Knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhances tau-induced toxicity and apoptosis in a humanized 0N4R mutant tau knock-in model.","method":"Co-immunoprecipitation from human brain tissue, immunohistochemistry, Drosophila genetic knockdown with rough eye and TUNEL assays","journal":"Acta neuropathologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP from human tissue plus Drosophila genetic epistasis, but single study","pmids":["34719765"],"is_preprint":false},{"year":2025,"finding":"Jade1 preferentially associates with Oct4 when Oct4 is bound to MORE (palindromic octamer-related element) DNA sequences that recruit Oct4 dimers; the Oct4 N-terminal activation domain acts as an autoinhibitory domain dampening Jade1 interaction. The HBO1 complex acetylates histone H3K9 within nucleosomes more efficiently when Oct4 is co-bound to a MORE. Jade1 knockdown reduces H3K9Ac specifically at MORE-bound Oct4 sites. Cryo-EM reveals Oct4 bound to MORE partially unwinds nucleosomal DNA and shows additional mass from the HBO1 complex.","method":"Co-immunoprecipitation, ChIP-seq, in vitro HAT assays with purified recombinant proteins and nucleosome complexes, Jade1 knockdown, cryo-EM","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure, in vitro reconstitution with nucleosomes, ChIP-seq, and knockdown with multiple orthogonal methods in one rigorous study","pmids":["41489900"],"is_preprint":false}],"current_model":"JADE1 is a PHD zinc finger scaffold protein that acts as a critical co-factor of the HBO1 histone acetyltransferase (HAT) complex, physically bridging HBO1 to its histone H3-H4 substrate and stimulating HAT activity (~5-fold in vitro); it also functions as an E3 ubiquitin ligase targeting both phosphorylated and non-phosphorylated β-catenin for proteasomal degradation to suppress canonical Wnt signaling; its stability and activity are regulated by direct interactions with pVHL (stabilization via the PHD module), polycystin-1, NPHP4 (nuclear translocation), and CK1α (phosphorylation at SLS motif that attenuates Wnt inhibitory activity); additionally, Jade1 binds and inhibits AKT1 kinase, undergoes cell cycle-dependent phosphorylation-regulated chromatin shuttling during mitosis, and preferentially co-operates with Oct4 at palindromic MORE DNA elements to drive H3K9 acetylation."},"narrative":{"mechanistic_narrative":"JADE1 is a PHD zinc-finger scaffold protein that operates at the interface of histone acetylation and Wnt signaling [PMID:18684714, PMID:18806787]. As an essential co-factor of the HBO1 histone acetyltransferase complex, its N-terminal domain physically bridges HBO1 to its histone H3-H4 substrate and increases HBO1 catalytic efficiency ~5-fold in vitro, with its PHD fingers required for acetyltransferase stimulation but not for HBO1 binding [PMID:18684714, PMID:29382722]; this complex is required for DNA synthesis and chromatin recruitment of the replication factor Mcm7 [PMID:23159946]. JADE1 directs HBO1 activity in a sequence-specific manner, preferentially partnering with Oct4 bound at palindromic MORE DNA elements to drive H3K9 acetylation [PMID:41489900]. Independently, JADE1 acts as an E3 ubiquitin ligase that ubiquitylates both phosphorylated and non-phosphorylated β-catenin, destabilizing wild-type β-catenin to suppress canonical Wnt signaling and linking the tumor suppressor pVHL to Wnt inhibition [PMID:18806787]. JADE1 abundance and activity are set by direct partners: pVHL stabilizes JADE1 via its PHD-extended module, and renal-cancer-associated VHL mutations fail to stabilize it [PMID:12169691, PMID:14973063]; the ciliary protein NPHP4 stabilizes and promotes nuclear translocation of JADE1 [PMID:22654112]; polycystin-1 stabilizes JADE1 while its cytoplasmic tail promotes Siah-1-mediated JADE1 ubiquitination [PMID:23001567]; and CK1α phosphorylation at a conserved SLS motif attenuates JADE1's Wnt-inhibitory activity [PMID:25100726]. JADE1 also binds and inhibits AKT1 kinase, and its overexpression promotes apoptosis and suppresses renal cancer cell growth [PMID:16046545, PMID:23824745]. Its chromatin association is cell-cycle-regulated, with Aurora A-dependent phosphorylation driving dissociation from chromatin at mitosis and re-association in telophase paralleling global H4 acetylation [PMID:24739512].","teleology":[{"year":2002,"claim":"Establishing JADE1 as a direct VHL-interacting partner whose stability is controlled by pVHL revealed a new VHL function and placed JADE1 in renal cancer biology.","evidence":"Yeast two-hybrid, reciprocal co-IP and metabolic labeling across cell lines","pmids":["12169691"],"confidence":"High","gaps":["Did not define the molecular function of JADE1 itself","Mechanism of pVHL-mediated half-life extension unresolved"]},{"year":2004,"claim":"Domain mapping showed VHL stabilization requires the JADE1 PHD module and that renal-cancer VHL mutants selectively fail to stabilize JADE1, tying JADE1 stabilization to tumor-suppressor function.","evidence":"Co-IP and metabolic labeling with VHL domain deletions and disease mutants","pmids":["14973063"],"confidence":"High","gaps":["Did not establish how loss of JADE1 stabilization contributes to tumorigenesis"]},{"year":2004,"claim":"First evidence of JADE1 as a transcriptional co-activator linked to histone acetylation, implicating its PHD fingers and a HAT partner.","evidence":"Gal4 reporter assays, acetyl-histone western blots, co-IP with TIP60, PHD deletions","pmids":["15502158"],"confidence":"Medium","gaps":["TIP60 association reported here was superseded by HBO1 as the principal partner","No genomic targets defined"]},{"year":2005,"claim":"Functional readout connected JADE1 to apoptosis and tumor suppression in renal cancer cells, motivating its mechanistic role downstream of VHL.","evidence":"Overexpression/antisense in renal cancer lines, apoptosis and colony assays, nude mouse xenografts","pmids":["16046545"],"confidence":"Medium","gaps":["Molecular pathway linking JADE1 to Bcl-2 loss not defined","Single-lab phenotype"]},{"year":2008,"claim":"Identification of JADE1 as an essential HBO1 HAT co-factor defined its core biochemical activity in promoting histone H4 acetylation.","evidence":"Co-expression, siRNA, in vitro HAT assay on reconstituted oligonucleosomes, PHD mutants","pmids":["18684714"],"confidence":"High","gaps":["Structural basis of substrate bridging not yet resolved","Genomic distribution of HBO1-JADE1 acetylation unknown"]},{"year":2008,"claim":"Discovery that JADE1 is an E3 ligase for β-catenin established the mechanism by which pVHL suppresses Wnt signaling through JADE1.","evidence":"Co-IP, ubiquitylation assays, siRNA, Wnt reporter assays","pmids":["18806787"],"confidence":"High","gaps":["The catalytic determinants of JADE1 ligase activity not mapped","How a PHD scaffold also acts catalytically as an E3 unclear"]},{"year":2012,"claim":"NPHP4 and polycystin-1 were shown to control JADE1 localization and stability, embedding JADE1 in ciliary and cystic-kidney signaling.","evidence":"Co-IP, colocalization at cilia transition zone, stability and ubiquitination assays, ADPKD mutants, zebrafish epistasis","pmids":["22654112","23001567"],"confidence":"Medium","gaps":["Whether ciliary regulation of JADE1 feeds back to HAT activity unknown","Single-lab co-IP evidence"]},{"year":2012,"claim":"The JADE1S-HBO1 complex was shown to be required for proliferation and DNA replication and to track kidney injury and regeneration.","evidence":"siRNA, DNA synthesis assays, Mcm7 ChIP, mouse ischemia-reperfusion model","pmids":["23159946"],"confidence":"Medium","gaps":["Direct mechanism linking JADE1 to Mcm7 chromatin loading not established","Isoform-specific roles incompletely separated"]},{"year":2013,"claim":"JADE1 was shown to bind and inhibit AKT1, extending its tumor-suppressive role to a kinase-inhibitory function downstream of pVHL.","evidence":"Kinase arrays, co-IP, overexpression/silencing, AKT domain-binding mapping","pmids":["23824745"],"confidence":"Medium","gaps":["Structural basis of AKT inhibition unresolved","Single-lab evidence"]},{"year":2014,"claim":"CK1α phosphorylation at the SLS motif was identified as a switch attenuating JADE1's Wnt-inhibitory activity, and Aurora A-dependent phosphorylation was shown to drive cell-cycle chromatin shuttling.","evidence":"In vitro kinase assays, SLS mutagenesis, Xenopus axis assay; fractionation, MS phosphosite mapping, Aurora A inhibitor, mouse kidney imaging","pmids":["25100726","24739512"],"confidence":"Medium","gaps":["How phosphorylation integrates with E3 versus HAT functions unclear","Direct kinase responsible for each mitotic phosphosite not fully assigned"]},{"year":2018,"claim":"Reconstitution defined JADE1 as the structural bridge linking HBO1 to histone H3-H4, mechanistically explaining its ~5-fold stimulation of HAT activity.","evidence":"In vitro reconstitution with recombinant proteins, HAT kinetics, deletion mapping in vitro and in vivo","pmids":["29382722"],"confidence":"High","gaps":["High-resolution structure of the bridged complex not provided","Determinants of substrate specificity not defined"]},{"year":2021,"claim":"JADE1 was linked to tauopathy, associating with 4R tau aggregates and modulating tau-induced neurotoxicity.","evidence":"Co-IP from human PART brain, immunohistochemistry, Drosophila rno knockdown with toxicity assays","pmids":["34719765"],"confidence":"Medium","gaps":["Whether HAT or E3 activity mediates the tau interaction unknown","Single study, mechanism of toxicity modulation unclear"]},{"year":2025,"claim":"Structural and genomic analysis showed JADE1-HBO1 is directed by Oct4 at palindromic MORE elements to drive site-specific H3K9 acetylation, defining a sequence-specific targeting mechanism for the complex.","evidence":"Co-IP, ChIP-seq, in vitro HAT assays on nucleosomes, knockdown, cryo-EM","pmids":["41489900"],"confidence":"High","gaps":["How Oct4 recruitment relates to JADE1's E3 and proliferative roles unknown","Generality beyond Oct4-MORE sites not established"]},{"year":null,"claim":"How JADE1's two distinct biochemical activities — HBO1 co-factor scaffolding and β-catenin E3 ubiquitin ligase — are coordinated within a single protein, and how its many regulatory inputs integrate to switch between them, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural/biochemical model reconciling scaffold and ligase functions","Catalytic mechanism of the E3 activity unmapped","Interplay between mitotic shuttling, Wnt regulation, and HAT targeting unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,12,5]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,12]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[12,4]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,6,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,11]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[11,8]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[4,12,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,9,6]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,7]}],"complexes":["HBO1 histone acetyltransferase complex"],"partners":["HBO1","VHL","CTNNB1","NPHP4","PKD1","AKT1","CSNK1A1","POU5F1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6IE81","full_name":"Protein Jade-1","aliases":["Jade family PHD finger protein 1","PHD finger protein 17"],"length_aa":842,"mass_kda":95.5,"function":"Scaffold subunit of some HBO1 complexes, which have a histone H4 acetyltransferase activity (PubMed:16387653, PubMed:19187766, PubMed:20129055, PubMed:24065767). Plays a key role in HBO1 complex by directing KAT7/HBO1 specificity towards histone H4 acetylation (H4K5ac, H4K8ac and H4K12ac), regulating DNA replication initiation, regulating DNA replication initiation (PubMed:20129055, PubMed:24065767). May also promote acetylation of nucleosomal histone H4 by KAT5 (PubMed:15502158). Promotes apoptosis (PubMed:16046545). May act as a renal tumor suppressor (PubMed:16046545). Negatively regulates canonical Wnt signaling; at least in part, cooperates with NPHP4 in this function (PubMed:22654112)","subcellular_location":"Nucleus; Chromosome; Cytoplasm; Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/Q6IE81/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/JADE1","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/JADE1","total_profiled":1310},"omim":[{"mim_id":"610515","title":"JADE FAMILY PHD FINGER 2; JADE2","url":"https://www.omim.org/entry/610515"},{"mim_id":"610514","title":"JADE FAMILY PHD FINGER 1; JADE1","url":"https://www.omim.org/entry/610514"},{"mim_id":"300618","title":"JADE FAMILY PHD FINGER 3; JADE3","url":"https://www.omim.org/entry/300618"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Centrosome","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/JADE1"},"hgnc":{"alias_symbol":["JADE-1"],"prev_symbol":["PHF17"]},"alphafold":{"accession":"Q6IE81","domains":[{"cath_id":"1.10.10","chopping":"139-193_427-467","consensus_level":"medium","plddt":93.3776,"start":139,"end":467},{"cath_id":"1.20.5","chopping":"479-534","consensus_level":"medium","plddt":91.5996,"start":479,"end":534}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6IE81","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6IE81-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6IE81-F1-predicted_aligned_error_v6.png","plddt_mean":61.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=JADE1","jax_strain_url":"https://www.jax.org/strain/search?query=JADE1"},"sequence":{"accession":"Q6IE81","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6IE81.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6IE81/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6IE81"}},"corpus_meta":[{"pmid":"18806787","id":"PMC_18806787","title":"Jade-1 inhibits Wnt signalling by ubiquitylating beta-catenin and mediates Wnt pathway inhibition by pVHL.","date":"2008","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18806787","citation_count":153,"is_preprint":false},{"pmid":"12169691","id":"PMC_12169691","title":"The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12169691","citation_count":68,"is_preprint":false},{"pmid":"18684714","id":"PMC_18684714","title":"Role of Jade-1 in the histone acetyltransferase (HAT) HBO1 complex.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18684714","citation_count":65,"is_preprint":false},{"pmid":"16046545","id":"PMC_16046545","title":"Jade-1, a candidate renal tumor suppressor that promotes apoptosis.","date":"2005","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16046545","citation_count":60,"is_preprint":false},{"pmid":"14973063","id":"PMC_14973063","title":"Tumor suppressor von Hippel-Lindau (VHL) stabilization of Jade-1 protein occurs through plant homeodomains and is VHL mutation dependent.","date":"2004","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/14973063","citation_count":55,"is_preprint":false},{"pmid":"22654112","id":"PMC_22654112","title":"The ciliary protein nephrocystin-4 translocates the canonical Wnt regulator Jade-1 to the nucleus to negatively regulate β-catenin signaling.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22654112","citation_count":47,"is_preprint":false},{"pmid":"23159946","id":"PMC_23159946","title":"Histone acetyl transferase (HAT) HBO1 and JADE1 in epithelial cell regeneration.","date":"2012","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23159946","citation_count":45,"is_preprint":false},{"pmid":"15502158","id":"PMC_15502158","title":"von Hippel-Lindau partner Jade-1 is a transcriptional co-activator associated with histone acetyltransferase activity.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15502158","citation_count":44,"is_preprint":false},{"pmid":"14612400","id":"PMC_14612400","title":"Identification of Jade1, a gene encoding a PHD zinc finger protein, in a gene trap mutagenesis screen for genes involved in anteroposterior axis development.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/14612400","citation_count":39,"is_preprint":false},{"pmid":"32351328","id":"PMC_32351328","title":"Silencing of microRNA-135b inhibits invasion, migration, and stemness of CD24+CD44+ pancreatic cancer stem cells through JADE-1-dependent AKT/mTOR pathway.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/32351328","citation_count":29,"is_preprint":false},{"pmid":"34719765","id":"PMC_34719765","title":"Genome-wide association study and functional validation implicates JADE1 in tauopathy.","date":"2021","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/34719765","citation_count":29,"is_preprint":false},{"pmid":"29382722","id":"PMC_29382722","title":"The scaffolding protein JADE1 physically links the acetyltransferase subunit HBO1 with its histone H3-H4 substrate.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29382722","citation_count":28,"is_preprint":false},{"pmid":"27155521","id":"PMC_27155521","title":"Structure, function and regulation of jade family PHD finger 1 (JADE1).","date":"2016","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/27155521","citation_count":23,"is_preprint":false},{"pmid":"24739512","id":"PMC_24739512","title":"Cell cycle-dependent chromatin shuttling of HBO1-JADE1 histone acetyl transferase (HAT) complex.","date":"2014","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/24739512","citation_count":23,"is_preprint":false},{"pmid":"25100726","id":"PMC_25100726","title":"Casein kinase 1 α phosphorylates the Wnt regulator Jade-1 and modulates its activity.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25100726","citation_count":20,"is_preprint":false},{"pmid":"23824745","id":"PMC_23824745","title":"Candidate tumor suppressor and pVHL partner Jade-1 binds and inhibits AKT in renal cell carcinoma.","date":"2013","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/23824745","citation_count":17,"is_preprint":false},{"pmid":"23001567","id":"PMC_23001567","title":"Polycystin-1 regulates the stability and ubiquitination of transcription factor Jade-1.","date":"2012","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23001567","citation_count":17,"is_preprint":false},{"pmid":"22516360","id":"PMC_22516360","title":"Expression and clinical significance of von Hippel-Lindau downstream genes: Jade-1 and β-catenin related to renal cell carcinoma.","date":"2012","source":"Urology","url":"https://pubmed.ncbi.nlm.nih.gov/22516360","citation_count":15,"is_preprint":false},{"pmid":"37175531","id":"PMC_37175531","title":"MicroRNA-155-5p Targets JADE-1, Promoting Proliferation, Migration, and Invasion in Clear Cell Renal Cell Carcinoma Cells.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37175531","citation_count":9,"is_preprint":false},{"pmid":"38171233","id":"PMC_38171233","title":"JADE1 is dispensable for the brain development in mice.","date":"2023","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/38171233","citation_count":2,"is_preprint":false},{"pmid":"26695694","id":"PMC_26695694","title":"Jade-1: its structure, regulation and functions in the renal cancer.","date":"2016","source":"Current molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26695694","citation_count":1,"is_preprint":false},{"pmid":"39574712","id":"PMC_39574712","title":"Jade1 and the HBO1 histone acetyltransferase complex are spatial-selective cofactors of the pluripotency transcription factor Oct4.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39574712","citation_count":1,"is_preprint":false},{"pmid":"41379394","id":"PMC_41379394","title":"JADE1 is not essential for spermatogenesis and male fertility in mice.","date":"2025","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/41379394","citation_count":0,"is_preprint":false},{"pmid":"41489900","id":"PMC_41489900","title":"Jade1 and the HBO1 histone acetyltransferase complex are spatial-selective cofactors of the pluripotency transcription factor Oct4.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41489900","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14450,"output_tokens":4152,"usd":0.052815,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12056,"output_tokens":4392,"usd":0.08504,"stage2_stop_reason":"end_turn"},"total_usd":0.137855,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"Jade-1 protein directly interacts with VHL protein (pVHL) as shown by yeast two-hybrid and co-immunoprecipitation; pVHL stabilizes Jade-1 protein by increasing its half-life up to 3-fold, identifying protein stabilization as a new VHL function. Jade-1 localizes to cytoplasm and nucleus (including speckles) where it partly colocalizes with VHL.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, metabolic labeling, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP and metabolic labeling, replicated across multiple cell lines and conditions\",\n      \"pmids\": [\"12169691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"VHL-mediated stabilization of Jade-1 requires the PHD-extended PHD module of Jade-1, not its PEST domain. Both the alpha and beta domains of VHL are required for Jade-1 stabilization, while the beta domain alone is sufficient for binding. VHL missense mutations associated with renal cancer (Leu118Pro, Arg167Trp) fail to stabilize Jade-1, whereas mutations without renal cancer risk (Tyr98His, Tyr112His) fully stabilize Jade-1.\",\n      \"method\": \"Co-immunoprecipitation, cotransfection with domain deletions/mutants, metabolic labeling\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple VHL mutants tested with domain mapping and metabolic labeling, multiple orthogonal methods\",\n      \"pmids\": [\"14973063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Jade-1 is a transcriptional co-activator: Gal4-Jade-1 fusion activates transcription 5–6-fold at Gal4-responsive promoters. Jade-1 overexpression specifically increases acetylated histone H4 but not H3, and this requires the PHD fingers. TIP60 HAT physically associates with Jade-1 and augments its HAT activity.\",\n      \"method\": \"Gal4 reporter co-transfection, western blot for acetylated histones, co-immunoprecipitation with TIP60, PHD deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays and co-IP from single lab with domain mutant validation\",\n      \"pmids\": [\"15502158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Jade-1 promotes apoptosis: overexpression increased apoptosis by 40–50% and decreased anti-apoptotic Bcl-2 levels; Jade-1 inhibited renal cancer cell growth, colony formation, and tumor formation in nude mice. Antisense Jade-1 confirmed these results.\",\n      \"method\": \"Overexpression and antisense knockdown in renal cancer cell lines, apoptosis assays, colony formation assay, nude mouse xenograft\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function experiments with multiple phenotypic readouts in a single lab\",\n      \"pmids\": [\"16046545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Jade-1 is a component of the HBO1 HAT complex and acts as a critical co-factor: co-expression of Jade-1/1L and HBO1 synergistically increases acetylation of endogenous histone H4 in epithelial cells; siRNA depletion of Jade-1 reduces H4 acetylation; Jade-1/1L enhances HBO1-mediated H4 acetylation severalfold in vitro with reconstituted oligonucleosome substrates. The PHD fingers of Jade-1 are required for this activity but not for HBO1 binding.\",\n      \"method\": \"Co-expression, siRNA knockdown, in vitro HAT assay with reconstituted oligonucleosomes, PHD finger deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with nucleosome substrates plus cell-based gain/loss-of-function and domain mutagenesis\",\n      \"pmids\": [\"18684714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Jade-1 binds beta-catenin in Wnt-responsive fashion and functions as an E3 ubiquitin ligase that ubiquitylates both phosphorylated and non-phosphorylated beta-catenin, thereby destabilizing wild-type beta-catenin but not cancer-causing forms. pVHL downregulates beta-catenin in a Jade-1-dependent manner and inhibits Wnt signaling, directly linking pVHL to the Wnt pathway through Jade-1.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays, siRNA knockdown, reporter assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical ubiquitylation assay, co-IP, genetic dependency (Jade-1-dependent pVHL effect), replicated across cell-based and biochemical systems\",\n      \"pmids\": [\"18806787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Jade-1 colocalizes with NPHP1 at the transition zone of primary cilia and interacts with NPHP4. NPHP4 stabilizes Jade-1 protein levels and promotes translocation of Jade-1 to the nucleus; NPHP4 and Jade-1 additively inhibit canonical Wnt signaling, conserved in zebrafish.\",\n      \"method\": \"Co-immunoprecipitation, co-localization imaging, protein stability assays, Wnt reporter assays, zebrafish genetic experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus localization imaging and functional epistasis in zebrafish, single lab\",\n      \"pmids\": [\"22654112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Full-length polycystin-1 (PC1) binds, stabilizes, and colocalizes with Jade-1 and inhibits Jade-1 ubiquitination. The PC1 cytoplasmic tail and PC1-CTF promote Jade-1 ubiquitination and degradation (dominant-negative mechanism). Jade-1 ubiquitination is mediated by the E3 ligase Siah-1 which binds PC1. ADPKD-associated PC1 mutants fail to regulate Jade-1.\",\n      \"method\": \"Co-immunoprecipitation, co-localization, ubiquitination assays, ADPKD mutant analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assays with domain variants and disease mutants, single lab\",\n      \"pmids\": [\"23001567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"JADE1S-HBO1 complex is required for cell proliferation: siRNA knockdown of JADE1 diminished DNA synthesis, decreased HBO1 protein expression, and prevented chromatin recruitment of replication factor Mcm7. In an acute kidney injury mouse model, JADE1S and JADE1L protein levels decrease after injury and recover during regeneration; JADE1S recovery correlated with histone H4 acetylation on K5 and K12 but not H3K14.\",\n      \"method\": \"siRNA knockdown, BrdU/DNA synthesis assay, chromatin immunoprecipitation (Mcm7), mouse ischemia-reperfusion injury model, western blot\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA with specific phenotypic readouts plus in vivo model, single lab\",\n      \"pmids\": [\"23159946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Jade-1 binds and inhibits AKT1: Jade-1 overexpression increases phospho-AKT/AKT1 levels while silencing decreases them; pVHL reintroduction increases Jade-1 and suppresses phospho-AKT. The N-terminus of Jade-1 binds both the catalytic domain and C-terminal regulatory tail of AKT1, suppressing AKT kinase activity.\",\n      \"method\": \"Kinase arrays, co-immunoprecipitation, overexpression and siRNA silencing, domain mapping with AKT binding assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase arrays plus co-IP with domain mapping and cell-based phenotype, single lab\",\n      \"pmids\": [\"23824745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Casein kinase 1α (CK1α) phosphorylates Jade-1 at a conserved SLS motif and reduces Jade-1's ability to inhibit β-catenin/Wnt signaling. A Jade-1 mutant lacking the SLS motif is more effective than wild-type at reducing β-catenin-induced secondary axis formation in Xenopus laevis embryos.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis of SLS motif, Xenopus secondary axis formation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — kinase assay plus in vivo Xenopus functional validation, single lab\",\n      \"pmids\": [\"25100726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HBO1-JADE1S complex undergoes cell cycle-dependent chromatin shuttling: JADE1S is nuclear/chromatin-associated in interphase, dissociates from chromatin and enters cytoplasm at prophase, and re-associates with chromatin in telophase/early G1. Cytoplasmic JADE1S is phosphorylated at 6 residues (S89, T92, S102, S121, S392, T468). Aurora A kinase inhibitor prevents the JADE1S band shift and chromatin dissociation. Chromatin re-association parallels global histone H4 acetylation.\",\n      \"method\": \"Cell fractionation, immunofluorescence, mass spectrometry of phosphorylated residues, Aurora A kinase inhibitor, in vivo mouse kidney immunostaining\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (fractionation, MS, inhibitor, in vivo) from single lab\",\n      \"pmids\": [\"24739512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JADE1 functions as a scaffolding protein that physically links HBO1 to its histone H3-H4 substrate. The N-terminal 21-residue domain of JADE1 binds both HBO1 and histones and increases HBO1 catalytic efficiency for H3-H4 acetylation ~5-fold. A second nearby domain in JADE1 also contacts the histone core. HBO1 contains an N-terminal histone-binding domain (HBD) that contacts H3-H4 independently of JADE1 but does not significantly contribute to HAT activity.\",\n      \"method\": \"In vitro reconstitution with recombinant proteins, HAT activity assays with histone substrates, JADE1 deletion mapping in vitro and in vivo\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with recombinant proteins plus domain deletion mapping both in vitro and in vivo, rigorous enzyme kinetics\",\n      \"pmids\": [\"29382722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"JADE1 protein co-immunoprecipitates with four-repeat tau (0N4R) from post-mortem human PART brain tissue. JADE1 protein localizes within tau aggregates containing 4R isoforms. Knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhances tau-induced toxicity and apoptosis in a humanized 0N4R mutant tau knock-in model.\",\n      \"method\": \"Co-immunoprecipitation from human brain tissue, immunohistochemistry, Drosophila genetic knockdown with rough eye and TUNEL assays\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP from human tissue plus Drosophila genetic epistasis, but single study\",\n      \"pmids\": [\"34719765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Jade1 preferentially associates with Oct4 when Oct4 is bound to MORE (palindromic octamer-related element) DNA sequences that recruit Oct4 dimers; the Oct4 N-terminal activation domain acts as an autoinhibitory domain dampening Jade1 interaction. The HBO1 complex acetylates histone H3K9 within nucleosomes more efficiently when Oct4 is co-bound to a MORE. Jade1 knockdown reduces H3K9Ac specifically at MORE-bound Oct4 sites. Cryo-EM reveals Oct4 bound to MORE partially unwinds nucleosomal DNA and shows additional mass from the HBO1 complex.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, in vitro HAT assays with purified recombinant proteins and nucleosome complexes, Jade1 knockdown, cryo-EM\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure, in vitro reconstitution with nucleosomes, ChIP-seq, and knockdown with multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"41489900\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"JADE1 is a PHD zinc finger scaffold protein that acts as a critical co-factor of the HBO1 histone acetyltransferase (HAT) complex, physically bridging HBO1 to its histone H3-H4 substrate and stimulating HAT activity (~5-fold in vitro); it also functions as an E3 ubiquitin ligase targeting both phosphorylated and non-phosphorylated β-catenin for proteasomal degradation to suppress canonical Wnt signaling; its stability and activity are regulated by direct interactions with pVHL (stabilization via the PHD module), polycystin-1, NPHP4 (nuclear translocation), and CK1α (phosphorylation at SLS motif that attenuates Wnt inhibitory activity); additionally, Jade1 binds and inhibits AKT1 kinase, undergoes cell cycle-dependent phosphorylation-regulated chromatin shuttling during mitosis, and preferentially co-operates with Oct4 at palindromic MORE DNA elements to drive H3K9 acetylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"JADE1 is a PHD zinc-finger scaffold protein that operates at the interface of histone acetylation and Wnt signaling [#4, #5]. As an essential co-factor of the HBO1 histone acetyltransferase complex, its N-terminal domain physically bridges HBO1 to its histone H3-H4 substrate and increases HBO1 catalytic efficiency ~5-fold in vitro, with its PHD fingers required for acetyltransferase stimulation but not for HBO1 binding [#4, #12]; this complex is required for DNA synthesis and chromatin recruitment of the replication factor Mcm7 [#8]. JADE1 directs HBO1 activity in a sequence-specific manner, preferentially partnering with Oct4 bound at palindromic MORE DNA elements to drive H3K9 acetylation [#14]. Independently, JADE1 acts as an E3 ubiquitin ligase that ubiquitylates both phosphorylated and non-phosphorylated \\u03b2-catenin, destabilizing wild-type \\u03b2-catenin to suppress canonical Wnt signaling and linking the tumor suppressor pVHL to Wnt inhibition [#5]. JADE1 abundance and activity are set by direct partners: pVHL stabilizes JADE1 via its PHD-extended module, and renal-cancer-associated VHL mutations fail to stabilize it [#0, #1]; the ciliary protein NPHP4 stabilizes and promotes nuclear translocation of JADE1 [#6]; polycystin-1 stabilizes JADE1 while its cytoplasmic tail promotes Siah-1-mediated JADE1 ubiquitination [#7]; and CK1\\u03b1 phosphorylation at a conserved SLS motif attenuates JADE1's Wnt-inhibitory activity [#10]. JADE1 also binds and inhibits AKT1 kinase, and its overexpression promotes apoptosis and suppresses renal cancer cell growth [#3, #9]. Its chromatin association is cell-cycle-regulated, with Aurora A-dependent phosphorylation driving dissociation from chromatin at mitosis and re-association in telophase paralleling global H4 acetylation [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing JADE1 as a direct VHL-interacting partner whose stability is controlled by pVHL revealed a new VHL function and placed JADE1 in renal cancer biology.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP and metabolic labeling across cell lines\",\n      \"pmids\": [\"12169691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular function of JADE1 itself\", \"Mechanism of pVHL-mediated half-life extension unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Domain mapping showed VHL stabilization requires the JADE1 PHD module and that renal-cancer VHL mutants selectively fail to stabilize JADE1, tying JADE1 stabilization to tumor-suppressor function.\",\n      \"evidence\": \"Co-IP and metabolic labeling with VHL domain deletions and disease mutants\",\n      \"pmids\": [\"14973063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how loss of JADE1 stabilization contributes to tumorigenesis\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"First evidence of JADE1 as a transcriptional co-activator linked to histone acetylation, implicating its PHD fingers and a HAT partner.\",\n      \"evidence\": \"Gal4 reporter assays, acetyl-histone western blots, co-IP with TIP60, PHD deletions\",\n      \"pmids\": [\"15502158\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TIP60 association reported here was superseded by HBO1 as the principal partner\", \"No genomic targets defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Functional readout connected JADE1 to apoptosis and tumor suppression in renal cancer cells, motivating its mechanistic role downstream of VHL.\",\n      \"evidence\": \"Overexpression/antisense in renal cancer lines, apoptosis and colony assays, nude mouse xenografts\",\n      \"pmids\": [\"16046545\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway linking JADE1 to Bcl-2 loss not defined\", \"Single-lab phenotype\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of JADE1 as an essential HBO1 HAT co-factor defined its core biochemical activity in promoting histone H4 acetylation.\",\n      \"evidence\": \"Co-expression, siRNA, in vitro HAT assay on reconstituted oligonucleosomes, PHD mutants\",\n      \"pmids\": [\"18684714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of substrate bridging not yet resolved\", \"Genomic distribution of HBO1-JADE1 acetylation unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery that JADE1 is an E3 ligase for \\u03b2-catenin established the mechanism by which pVHL suppresses Wnt signaling through JADE1.\",\n      \"evidence\": \"Co-IP, ubiquitylation assays, siRNA, Wnt reporter assays\",\n      \"pmids\": [\"18806787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The catalytic determinants of JADE1 ligase activity not mapped\", \"How a PHD scaffold also acts catalytically as an E3 unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"NPHP4 and polycystin-1 were shown to control JADE1 localization and stability, embedding JADE1 in ciliary and cystic-kidney signaling.\",\n      \"evidence\": \"Co-IP, colocalization at cilia transition zone, stability and ubiquitination assays, ADPKD mutants, zebrafish epistasis\",\n      \"pmids\": [\"22654112\", \"23001567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ciliary regulation of JADE1 feeds back to HAT activity unknown\", \"Single-lab co-IP evidence\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The JADE1S-HBO1 complex was shown to be required for proliferation and DNA replication and to track kidney injury and regeneration.\",\n      \"evidence\": \"siRNA, DNA synthesis assays, Mcm7 ChIP, mouse ischemia-reperfusion model\",\n      \"pmids\": [\"23159946\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism linking JADE1 to Mcm7 chromatin loading not established\", \"Isoform-specific roles incompletely separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"JADE1 was shown to bind and inhibit AKT1, extending its tumor-suppressive role to a kinase-inhibitory function downstream of pVHL.\",\n      \"evidence\": \"Kinase arrays, co-IP, overexpression/silencing, AKT domain-binding mapping\",\n      \"pmids\": [\"23824745\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of AKT inhibition unresolved\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"CK1\\u03b1 phosphorylation at the SLS motif was identified as a switch attenuating JADE1's Wnt-inhibitory activity, and Aurora A-dependent phosphorylation was shown to drive cell-cycle chromatin shuttling.\",\n      \"evidence\": \"In vitro kinase assays, SLS mutagenesis, Xenopus axis assay; fractionation, MS phosphosite mapping, Aurora A inhibitor, mouse kidney imaging\",\n      \"pmids\": [\"25100726\", \"24739512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How phosphorylation integrates with E3 versus HAT functions unclear\", \"Direct kinase responsible for each mitotic phosphosite not fully assigned\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Reconstitution defined JADE1 as the structural bridge linking HBO1 to histone H3-H4, mechanistically explaining its ~5-fold stimulation of HAT activity.\",\n      \"evidence\": \"In vitro reconstitution with recombinant proteins, HAT kinetics, deletion mapping in vitro and in vivo\",\n      \"pmids\": [\"29382722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the bridged complex not provided\", \"Determinants of substrate specificity not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"JADE1 was linked to tauopathy, associating with 4R tau aggregates and modulating tau-induced neurotoxicity.\",\n      \"evidence\": \"Co-IP from human PART brain, immunohistochemistry, Drosophila rno knockdown with toxicity assays\",\n      \"pmids\": [\"34719765\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HAT or E3 activity mediates the tau interaction unknown\", \"Single study, mechanism of toxicity modulation unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Structural and genomic analysis showed JADE1-HBO1 is directed by Oct4 at palindromic MORE elements to drive site-specific H3K9 acetylation, defining a sequence-specific targeting mechanism for the complex.\",\n      \"evidence\": \"Co-IP, ChIP-seq, in vitro HAT assays on nucleosomes, knockdown, cryo-EM\",\n      \"pmids\": [\"41489900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Oct4 recruitment relates to JADE1's E3 and proliferative roles unknown\", \"Generality beyond Oct4-MORE sites not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How JADE1's two distinct biochemical activities — HBO1 co-factor scaffolding and \\u03b2-catenin E3 ubiquitin ligase — are coordinated within a single protein, and how its many regulatory inputs integrate to switch between them, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural/biochemical model reconciling scaffold and ligase functions\", \"Catalytic mechanism of the E3 activity unmapped\", \"Interplay between mitotic shuttling, Wnt regulation, and HAT targeting unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 12, 5]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 12]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [12, 4]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 6, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [11, 8]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [4, 12, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 9, 6]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 7]}\n    ],\n    \"complexes\": [\n      \"HBO1 histone acetyltransferase complex\"\n    ],\n    \"partners\": [\n      \"HBO1\",\n      \"VHL\",\n      \"CTNNB1\",\n      \"NPHP4\",\n      \"PKD1\",\n      \"AKT1\",\n      \"CSNK1A1\",\n      \"POU5F1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}