{"gene":"JUP","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1991,"finding":"The plakoglobin gene (DPIII/JUP) was mapped to human chromosome 17 using PCR assays on human-mouse and human-rat somatic cell hybrids.","method":"PCR-based chromosomal assignment using somatic cell hybrids","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal mapping by PCR in somatic cell hybrids, single lab, single method","pmids":["1889810"],"is_preprint":false},{"year":2000,"finding":"The human plakoglobin gene (JUP) comprises 13 distinct exons spanning approximately 17 kb on chromosome 17q21, establishing its intron-exon genomic organization.","method":"Genomic cloning, sequencing, and PCR-based exon mapping","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic sequencing and PCR characterization, single lab","pmids":["11016852"],"is_preprint":false},{"year":2005,"finding":"JUP (gamma-catenin/plakoglobin) mRNA is expressed in adult primate neurons of the dorsolateral prefrontal cortex and hippocampus, with diffuse localization in the cortex and distinct localization in granule cells of the dentate gyrus and pyramidal cells of Ammon's horn, as determined by in situ hybridization.","method":"In situ hybridization in adult primate brain sections","journal":"Brain research. Molecular brain research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization method (ISH), no functional consequence tested, single lab","pmids":["15857685"],"is_preprint":false},{"year":2010,"finding":"Homozygous loss-of-function mutations in the 5' region of JUP (nonsense p.S24X and splice site c.468G>A) result in skin fragility, diffuse palmoplantar keratoderma, and woolly hair without cardiomyopathy, establishing that plakoglobin is required for skin integrity and that its absence does not compromise normal human heart development in children. Barely detectable plakoglobin immunostaining was found in patient skin sections, and an alternative AUG codon in the p.S24X mRNA was shown to produce a 42-amino-acid N-terminally truncated protein.","method":"Mutation identification by sequencing, immunostaining of patient skin sections, and analysis of alternative translation initiation","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — human genetic loss-of-function with defined molecular mechanism (alternative AUG translation), immunostaining validation, clear phenotypic readout","pmids":["20130592"],"is_preprint":false},{"year":2011,"finding":"A homozygous missense mutation p.R265H in JUP encoding plakoglobin causes a novel autosomal recessive syndrome (CAPK) comprising arrhythmogenic right ventricular cardiomyopathy, alopecia, and palmoplantar keratoderma, demonstrating that this specific JUP mutation disrupts both cardiac and cutaneous desmosomal function.","method":"Genetic mapping and mutation identification in an affected family","journal":"The British journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — human disease genetics establishing loss-of-function phenotype, single family, no molecular reconstitution","pmids":["21668431"],"is_preprint":false},{"year":2020,"finding":"JUP (junction plakoglobin) localizes to the cell membrane and cytoplasm in epithelium-like gastric cancer (GC) cells, where it restrains EGFR at the cell membrane. Loss of membrane/cytoplasmic JUP in GC cells increases p-AKT levels and activates AKT/GSK3β/β-catenin signaling, promoting epithelial-mesenchymal transition (EMT), migration, and invasion. Conversely, nuclear JUP interacts with nuclear β-catenin and TCF4 to synergistically promote TCF4 transcription and downstream MMP7 expression, fueling GC cell invasion. Knockdown of JUP in epithelium-like GC cells caused EMT and promoted migration and invasion; ectopic expression in malignant GC cells reduced invasive potential.","method":"JUP knockdown and overexpression in GC cell lines, co-immunoprecipitation, western blotting, migration/invasion assays","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal functional studies (KD and OE), co-IP for nuclear complex, mechanistic pathway placement, single lab","pmids":["33364056"],"is_preprint":false},{"year":2023,"finding":"XAF1 acts as an adaptor for valosin-containing protein (VCP), facilitating VCP-mediated deubiquitination of the E3 ligase RNF114, which in turn promotes K48-linked ubiquitination and proteasomal degradation of JUP (junction plakoglobin). Degradation of JUP via the XAF1-VCP-RNF114 axis promotes colorectal cancer cell migration and metastasis.","method":"Co-immunoprecipitation, ubiquitination assays, protein interaction studies, knockdown/overexpression in CRC cells, correlation with clinical samples","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, defined ubiquitin linkage (K48), functional rescue experiments, validated in clinical samples, multiple orthogonal methods in single study","pmids":["38095639"],"is_preprint":false},{"year":2023,"finding":"In bladder cancer cells, dihydrotestosterone (DHT) binds to EPPK1, which activates p38 MAPK signaling and c-Jun, leading to c-Jun binding to the JUP promoter and upregulation of JUP expression. Elevated JUP expression downstream of EPPK1/p38 MAPK promotes bladder cancer cell proliferation and invasion; JUP knockdown inhibited these DHT-induced effects.","method":"Biotinylated DHT-binding pull-down, JUP knockdown, p38 inhibition, ChIP-like promoter binding assay, xenograft mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple orthogonal methods (pull-down, KD, inhibitor, in vivo), defined transcriptional mechanism (c-Jun/JUP promoter), single lab","pmids":["37328487"],"is_preprint":false},{"year":2022,"finding":"In gastric cancer, TROP2 downregulates DSG2 expression and disrupts the DSG2/plakoglobin (PG/JUP)/β-catenin signaling pathway, promoting cell invasion and migration. Co-immunoprecipitation identified DSG2 as an interacting protein of TROP2.","method":"Co-immunoprecipitation with mass spectrometry, TROP2 overexpression/knockdown, western blotting, cell adhesion and invasion assays, electron microscopy of desmosomes","journal":"Current cancer drug targets","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP/MS identification of interaction, functional manipulation of pathway, single lab, partial mechanistic follow-up of JUP specifically","pmids":["35392784"],"is_preprint":false}],"current_model":"Plakoglobin (JUP) is a dual-compartment scaffold protein that functions at desmosomes and adherens junctions to maintain cell adhesion and tissue integrity in skin and heart; at the membrane/cytoplasm it sequesters EGFR and restrains AKT/GSK3β/β-catenin signaling, while in the nucleus it forms a complex with β-catenin and TCF4 to drive transcription of invasion-promoting genes such as MMP7; its abundance is regulated by K48-linked ubiquitination and proteasomal degradation via the XAF1-VCP-RNF114 E3 ligase axis, and its expression can be transcriptionally induced through a non-canonical DHT/EPPK1/p38 MAPK/c-Jun pathway in bladder cancer cells."},"narrative":{"mechanistic_narrative":"Plakoglobin (JUP) is a desmosomal junction protein required for the integrity of skin and heart, as established by human loss-of-function and missense mutations that produce palmoplantar keratoderma, woolly hair, skin fragility, and arrhythmogenic right ventricular cardiomyopathy [PMID:20130592, PMID:21668431]. Beyond its structural adhesion role, JUP behaves as a dual-compartment scaffold that shapes signaling: at the membrane and cytoplasm it restrains EGFR and thereby suppresses AKT/GSK3β/β-catenin signaling, whereas in the nucleus it complexes with β-catenin and TCF4 to drive transcription of invasion genes including MMP7, with loss of membrane JUP promoting epithelial-mesenchymal transition and invasion in gastric cancer [PMID:33364056]. JUP function in adhesion-linked signaling is also coupled to the desmoglein DSG2/plakoglobin/β-catenin axis, which TROP2 disrupts to promote gastric cancer invasion [PMID:35392784]. JUP abundance is controlled by K48-linked ubiquitination and proteasomal degradation through the XAF1-VCP-RNF114 E3 ligase axis, and its degradation promotes colorectal cancer migration and metastasis [PMID:38095639]. JUP transcription can be induced via a non-canonical DHT/EPPK1/p38 MAPK/c-Jun pathway in bladder cancer, where c-Jun binds the JUP promoter to drive proliferation and invasion [PMID:37328487].","teleology":[{"year":1991,"claim":"Establishing the chromosomal location of the plakoglobin gene was the first step toward genetic characterization of the locus.","evidence":"PCR-based chromosomal assignment using human-rodent somatic cell hybrids","pmids":["1889810"],"confidence":"Medium","gaps":["No functional or protein-level characterization","Did not define gene structure or expression"]},{"year":2000,"claim":"Resolving the intron-exon organization of JUP provided the genomic framework needed for mutation analysis.","evidence":"Genomic cloning, sequencing, and PCR-based exon mapping","pmids":["11016852"],"confidence":"Medium","gaps":["No link to disease or function at this stage","Regulatory elements not mapped"]},{"year":2005,"claim":"Detection of JUP mRNA in primate neurons raised the question of a role outside epithelial/cardiac junctions, though function was not tested.","evidence":"In situ hybridization in adult primate prefrontal cortex and hippocampus","pmids":["15857685"],"confidence":"Low","gaps":["Single localization method, no functional consequence tested","Protein-level confirmation absent","Neuronal role unestablished"]},{"year":2010,"claim":"Human homozygous loss-of-function mutations showed plakoglobin is essential for skin integrity and that its absence need not compromise heart development, also revealing an alternative-AUG truncated protein.","evidence":"Mutation sequencing, patient skin immunostaining, and analysis of alternative translation initiation","pmids":["20130592"],"confidence":"High","gaps":["Does not explain genotype-specific cardiac sparing mechanistically","Function of the truncated protein unresolved"]},{"year":2011,"claim":"A recessive missense mutation linked JUP to a combined cardiac-cutaneous syndrome, showing specific alleles disrupt both heart and skin desmosomal function.","evidence":"Genetic mapping and mutation identification in an affected family","pmids":["21668431"],"confidence":"Medium","gaps":["Single family, no molecular reconstitution","Mechanism of mutation effect on desmosome not defined"]},{"year":2022,"claim":"Identification of the DSG2/plakoglobin/β-catenin axis as a TROP2 target connected JUP-linked desmosomal signaling to cancer invasion control.","evidence":"Co-IP/MS, TROP2 manipulation, invasion assays, and desmosome electron microscopy in gastric cancer cells","pmids":["35392784"],"confidence":"Medium","gaps":["Direct JUP interaction with TROP2 not the focus","Single lab, partial JUP-specific follow-up"]},{"year":2020,"claim":"Reciprocal functional studies defined JUP as a dual-compartment signaling switch: membrane JUP restrains EGFR/AKT signaling and suppresses EMT, while nuclear JUP/β-catenin/TCF4 drives invasion genes.","evidence":"JUP knockdown/overexpression, co-IP, and migration/invasion assays in gastric cancer cell lines","pmids":["33364056"],"confidence":"Medium","gaps":["Single lab","Determinants of JUP nuclear versus membrane partitioning not defined","Direct EGFR binding not structurally resolved"]},{"year":2023,"claim":"Defining the XAF1-VCP-RNF114 axis established how JUP protein abundance is post-translationally controlled and linked its degradation to metastasis.","evidence":"Reciprocal Co-IP, K48-linkage ubiquitination assays, rescue experiments, and clinical correlation in colorectal cancer","pmids":["38095639"],"confidence":"High","gaps":["Ubiquitination site on JUP not mapped","Whether degradation occurs in specific subcellular pools unknown"]},{"year":2023,"claim":"Mapping the DHT/EPPK1/p38 MAPK/c-Jun pathway showed JUP expression can be transcriptionally induced non-canonically to drive bladder cancer growth.","evidence":"Biotinylated DHT pull-down, p38 inhibition, c-Jun promoter binding, JUP knockdown, and xenografts","pmids":["37328487"],"confidence":"Medium","gaps":["Direct c-Jun/JUP promoter binding shown by ChIP-like assay only","Generalizability beyond bladder cancer untested"]},{"year":null,"claim":"How JUP's subcellular partitioning between adhesion, cytoplasmic signaling restraint, and nuclear transcription is coordinated, and how this integrates with its tissue-specific roles in skin and heart, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model connecting adhesion and signaling functions","Mechanism partitioning JUP to nucleus versus membrane unknown","Cardiac versus cutaneous mutation specificity unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6]}],"complexes":["desmosome","JUP/β-catenin/TCF4 complex"],"partners":["CTNNB1","TCF4","EGFR","DSG2","TROP2","RNF114"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P14923","full_name":"Junction plakoglobin","aliases":["Catenin gamma","Desmoplakin III","Desmoplakin-3"],"length_aa":745,"mass_kda":81.7,"function":"Common junctional plaque protein. The membrane-associated plaques are architectural elements in an important strategic position to influence the arrangement and function of both the cytoskeleton and the cells within the tissue. The presence of plakoglobin in both the desmosomes and in the intermediate junctions suggests that it plays a central role in the structure and function of submembranous plaques. Acts as a substrate for VE-PTP and is required by it to stimulate VE-cadherin function in endothelial cells. Can replace beta-catenin in E-cadherin/catenin adhesion complexes which are proposed to couple cadherins to the actin cytoskeleton (By similarity). May promote axon outgrowth and motor fiber repair via DSP-mediated recruitment to outgrowth tips (By similarity)","subcellular_location":"Cell junction, adherens junction; Cell junction, desmosome; Cytoplasm, cytoskeleton; Cell membrane; Cytoplasm; Cell junction; Nucleus; Cell projection, axon","url":"https://www.uniprot.org/uniprotkb/P14923/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/JUP","classification":"Not Classified","n_dependent_lines":20,"n_total_lines":1208,"dependency_fraction":0.016556291390728478},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDOST","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/JUP","total_profiled":1310},"omim":[{"mim_id":"620411","title":"PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC, 2; EPPK2","url":"https://www.omim.org/entry/620411"},{"mim_id":"618052","title":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 27; CMH27","url":"https://www.omim.org/entry/618052"},{"mim_id":"615821","title":"CARDIOMYOPATHY, DILATED, WITH WOOLLY HAIR, KERATODERMA, AND TOOTH AGENESIS; DCWHKTA","url":"https://www.omim.org/entry/615821"},{"mim_id":"614071","title":"MYOCARDIAL ZONULA ADHERENS PROTEIN; MYZAP","url":"https://www.omim.org/entry/614071"},{"mim_id":"613532","title":"RAS-ASSOCIATED PROTEIN RAB8B; RAB8B","url":"https://www.omim.org/entry/613532"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"esophagus","ntpm":914.3},{"tissue":"skin 1","ntpm":886.7}],"url":"https://www.proteinatlas.org/search/JUP"},"hgnc":{"alias_symbol":["DP3","PDGB","PKGB","DPIII","PG"],"prev_symbol":["CTNNG"]},"alphafold":{"accession":"P14923","domains":[{"cath_id":"1.25.10.10","chopping":"522-675","consensus_level":"medium","plddt":90.8251,"start":522,"end":675}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P14923","model_url":"https://alphafold.ebi.ac.uk/files/AF-P14923-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P14923-F1-predicted_aligned_error_v6.png","plddt_mean":81.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=JUP","jax_strain_url":"https://www.jax.org/strain/search?query=JUP"},"sequence":{"accession":"P14923","fasta_url":"https://rest.uniprot.org/uniprotkb/P14923.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P14923/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P14923"}},"corpus_meta":[{"pmid":"2531085","id":"PMC_2531085","title":"A collagen-binding 59-kd protein (fibromodulin) is structurally related to the small interstitial proteoglycans PG-S1 and PG-S2 (decorin).","date":"1989","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/2531085","citation_count":274,"is_preprint":false},{"pmid":"7822336","id":"PMC_7822336","title":"Multiple forms of mouse PG-M, a large chondroitin sulfate proteoglycan generated by alternative splicing.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7822336","citation_count":157,"is_preprint":false},{"pmid":"14766798","id":"PMC_14766798","title":"Versican/PG-M G3 domain promotes tumor growth and angiogenesis.","date":"2004","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/14766798","citation_count":151,"is_preprint":false},{"pmid":"2162845","id":"PMC_2162845","title":"Altered expression of chondroitin sulfate proteoglycan in the stroma of human colon carcinoma. 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II: mRNA for PGF2α, EP1, EP2, EP3 (A-D), EP3A, EP3B, EP3C, EP3D, and EP4 prostanoid receptors in luteal tissue.","date":"2011","source":"Prostaglandins & other lipid mediators","url":"https://pubmed.ncbi.nlm.nih.gov/22120546","citation_count":16,"is_preprint":false},{"pmid":"10370116","id":"PMC_10370116","title":"Genetic analysis of steel and the PG-M/versican-encoding gene AxPG as candidates for the white (d) pigmentation mutant in the salamander Ambystoma mexicanum.","date":"1999","source":"Development genes and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/10370116","citation_count":16,"is_preprint":false},{"pmid":"21601649","id":"PMC_21601649","title":"In vivo intra-luteal implants of prostaglandin (PG) E(1) or E(2) (PGE(1), PGE(2)) prevent luteolysis in cows. I. Luteal weight, circulating progesterone, mRNA for luteal luteinizing hormone (LH) receptor, and occupied and unoccupied luteal receptors for LH.","date":"2011","source":"Prostaglandins & other lipid mediators","url":"https://pubmed.ncbi.nlm.nih.gov/21601649","citation_count":16,"is_preprint":false},{"pmid":"20690843","id":"PMC_20690843","title":"Large-pore PDS mesh compared to small-pore PG mesh.","date":"2010","source":"Journal of investigative surgery : the official journal of the Academy of Surgical Research","url":"https://pubmed.ncbi.nlm.nih.gov/20690843","citation_count":16,"is_preprint":false},{"pmid":"35593099","id":"PMC_35593099","title":"Breathable, Moisturizing, Anti-Oxidation SSD-PG-PVA/KGM Fibrous Membranes for Accelerating Diabetic Wound Tissue Regeneration.","date":"2022","source":"ACS applied bio materials","url":"https://pubmed.ncbi.nlm.nih.gov/35593099","citation_count":15,"is_preprint":false},{"pmid":"35392784","id":"PMC_35392784","title":"TROP2 Down-regulated DSG2 to Promote Gastric Cancer Cell Invasion and Migration by EGFR/AKT and DSG2/PG/β-Catenin Pathways.","date":"2022","source":"Current cancer drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/35392784","citation_count":15,"is_preprint":false},{"pmid":"32277539","id":"PMC_32277539","title":"HBcrAg and pg RNA and the therapeutic effect in HBeAg-positive patients receiving anti-viral therapy, baseline serum HBV-RNA is a powerful predictor of response.","date":"2020","source":"Journal of viral hepatitis","url":"https://pubmed.ncbi.nlm.nih.gov/32277539","citation_count":15,"is_preprint":false},{"pmid":"12846582","id":"PMC_12846582","title":"G3 domains of aggrecan and PG-M/versican form intermolecular disulfide bonds that stabilize cell-matrix interaction.","date":"2003","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12846582","citation_count":15,"is_preprint":false},{"pmid":"11090914","id":"PMC_11090914","title":"Effects of supraspinal administration of PG-SPI and PG-KII, two amphibian tachykinin peptides, on nociception in the rat.","date":"2000","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/11090914","citation_count":15,"is_preprint":false},{"pmid":"30347872","id":"PMC_30347872","title":"PG-Priming Enhances Doxorubicin Influx to Trigger Necrotic and Autophagic Cell Death in Oral Squamous Cell Carcinoma.","date":"2018","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30347872","citation_count":15,"is_preprint":false},{"pmid":"33535605","id":"PMC_33535605","title":"Mechanical Stress Induce PG-E2 in Murine Synovial Fibroblasts Originating from the Temporomandibular Joint.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/33535605","citation_count":14,"is_preprint":false},{"pmid":"33393852","id":"PMC_33393852","title":"Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) influences adipocytes injuries through triggering XBP1 and activating mitochondria-mediated apoptosis.","date":"2021","source":"Adipocyte","url":"https://pubmed.ncbi.nlm.nih.gov/33393852","citation_count":14,"is_preprint":false},{"pmid":"33215270","id":"PMC_33215270","title":"A Phase Ib multicenter, dose-escalation study of the polyamine analogue PG-11047 in combination with gemcitabine, docetaxel, bevacizumab, erlotinib, cisplatin, 5-fluorouracil, or sunitinib in patients with advanced solid tumors or lymphoma.","date":"2020","source":"Cancer chemotherapy and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33215270","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55668,"output_tokens":2618,"usd":0.103137,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9481,"output_tokens":2988,"usd":0.061053,"stage2_stop_reason":"end_turn"},"total_usd":0.16419,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about the canonical JUP gene (plakoglobin/junction plakoglobin, also known as DPIII, PG, CTNNG, PDGB, PKGB).\n\nThe relevant papers are:\n- [22] - Chromosomal assignment of JUP (plakoglobin/DPIII)\n- [41] - JUP mutations and skin/heart phenotypes\n- [75] - JUP mutation causing CAPK syndrome\n- [63] - JUP/gamma-catenin expression in brain\n- [67] - JUP role in gastric cancer\n- [84] - XAF1-VCP-RNF114-JUP axis in colorectal cancer\n- [85] - JUP genomic organization\n- [73] - EPPK1-MAPK-JUP signaling in bladder cancer\n- [93] - DSG2/PG/β-catenin pathways in gastric cancer\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"The plakoglobin gene (DPIII/JUP) was mapped to human chromosome 17 using PCR assays on human-mouse and human-rat somatic cell hybrids.\",\n      \"method\": \"PCR-based chromosomal assignment using somatic cell hybrids\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal mapping by PCR in somatic cell hybrids, single lab, single method\",\n      \"pmids\": [\"1889810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The human plakoglobin gene (JUP) comprises 13 distinct exons spanning approximately 17 kb on chromosome 17q21, establishing its intron-exon genomic organization.\",\n      \"method\": \"Genomic cloning, sequencing, and PCR-based exon mapping\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic sequencing and PCR characterization, single lab\",\n      \"pmids\": [\"11016852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"JUP (gamma-catenin/plakoglobin) mRNA is expressed in adult primate neurons of the dorsolateral prefrontal cortex and hippocampus, with diffuse localization in the cortex and distinct localization in granule cells of the dentate gyrus and pyramidal cells of Ammon's horn, as determined by in situ hybridization.\",\n      \"method\": \"In situ hybridization in adult primate brain sections\",\n      \"journal\": \"Brain research. Molecular brain research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization method (ISH), no functional consequence tested, single lab\",\n      \"pmids\": [\"15857685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Homozygous loss-of-function mutations in the 5' region of JUP (nonsense p.S24X and splice site c.468G>A) result in skin fragility, diffuse palmoplantar keratoderma, and woolly hair without cardiomyopathy, establishing that plakoglobin is required for skin integrity and that its absence does not compromise normal human heart development in children. Barely detectable plakoglobin immunostaining was found in patient skin sections, and an alternative AUG codon in the p.S24X mRNA was shown to produce a 42-amino-acid N-terminally truncated protein.\",\n      \"method\": \"Mutation identification by sequencing, immunostaining of patient skin sections, and analysis of alternative translation initiation\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic loss-of-function with defined molecular mechanism (alternative AUG translation), immunostaining validation, clear phenotypic readout\",\n      \"pmids\": [\"20130592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A homozygous missense mutation p.R265H in JUP encoding plakoglobin causes a novel autosomal recessive syndrome (CAPK) comprising arrhythmogenic right ventricular cardiomyopathy, alopecia, and palmoplantar keratoderma, demonstrating that this specific JUP mutation disrupts both cardiac and cutaneous desmosomal function.\",\n      \"method\": \"Genetic mapping and mutation identification in an affected family\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — human disease genetics establishing loss-of-function phenotype, single family, no molecular reconstitution\",\n      \"pmids\": [\"21668431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JUP (junction plakoglobin) localizes to the cell membrane and cytoplasm in epithelium-like gastric cancer (GC) cells, where it restrains EGFR at the cell membrane. Loss of membrane/cytoplasmic JUP in GC cells increases p-AKT levels and activates AKT/GSK3β/β-catenin signaling, promoting epithelial-mesenchymal transition (EMT), migration, and invasion. Conversely, nuclear JUP interacts with nuclear β-catenin and TCF4 to synergistically promote TCF4 transcription and downstream MMP7 expression, fueling GC cell invasion. Knockdown of JUP in epithelium-like GC cells caused EMT and promoted migration and invasion; ectopic expression in malignant GC cells reduced invasive potential.\",\n      \"method\": \"JUP knockdown and overexpression in GC cell lines, co-immunoprecipitation, western blotting, migration/invasion assays\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal functional studies (KD and OE), co-IP for nuclear complex, mechanistic pathway placement, single lab\",\n      \"pmids\": [\"33364056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"XAF1 acts as an adaptor for valosin-containing protein (VCP), facilitating VCP-mediated deubiquitination of the E3 ligase RNF114, which in turn promotes K48-linked ubiquitination and proteasomal degradation of JUP (junction plakoglobin). Degradation of JUP via the XAF1-VCP-RNF114 axis promotes colorectal cancer cell migration and metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, protein interaction studies, knockdown/overexpression in CRC cells, correlation with clinical samples\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, defined ubiquitin linkage (K48), functional rescue experiments, validated in clinical samples, multiple orthogonal methods in single study\",\n      \"pmids\": [\"38095639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In bladder cancer cells, dihydrotestosterone (DHT) binds to EPPK1, which activates p38 MAPK signaling and c-Jun, leading to c-Jun binding to the JUP promoter and upregulation of JUP expression. Elevated JUP expression downstream of EPPK1/p38 MAPK promotes bladder cancer cell proliferation and invasion; JUP knockdown inhibited these DHT-induced effects.\",\n      \"method\": \"Biotinylated DHT-binding pull-down, JUP knockdown, p38 inhibition, ChIP-like promoter binding assay, xenograft mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple orthogonal methods (pull-down, KD, inhibitor, in vivo), defined transcriptional mechanism (c-Jun/JUP promoter), single lab\",\n      \"pmids\": [\"37328487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In gastric cancer, TROP2 downregulates DSG2 expression and disrupts the DSG2/plakoglobin (PG/JUP)/β-catenin signaling pathway, promoting cell invasion and migration. Co-immunoprecipitation identified DSG2 as an interacting protein of TROP2.\",\n      \"method\": \"Co-immunoprecipitation with mass spectrometry, TROP2 overexpression/knockdown, western blotting, cell adhesion and invasion assays, electron microscopy of desmosomes\",\n      \"journal\": \"Current cancer drug targets\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP/MS identification of interaction, functional manipulation of pathway, single lab, partial mechanistic follow-up of JUP specifically\",\n      \"pmids\": [\"35392784\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Plakoglobin (JUP) is a dual-compartment scaffold protein that functions at desmosomes and adherens junctions to maintain cell adhesion and tissue integrity in skin and heart; at the membrane/cytoplasm it sequesters EGFR and restrains AKT/GSK3β/β-catenin signaling, while in the nucleus it forms a complex with β-catenin and TCF4 to drive transcription of invasion-promoting genes such as MMP7; its abundance is regulated by K48-linked ubiquitination and proteasomal degradation via the XAF1-VCP-RNF114 E3 ligase axis, and its expression can be transcriptionally induced through a non-canonical DHT/EPPK1/p38 MAPK/c-Jun pathway in bladder cancer cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Plakoglobin (JUP) is a desmosomal junction protein required for the integrity of skin and heart, as established by human loss-of-function and missense mutations that produce palmoplantar keratoderma, woolly hair, skin fragility, and arrhythmogenic right ventricular cardiomyopathy [#3, #4]. Beyond its structural adhesion role, JUP behaves as a dual-compartment scaffold that shapes signaling: at the membrane and cytoplasm it restrains EGFR and thereby suppresses AKT/GSK3\\u03b2/\\u03b2-catenin signaling, whereas in the nucleus it complexes with \\u03b2-catenin and TCF4 to drive transcription of invasion genes including MMP7, with loss of membrane JUP promoting epithelial-mesenchymal transition and invasion in gastric cancer [#5]. JUP function in adhesion-linked signaling is also coupled to the desmoglein DSG2/plakoglobin/\\u03b2-catenin axis, which TROP2 disrupts to promote gastric cancer invasion [#8]. JUP abundance is controlled by K48-linked ubiquitination and proteasomal degradation through the XAF1-VCP-RNF114 E3 ligase axis, and its degradation promotes colorectal cancer migration and metastasis [#6]. JUP transcription can be induced via a non-canonical DHT/EPPK1/p38 MAPK/c-Jun pathway in bladder cancer, where c-Jun binds the JUP promoter to drive proliferation and invasion [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing the chromosomal location of the plakoglobin gene was the first step toward genetic characterization of the locus.\",\n      \"evidence\": \"PCR-based chromosomal assignment using human-rodent somatic cell hybrids\",\n      \"pmids\": [\"1889810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or protein-level characterization\", \"Did not define gene structure or expression\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Resolving the intron-exon organization of JUP provided the genomic framework needed for mutation analysis.\",\n      \"evidence\": \"Genomic cloning, sequencing, and PCR-based exon mapping\",\n      \"pmids\": [\"11016852\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No link to disease or function at this stage\", \"Regulatory elements not mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Detection of JUP mRNA in primate neurons raised the question of a role outside epithelial/cardiac junctions, though function was not tested.\",\n      \"evidence\": \"In situ hybridization in adult primate prefrontal cortex and hippocampus\",\n      \"pmids\": [\"15857685\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single localization method, no functional consequence tested\", \"Protein-level confirmation absent\", \"Neuronal role unestablished\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Human homozygous loss-of-function mutations showed plakoglobin is essential for skin integrity and that its absence need not compromise heart development, also revealing an alternative-AUG truncated protein.\",\n      \"evidence\": \"Mutation sequencing, patient skin immunostaining, and analysis of alternative translation initiation\",\n      \"pmids\": [\"20130592\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not explain genotype-specific cardiac sparing mechanistically\", \"Function of the truncated protein unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"A recessive missense mutation linked JUP to a combined cardiac-cutaneous syndrome, showing specific alleles disrupt both heart and skin desmosomal function.\",\n      \"evidence\": \"Genetic mapping and mutation identification in an affected family\",\n      \"pmids\": [\"21668431\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family, no molecular reconstitution\", \"Mechanism of mutation effect on desmosome not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of the DSG2/plakoglobin/\\u03b2-catenin axis as a TROP2 target connected JUP-linked desmosomal signaling to cancer invasion control.\",\n      \"evidence\": \"Co-IP/MS, TROP2 manipulation, invasion assays, and desmosome electron microscopy in gastric cancer cells\",\n      \"pmids\": [\"35392784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct JUP interaction with TROP2 not the focus\", \"Single lab, partial JUP-specific follow-up\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reciprocal functional studies defined JUP as a dual-compartment signaling switch: membrane JUP restrains EGFR/AKT signaling and suppresses EMT, while nuclear JUP/\\u03b2-catenin/TCF4 drives invasion genes.\",\n      \"evidence\": \"JUP knockdown/overexpression, co-IP, and migration/invasion assays in gastric cancer cell lines\",\n      \"pmids\": [\"33364056\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Determinants of JUP nuclear versus membrane partitioning not defined\", \"Direct EGFR binding not structurally resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defining the XAF1-VCP-RNF114 axis established how JUP protein abundance is post-translationally controlled and linked its degradation to metastasis.\",\n      \"evidence\": \"Reciprocal Co-IP, K48-linkage ubiquitination assays, rescue experiments, and clinical correlation in colorectal cancer\",\n      \"pmids\": [\"38095639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitination site on JUP not mapped\", \"Whether degradation occurs in specific subcellular pools unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapping the DHT/EPPK1/p38 MAPK/c-Jun pathway showed JUP expression can be transcriptionally induced non-canonically to drive bladder cancer growth.\",\n      \"evidence\": \"Biotinylated DHT pull-down, p38 inhibition, c-Jun promoter binding, JUP knockdown, and xenografts\",\n      \"pmids\": [\"37328487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct c-Jun/JUP promoter binding shown by ChIP-like assay only\", \"Generalizability beyond bladder cancer untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How JUP's subcellular partitioning between adhesion, cytoplasmic signaling restraint, and nuclear transcription is coordinated, and how this integrates with its tissue-specific roles in skin and heart, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model connecting adhesion and signaling functions\", \"Mechanism partitioning JUP to nucleus versus membrane unknown\", \"Cardiac versus cutaneous mutation specificity unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [\"desmosome\", \"JUP/\\u03b2-catenin/TCF4 complex\"],\n    \"partners\": [\"CTNNB1\", \"TCF4\", \"EGFR\", \"DSG2\", \"TROP2\", \"RNF114\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}