{"gene":"PSMD2","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2018,"finding":"PSMD2 physically interacts with p21 and p27 and mediates their ubiquitin-proteasome degradation in cooperation with USP14, thereby promoting cell cycle progression in breast cancer cells.","method":"Co-immunoprecipitation, rescue assays (siRNA knockdown with p21/p27 measurement), in vitro and in vivo functional assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional rescue experiments in single lab, two orthogonal methods","pmids":["29777785"],"is_preprint":false},{"year":2011,"finding":"Knockdown of PSMD2 decreases overall proteasome activity in lung cancer cells, induces growth inhibition and apoptosis, and alters the balance between phosphorylated AKT and p38 signaling with induction of p21.","method":"siRNA knockdown, proteasome activity assay, Western blot for pAKT/p38/p21","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct proteasome activity assay plus signaling pathway readouts, single lab","pmids":["21465578"],"is_preprint":false},{"year":2019,"finding":"PSMD2 co-immunoprecipitates and co-localizes with Asporin (ASPN) in gastric cancer cells; PSMD2 suppresses DUSP7, WIP1, and PTEN to promote phosphorylation of ERK, P38, and AKT, mediating ASPN-driven proliferation.","method":"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown epistasis","journal":"Frontiers in bioscience (Landmark edition)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus co-localization plus epistasis knockdown, single lab","pmids":["31136974"],"is_preprint":false},{"year":2019,"finding":"PSMD1 and PSMD2 regulate de novo lipid synthesis and lipid droplet accumulation in HepG2 hepatocellular carcinoma cells via p38-JNK and AKT signaling pathways, promoting tumor cell proliferation.","method":"siRNA knockdown, lipid droplet staining, gene expression analysis of lipid synthesis genes, signaling pathway Western blots","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with defined pathway readouts, single lab, two orthogonal methods","pmids":["31703613"],"is_preprint":false},{"year":2018,"finding":"In Dictyostelium discoideum, PSMD2 (and PSMD1) directly interact with ATG16, a core autophagosomal protein; the C-terminal half of ATG16 is required for this interaction. PSMD2-positive puncta co-localize with ATG16-GFP and GFP-ATG8a (LC3) and are confirmed as autolysosomes by LysoTracker labeling and proteolytic cleavage assay, establishing that ATG16 mediates autophagic degradation of PSMD2.","method":"Deletion analysis, co-localization (fluorescence microscopy), LysoTracker labeling, proteolytic cleavage assay, genetic knockout (atg16−, atg9−)","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (genetic KO, co-localization, lysosomal assay) in single lab; Dictyostelium ortholog study","pmids":["30269947"],"is_preprint":false},{"year":2023,"finding":"RACK1 binds PSMD2 competitively with β-catenin; this competitive binding prevents ubiquitinated β-catenin from interacting with PSMD2 and thus protects β-catenin from proteasomal degradation, activating WNT signaling and promoting breast cancer proliferation.","method":"Co-immunoprecipitation, competitive binding assays, siRNA knockdown, in vitro and in vivo proliferation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with competitive binding evidence and functional rescue, single lab","pmids":["37848434"],"is_preprint":false},{"year":2023,"finding":"DNAJA4 recruits PSMD2 to facilitate ubiquitin-proteasome-mediated degradation of MYH9, thereby suppressing EMT, migration, and invasion in nasopharyngeal carcinoma.","method":"Co-immunoprecipitation, overexpression/knockdown experiments, in vitro migration/invasion assays, in vivo metastasis model, rescue with MYH9 overexpression","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus rescue epistasis plus in vivo validation, single lab","pmids":["37875476"],"is_preprint":false},{"year":2022,"finding":"PSMD2 interacts with DIRAS2 and facilitates its proteasome-mediated degradation in colorectal cancer cells.","method":"Co-immunoprecipitation, proteasome inhibitor treatment, knockdown/overexpression functional assays","journal":"International journal of biological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with limited mechanistic follow-up, single lab","pmids":["35173535"],"is_preprint":false},{"year":2023,"finding":"PSMD2 activates the mTOR pathway by upregulating argininosuccinate synthase 1 (ASS1), thereby inhibiting autophagy and promoting esophageal squamous cell carcinoma cell growth.","method":"DIA quantification proteomics, immunoblotting, knockdown/overexpression, autophagy (DAPgreen staining) assays, xenograft model","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus functional rescue plus pathway validation in single lab","pmids":["36998052"],"is_preprint":false},{"year":2024,"finding":"PSMD2 activates the AKT/mTOR signaling pathway in pancreatic cancer cells; knockdown increases apoptosis and gemcitabine sensitivity, while overexpression promotes proliferation; AKT inhibitor MK-2206 reverses PSMD2 oncogenic effects.","method":"siRNA knockdown, overexpression, immunoblotting of AKT/mTOR pathway, pharmacological rescue with MK-2206, cell viability/apoptosis assays","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss of function with pharmacological epistasis validation, single lab","pmids":["39634424"],"is_preprint":false},{"year":2025,"finding":"PSMD2 (Rpn1) in the 26S proteasome interacts not only with ubiquitinated/ubiquitin-like proteins but also with the midnolin nuclear localization sequence; this interaction restricts midnolin's proteolytic activity to the nucleus. Cryo-EM structures of the midnolin-proteasome complex reveal that PSMD14/Rpn11 acts non-enzymatically as a receptor for the midnolin Ubl domain, positioning the substrate-binding Catch domain above the proteasomal entry site.","method":"Cryo-EM structural determination, biochemical binding assays, mutagenesis (implied by structural validation), functional nuclear localization assays","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with functional validation of PSMD2 NLS-binding role; multiple orthogonal methods in single rigorous study","pmids":["bio_10.1101_2025.02.22.639686"],"is_preprint":true},{"year":2025,"finding":"CX26 competes with c-Myc for binding to the Armadillo-like helical domain of PSMD2, preventing c-Myc from being degraded by the proteasome and thereby stabilizing c-Myc to promote pancreatic cancer progression.","method":"Co-immunoprecipitation, immunofluorescence, molecular docking, proteomic analysis, in vivo xenograft model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with domain-level molecular docking and in vivo validation, single lab","pmids":["40830962"],"is_preprint":false},{"year":2026,"finding":"PSMD2 promotes MEK and ERK phosphorylation within the MAPK signaling pathway in bladder cancer cells, and via MAPK signaling downregulates CXCL14 expression and secretion, remodeling the immune microenvironment.","method":"Western blot for MEK/ERK phosphorylation, siRNA knockdown, in vitro/in vivo functional assays, KEGG/GO pathway analysis, CXCL14 measurement","journal":"Oncology research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — signaling pathway Western blot with knockdown, single lab, limited mechanistic depth","pmids":["41930182"],"is_preprint":false},{"year":2026,"finding":"PPARγ promotes transcription of miR-802, which in turn suppresses Psmd2 expression in hepatocytes; exercise and time-restricted feeding reduce hepatic PPARγ and miR-802, thereby increasing Psmd2 and ameliorating MASLD via this PPARγ-miR-802-Psmd2 axis.","method":"Luciferase reporter validation, gain/loss-of-function in vivo and in vitro, qPCR, exercise and dietary intervention in mouse models","journal":"eGastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validation plus in vivo genetic epistasis across multiple interventions, single lab","pmids":["41789415"],"is_preprint":false}],"current_model":"PSMD2 is a non-ATPase regulatory subunit of the 19S proteasome whose Armadillo-like helical domain serves as a receptor for ubiquitinated substrates, ubiquitin-like domains (including midnolin's NLS), and competitive binding partners (RACK1, CX26); it mediates proteasomal degradation of substrates including p21, p27, MYH9, DIRAS2, and c-Myc, while activating downstream AKT/mTOR and MAPK/ERK signaling pathways, and is itself subject to autophagic turnover via ATG16-dependent delivery to autolysosomes."},"narrative":{"mechanistic_narrative":"PSMD2 is a non-ATPase regulatory subunit of the 19S/26S proteasome whose substrate-receptor function couples ubiquitin-proteasome degradation to control of cell proliferation and growth signaling [PMID:29777785, PMID:bio_10.1101_2025.02.22.639686]. Its Armadillo-like helical domain engages ubiquitinated and ubiquitin-like substrates and serves as a competitive docking site: cryo-EM of the midnolin–proteasome complex shows PSMD2 (Rpn1) binding the midnolin nuclear localization sequence to restrict that protease's activity to the nucleus [PMID:bio_10.1101_2025.02.22.639686], while RACK1, CX26, and other partners can occupy this surface to block delivery of degradation targets such as β-catenin and c-Myc [PMID:37848434, PMID:40830962]. Through this receptor activity PSMD2 mediates proteasomal turnover of cell-cycle inhibitors p21 and p27 (in cooperation with USP14) and of additional substrates including MYH9 and DIRAS2, with degradation of MYH9 recruited via DNAJA4 [PMID:29777785, PMID:37875476, PMID:35173535]. Loss of PSMD2 lowers overall proteasome activity and triggers growth inhibition and apoptosis [PMID:21465578]. Beyond degradation, PSMD2 activates AKT/mTOR and MAPK/ERK signaling and modulates lipid synthesis and autophagy, generally promoting tumor cell proliferation across multiple cancers [PMID:31703613, PMID:36998052, PMID:39634424, PMID:41930182]. PSMD2 is itself a degradation target, being delivered to autolysosomes for autophagic turnover through interaction with the core autophagy protein ATG16 [PMID:30269947], and its expression is transcriptionally constrained by a PPARγ–miR-802 axis in hepatocytes [PMID:41789415].","teleology":[{"year":2011,"claim":"Established that PSMD2 is functionally required for proteasome activity and cell survival, linking its loss to growth arrest and altered AKT/p38 signaling.","evidence":"siRNA knockdown with proteasome activity assay and pAKT/p38/p21 Western blots in lung cancer cells","pmids":["21465578"],"confidence":"Medium","gaps":["Did not identify direct substrates","Mechanism linking PSMD2 to AKT/p38 not resolved"]},{"year":2018,"claim":"Identified specific degradation substrates, showing PSMD2 drives turnover of cell-cycle inhibitors p21 and p27 to promote proliferation.","evidence":"Reciprocal Co-IP, USP14 cooperation, and rescue assays in breast cancer cells with in vivo validation","pmids":["29777785"],"confidence":"Medium","gaps":["Direct vs. proteasome-general effect on p21/p27 not fully separated","Binding interface not mapped"]},{"year":2018,"claim":"Revealed that PSMD2 is itself subject to autophagic degradation, defining a reciprocal relationship between the proteasome subunit and the autophagy machinery.","evidence":"Deletion mapping, co-localization with ATG16/ATG8a, LysoTracker and proteolytic cleavage assays, and atg16/atg9 knockouts in Dictyostelium","pmids":["30269947"],"confidence":"Medium","gaps":["Conservation of ATG16-mediated turnover in mammalian cells not shown","Trigger for autophagic delivery unknown"]},{"year":2019,"claim":"Extended PSMD2's role to growth-signaling and metabolic outputs, showing it suppresses phosphatases (DUSP7, WIP1, PTEN) and regulates lipid synthesis to drive proliferation.","evidence":"Co-IP/co-localization with ASPN and epistasis knockdowns in gastric cancer; lipid droplet staining and pathway Western blots in HepG2","pmids":["31136974","31703613"],"confidence":"Medium","gaps":["Whether phosphatase suppression is degradation-dependent unclear","Mechanism connecting PSMD2 to lipogenic genes not defined"]},{"year":2023,"claim":"Defined PSMD2 as a competitive substrate-receptor hub, where partner binding blocks delivery of ubiquitinated targets and thereby stabilizes oncogenic proteins.","evidence":"Reciprocal/competitive Co-IP for RACK1 vs β-catenin and DNAJA4-mediated MYH9 recruitment, with functional rescue and in vivo models","pmids":["37848434","37875476"],"confidence":"Medium","gaps":["Binding sites for RACK1/β-catenin not structurally resolved","Selectivity rules for competitive occupancy unknown"]},{"year":2023,"claim":"Connected PSMD2 to mTOR-dependent autophagy control and AKT/mTOR-driven proliferation and drug resistance.","evidence":"Proteomics, knockdown/overexpression, autophagy staining, and pharmacological rescue (MK-2206) across esophageal and pancreatic cancer models","pmids":["36998052","39634424"],"confidence":"Medium","gaps":["Mechanism upstream of ASS1/mTOR not established","Direct vs. indirect AKT regulation unresolved"]},{"year":2025,"claim":"Provided structural definition of PSMD2 as a proteasomal substrate receptor, showing it binds ubiquitin-like and NLS sequences to spatially restrict midnolin-mediated proteolysis.","evidence":"Cryo-EM of the midnolin-proteasome complex with biochemical binding and nuclear localization assays (preprint)","pmids":["bio_10.1101_2025.02.22.639686"],"confidence":"High","gaps":["Preprint, not yet peer-reviewed","Generality of NLS-receptor mode to other substrates untested"]},{"year":2025,"claim":"Mapped a competitive binding event to the Armadillo-like helical domain, showing CX26 displaces c-Myc to stabilize it.","evidence":"Co-IP, immunofluorescence, molecular docking, and xenograft validation in pancreatic cancer","pmids":["40830962"],"confidence":"Medium","gaps":["Docking-based interface lacks experimental structure","Whether CX26 affects other substrates unknown"]},{"year":2026,"claim":"Linked PSMD2 to MAPK signaling and immune microenvironment remodeling via CXCL14 regulation.","evidence":"MEK/ERK phosphorylation Western blots, knockdown, and CXCL14 measurement in bladder cancer","pmids":["41930182"],"confidence":"Low","gaps":["Limited mechanistic depth linking PSMD2 to MAPK","Direct effector for CXCL14 downregulation not identified"]},{"year":2026,"claim":"Established upstream transcriptional control of PSMD2 through a PPARγ-miR-802 axis relevant to metabolic disease.","evidence":"Luciferase reporter validation and in vivo gain/loss-of-function with exercise and dietary interventions in mice","pmids":["41789415"],"confidence":"Medium","gaps":["Downstream proteasomal targets in MASLD not defined","Tissue specificity of the axis untested"]},{"year":null,"claim":"It remains unresolved how PSMD2's receptor surface discriminates among substrates and competitive partners, and which interactions reflect direct degradation versus indirect signaling.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No experimental structure of PSMD2 bound to ubiquitinated substrates or competitive partners","Mechanistic basis for AKT/mTOR and MAPK activation not established","Substrate-selectivity code unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,6,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10,5,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,6,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,12,2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4,8]}],"complexes":["26S proteasome","19S regulatory particle"],"partners":["RACK1","CX26","DNAJA4","MYH9","DIRAS2","ASPN","MIDNOLIN","ATG16"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13200","full_name":"26S proteasome non-ATPase regulatory subunit 2","aliases":["26S proteasome regulatory subunit RPN1","26S proteasome regulatory subunit S2","26S proteasome subunit p97","Protein 55.11","Tumor necrosis factor type 1 receptor-associated protein 2"],"length_aa":908,"mass_kda":100.2,"function":"Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair Binds to the intracellular domain of tumor necrosis factor type 1 receptor. The binding domain of TRAP1 and TRAP2 resides outside the death domain of TNFR1","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q13200/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMD2","classification":"Common Essential","n_dependent_lines":1190,"n_total_lines":1208,"dependency_fraction":0.9850993377483444},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000175166","cell_line_id":"CID000105","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"PSMA1","stoichiometry":10.0},{"gene":"PSMA2","stoichiometry":10.0},{"gene":"PSMA3","stoichiometry":10.0},{"gene":"PSMA4","stoichiometry":10.0},{"gene":"PSMB1","stoichiometry":10.0},{"gene":"PSMB2","stoichiometry":10.0},{"gene":"PSMB3","stoichiometry":10.0},{"gene":"PSMB4","stoichiometry":10.0},{"gene":"PSMB5","stoichiometry":10.0},{"gene":"PSMB7","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000105","total_profiled":1310},"omim":[{"mim_id":"617676","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 3; PSMD3","url":"https://www.omim.org/entry/617676"},{"mim_id":"614454","title":"UBIQUITIN PROTEIN LIGASE E3C; UBE3C","url":"https://www.omim.org/entry/614454"},{"mim_id":"606223","title":"PROTEASOME 26S SUBUNIT, NON-ATPASE, 2; PSMD2","url":"https://www.omim.org/entry/606223"},{"mim_id":"602422","title":"STEM-LOOP BINDING PROTEIN; SLBP","url":"https://www.omim.org/entry/602422"},{"mim_id":"601623","title":"UBIQUITIN-PROTEIN LIGASE E3A; UBE3A","url":"https://www.omim.org/entry/601623"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Centriolar satellite","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Flagellar centriole","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":300.1}],"url":"https://www.proteinatlas.org/search/PSMD2"},"hgnc":{"alias_symbol":["S2","P97","TRAP2","MGC14274","Rpn1"],"prev_symbol":[]},"alphafold":{"accession":"Q13200","domains":[{"cath_id":"-","chopping":"829-901","consensus_level":"high","plddt":63.9319,"start":829,"end":901}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13200","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13200-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13200-F1-predicted_aligned_error_v6.png","plddt_mean":65.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMD2","jax_strain_url":"https://www.jax.org/strain/search?query=PSMD2"},"sequence":{"accession":"Q13200","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13200.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13200/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13200"}},"corpus_meta":[{"pmid":"29777785","id":"PMC_29777785","title":"PSMD2 regulates breast cancer cell proliferation and cell cycle progression by modulating p21 and p27 proteasomal degradation.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/29777785","citation_count":88,"is_preprint":false},{"pmid":"21465578","id":"PMC_21465578","title":"Proteasomal non-catalytic subunit PSMD2 as a potential therapeutic target in association with various clinicopathologic features in lung adenocarcinomas.","date":"2011","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/21465578","citation_count":52,"is_preprint":false},{"pmid":"31703613","id":"PMC_31703613","title":"PSMD1 and PSMD2 regulate HepG2 cell proliferation and apoptosis via modulating cellular lipid droplet metabolism.","date":"2019","source":"BMC molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/31703613","citation_count":45,"is_preprint":false},{"pmid":"31136974","id":"PMC_31136974","title":"Asporin promotes cell proliferation via interacting with PSMD2 in gastric cancer.","date":"2019","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/31136974","citation_count":35,"is_preprint":false},{"pmid":"37848434","id":"PMC_37848434","title":"RACK1 facilitates breast cancer progression by competitively inhibiting the binding of β-catenin to PSMD2 and enhancing the stability of β-catenin.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37848434","citation_count":23,"is_preprint":false},{"pmid":"30269947","id":"PMC_30269947","title":"ATG16 mediates the autophagic degradation of the 19S proteasomal subunits PSMD1 and PSMD2.","date":"2018","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30269947","citation_count":23,"is_preprint":false},{"pmid":"37875476","id":"PMC_37875476","title":"DNAJA4 suppresses epithelial-mesenchymal transition and metastasis in nasopharyngeal carcinoma via PSMD2-mediated MYH9 degradation.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37875476","citation_count":18,"is_preprint":false},{"pmid":"35173535","id":"PMC_35173535","title":"Diverse Ras-related GTPase DIRAS2, downregulated by PSMD2 in a proteasome-mediated way, inhibits colorectal cancer proliferation by blocking NF-κB signaling.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35173535","citation_count":14,"is_preprint":false},{"pmid":"36998052","id":"PMC_36998052","title":"PSMD2 contributes to the progression of esophageal squamous cell carcinoma by repressing autophagy.","date":"2023","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/36998052","citation_count":10,"is_preprint":false},{"pmid":"34124444","id":"PMC_34124444","title":"Proteomic Analysis Reveals That Metformin Suppresses PSMD2, STIP1, and CAP1 for Preventing Gastric Cancer AGS Cell Proliferation and Migration.","date":"2021","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/34124444","citation_count":10,"is_preprint":false},{"pmid":"39634424","id":"PMC_39634424","title":"Identification of PSMD2 as a promising biomarker for pancreatic cancer patients based on comprehensive bioinformatics and in vitro studies.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/39634424","citation_count":2,"is_preprint":false},{"pmid":"40830962","id":"PMC_40830962","title":"CX26 promotes pancreatic cancer progression by competitively inhibiting interaction of c-Myc with PSMD2 and enhancing c-Myc stability.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40830962","citation_count":1,"is_preprint":false},{"pmid":"40016166","id":"PMC_40016166","title":"Impact of PSMD2 on Gastric Cancer Tissue Stiffness Investigated via Motor-Piezoceramic Coupled Atomic Force Microscopy.","date":"2025","source":"Nano letters","url":"https://pubmed.ncbi.nlm.nih.gov/40016166","citation_count":1,"is_preprint":false},{"pmid":"41930182","id":"PMC_41930182","title":"PSMD2-Mediated MAPK Signaling Promotes Bladder Cancer Development and Immune Microenvironment Remodeling.","date":"2026","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/41930182","citation_count":0,"is_preprint":false},{"pmid":"41804662","id":"PMC_41804662","title":"De Novo 3q27.1 Microdeletion Refines the Critical Region and Implicates PSMD2 Haploinsufficiency in Growth and Neurodevelopmental Abnormalities.","date":"2026","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/41804662","citation_count":0,"is_preprint":false},{"pmid":"41789415","id":"PMC_41789415","title":"Exercise and dietary interventions ameliorate MASLD via the hepatic PPARγ-miR-802-Psmd2 axis.","date":"2026","source":"eGastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/41789415","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.22.639686","title":"Structural basis for the midnolin-proteasome pathway and its role in suppressing myeloma","date":"2025-02-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.22.639686","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10749,"output_tokens":3142,"usd":0.039689,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10585,"output_tokens":3363,"usd":0.0685,"stage2_stop_reason":"end_turn"},"total_usd":0.108189,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"PSMD2 physically interacts with p21 and p27 and mediates their ubiquitin-proteasome degradation in cooperation with USP14, thereby promoting cell cycle progression in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, rescue assays (siRNA knockdown with p21/p27 measurement), in vitro and in vivo functional assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional rescue experiments in single lab, two orthogonal methods\",\n      \"pmids\": [\"29777785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Knockdown of PSMD2 decreases overall proteasome activity in lung cancer cells, induces growth inhibition and apoptosis, and alters the balance between phosphorylated AKT and p38 signaling with induction of p21.\",\n      \"method\": \"siRNA knockdown, proteasome activity assay, Western blot for pAKT/p38/p21\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct proteasome activity assay plus signaling pathway readouts, single lab\",\n      \"pmids\": [\"21465578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PSMD2 co-immunoprecipitates and co-localizes with Asporin (ASPN) in gastric cancer cells; PSMD2 suppresses DUSP7, WIP1, and PTEN to promote phosphorylation of ERK, P38, and AKT, mediating ASPN-driven proliferation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown epistasis\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus co-localization plus epistasis knockdown, single lab\",\n      \"pmids\": [\"31136974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PSMD1 and PSMD2 regulate de novo lipid synthesis and lipid droplet accumulation in HepG2 hepatocellular carcinoma cells via p38-JNK and AKT signaling pathways, promoting tumor cell proliferation.\",\n      \"method\": \"siRNA knockdown, lipid droplet staining, gene expression analysis of lipid synthesis genes, signaling pathway Western blots\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with defined pathway readouts, single lab, two orthogonal methods\",\n      \"pmids\": [\"31703613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Dictyostelium discoideum, PSMD2 (and PSMD1) directly interact with ATG16, a core autophagosomal protein; the C-terminal half of ATG16 is required for this interaction. PSMD2-positive puncta co-localize with ATG16-GFP and GFP-ATG8a (LC3) and are confirmed as autolysosomes by LysoTracker labeling and proteolytic cleavage assay, establishing that ATG16 mediates autophagic degradation of PSMD2.\",\n      \"method\": \"Deletion analysis, co-localization (fluorescence microscopy), LysoTracker labeling, proteolytic cleavage assay, genetic knockout (atg16−, atg9−)\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (genetic KO, co-localization, lysosomal assay) in single lab; Dictyostelium ortholog study\",\n      \"pmids\": [\"30269947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RACK1 binds PSMD2 competitively with β-catenin; this competitive binding prevents ubiquitinated β-catenin from interacting with PSMD2 and thus protects β-catenin from proteasomal degradation, activating WNT signaling and promoting breast cancer proliferation.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assays, siRNA knockdown, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with competitive binding evidence and functional rescue, single lab\",\n      \"pmids\": [\"37848434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DNAJA4 recruits PSMD2 to facilitate ubiquitin-proteasome-mediated degradation of MYH9, thereby suppressing EMT, migration, and invasion in nasopharyngeal carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown experiments, in vitro migration/invasion assays, in vivo metastasis model, rescue with MYH9 overexpression\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus rescue epistasis plus in vivo validation, single lab\",\n      \"pmids\": [\"37875476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PSMD2 interacts with DIRAS2 and facilitates its proteasome-mediated degradation in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor treatment, knockdown/overexpression functional assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with limited mechanistic follow-up, single lab\",\n      \"pmids\": [\"35173535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PSMD2 activates the mTOR pathway by upregulating argininosuccinate synthase 1 (ASS1), thereby inhibiting autophagy and promoting esophageal squamous cell carcinoma cell growth.\",\n      \"method\": \"DIA quantification proteomics, immunoblotting, knockdown/overexpression, autophagy (DAPgreen staining) assays, xenograft model\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus functional rescue plus pathway validation in single lab\",\n      \"pmids\": [\"36998052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PSMD2 activates the AKT/mTOR signaling pathway in pancreatic cancer cells; knockdown increases apoptosis and gemcitabine sensitivity, while overexpression promotes proliferation; AKT inhibitor MK-2206 reverses PSMD2 oncogenic effects.\",\n      \"method\": \"siRNA knockdown, overexpression, immunoblotting of AKT/mTOR pathway, pharmacological rescue with MK-2206, cell viability/apoptosis assays\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss of function with pharmacological epistasis validation, single lab\",\n      \"pmids\": [\"39634424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PSMD2 (Rpn1) in the 26S proteasome interacts not only with ubiquitinated/ubiquitin-like proteins but also with the midnolin nuclear localization sequence; this interaction restricts midnolin's proteolytic activity to the nucleus. Cryo-EM structures of the midnolin-proteasome complex reveal that PSMD14/Rpn11 acts non-enzymatically as a receptor for the midnolin Ubl domain, positioning the substrate-binding Catch domain above the proteasomal entry site.\",\n      \"method\": \"Cryo-EM structural determination, biochemical binding assays, mutagenesis (implied by structural validation), functional nuclear localization assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with functional validation of PSMD2 NLS-binding role; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"bio_10.1101_2025.02.22.639686\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CX26 competes with c-Myc for binding to the Armadillo-like helical domain of PSMD2, preventing c-Myc from being degraded by the proteasome and thereby stabilizing c-Myc to promote pancreatic cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, molecular docking, proteomic analysis, in vivo xenograft model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with domain-level molecular docking and in vivo validation, single lab\",\n      \"pmids\": [\"40830962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PSMD2 promotes MEK and ERK phosphorylation within the MAPK signaling pathway in bladder cancer cells, and via MAPK signaling downregulates CXCL14 expression and secretion, remodeling the immune microenvironment.\",\n      \"method\": \"Western blot for MEK/ERK phosphorylation, siRNA knockdown, in vitro/in vivo functional assays, KEGG/GO pathway analysis, CXCL14 measurement\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — signaling pathway Western blot with knockdown, single lab, limited mechanistic depth\",\n      \"pmids\": [\"41930182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PPARγ promotes transcription of miR-802, which in turn suppresses Psmd2 expression in hepatocytes; exercise and time-restricted feeding reduce hepatic PPARγ and miR-802, thereby increasing Psmd2 and ameliorating MASLD via this PPARγ-miR-802-Psmd2 axis.\",\n      \"method\": \"Luciferase reporter validation, gain/loss-of-function in vivo and in vitro, qPCR, exercise and dietary intervention in mouse models\",\n      \"journal\": \"eGastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validation plus in vivo genetic epistasis across multiple interventions, single lab\",\n      \"pmids\": [\"41789415\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMD2 is a non-ATPase regulatory subunit of the 19S proteasome whose Armadillo-like helical domain serves as a receptor for ubiquitinated substrates, ubiquitin-like domains (including midnolin's NLS), and competitive binding partners (RACK1, CX26); it mediates proteasomal degradation of substrates including p21, p27, MYH9, DIRAS2, and c-Myc, while activating downstream AKT/mTOR and MAPK/ERK signaling pathways, and is itself subject to autophagic turnover via ATG16-dependent delivery to autolysosomes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMD2 is a non-ATPase regulatory subunit of the 19S/26S proteasome whose substrate-receptor function couples ubiquitin-proteasome degradation to control of cell proliferation and growth signaling [#0, #10]. Its Armadillo-like helical domain engages ubiquitinated and ubiquitin-like substrates and serves as a competitive docking site: cryo-EM of the midnolin–proteasome complex shows PSMD2 (Rpn1) binding the midnolin nuclear localization sequence to restrict that protease's activity to the nucleus [#10], while RACK1, CX26, and other partners can occupy this surface to block delivery of degradation targets such as \\u03b2-catenin and c-Myc [#5, #11]. Through this receptor activity PSMD2 mediates proteasomal turnover of cell-cycle inhibitors p21 and p27 (in cooperation with USP14) and of additional substrates including MYH9 and DIRAS2, with degradation of MYH9 recruited via DNAJA4 [#0, #6, #7]. Loss of PSMD2 lowers overall proteasome activity and triggers growth inhibition and apoptosis [#1]. Beyond degradation, PSMD2 activates AKT/mTOR and MAPK/ERK signaling and modulates lipid synthesis and autophagy, generally promoting tumor cell proliferation across multiple cancers [#3, #8, #9, #12]. PSMD2 is itself a degradation target, being delivered to autolysosomes for autophagic turnover through interaction with the core autophagy protein ATG16 [#4], and its expression is transcriptionally constrained by a PPAR\\u03b3–miR-802 axis in hepatocytes [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that PSMD2 is functionally required for proteasome activity and cell survival, linking its loss to growth arrest and altered AKT/p38 signaling.\",\n      \"evidence\": \"siRNA knockdown with proteasome activity assay and pAKT/p38/p21 Western blots in lung cancer cells\",\n      \"pmids\": [\"21465578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify direct substrates\", \"Mechanism linking PSMD2 to AKT/p38 not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified specific degradation substrates, showing PSMD2 drives turnover of cell-cycle inhibitors p21 and p27 to promote proliferation.\",\n      \"evidence\": \"Reciprocal Co-IP, USP14 cooperation, and rescue assays in breast cancer cells with in vivo validation\",\n      \"pmids\": [\"29777785\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. proteasome-general effect on p21/p27 not fully separated\", \"Binding interface not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed that PSMD2 is itself subject to autophagic degradation, defining a reciprocal relationship between the proteasome subunit and the autophagy machinery.\",\n      \"evidence\": \"Deletion mapping, co-localization with ATG16/ATG8a, LysoTracker and proteolytic cleavage assays, and atg16/atg9 knockouts in Dictyostelium\",\n      \"pmids\": [\"30269947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of ATG16-mediated turnover in mammalian cells not shown\", \"Trigger for autophagic delivery unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended PSMD2's role to growth-signaling and metabolic outputs, showing it suppresses phosphatases (DUSP7, WIP1, PTEN) and regulates lipid synthesis to drive proliferation.\",\n      \"evidence\": \"Co-IP/co-localization with ASPN and epistasis knockdowns in gastric cancer; lipid droplet staining and pathway Western blots in HepG2\",\n      \"pmids\": [\"31136974\", \"31703613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether phosphatase suppression is degradation-dependent unclear\", \"Mechanism connecting PSMD2 to lipogenic genes not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined PSMD2 as a competitive substrate-receptor hub, where partner binding blocks delivery of ubiquitinated targets and thereby stabilizes oncogenic proteins.\",\n      \"evidence\": \"Reciprocal/competitive Co-IP for RACK1 vs \\u03b2-catenin and DNAJA4-mediated MYH9 recruitment, with functional rescue and in vivo models\",\n      \"pmids\": [\"37848434\", \"37875476\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding sites for RACK1/\\u03b2-catenin not structurally resolved\", \"Selectivity rules for competitive occupancy unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected PSMD2 to mTOR-dependent autophagy control and AKT/mTOR-driven proliferation and drug resistance.\",\n      \"evidence\": \"Proteomics, knockdown/overexpression, autophagy staining, and pharmacological rescue (MK-2206) across esophageal and pancreatic cancer models\",\n      \"pmids\": [\"36998052\", \"39634424\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism upstream of ASS1/mTOR not established\", \"Direct vs. indirect AKT regulation unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided structural definition of PSMD2 as a proteasomal substrate receptor, showing it binds ubiquitin-like and NLS sequences to spatially restrict midnolin-mediated proteolysis.\",\n      \"evidence\": \"Cryo-EM of the midnolin-proteasome complex with biochemical binding and nuclear localization assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.02.22.639686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Generality of NLS-receptor mode to other substrates untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapped a competitive binding event to the Armadillo-like helical domain, showing CX26 displaces c-Myc to stabilize it.\",\n      \"evidence\": \"Co-IP, immunofluorescence, molecular docking, and xenograft validation in pancreatic cancer\",\n      \"pmids\": [\"40830962\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Docking-based interface lacks experimental structure\", \"Whether CX26 affects other substrates unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked PSMD2 to MAPK signaling and immune microenvironment remodeling via CXCL14 regulation.\",\n      \"evidence\": \"MEK/ERK phosphorylation Western blots, knockdown, and CXCL14 measurement in bladder cancer\",\n      \"pmids\": [\"41930182\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Limited mechanistic depth linking PSMD2 to MAPK\", \"Direct effector for CXCL14 downregulation not identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established upstream transcriptional control of PSMD2 through a PPAR\\u03b3-miR-802 axis relevant to metabolic disease.\",\n      \"evidence\": \"Luciferase reporter validation and in vivo gain/loss-of-function with exercise and dietary interventions in mice\",\n      \"pmids\": [\"41789415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream proteasomal targets in MASLD not defined\", \"Tissue specificity of the axis untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how PSMD2's receptor surface discriminates among substrates and competitive partners, and which interactions reflect direct degradation versus indirect signaling.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental structure of PSMD2 bound to ubiquitinated substrates or competitive partners\", \"Mechanistic basis for AKT/mTOR and MAPK activation not established\", \"Substrate-selectivity code unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 6, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10, 5, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 6, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 12, 2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"complexes\": [\"26S proteasome\", \"19S regulatory particle\"],\n    \"partners\": [\"RACK1\", \"CX26\", \"DNAJA4\", \"MYH9\", \"DIRAS2\", \"ASPN\", \"midnolin\", \"ATG16\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}