{"gene":"PSMC2","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1999,"finding":"Genetic epistasis in yeast shows that RPT1 (PSMC2 ortholog) physically or functionally interacts with RPN12 (a lid component of the 19S regulatory particle): a single amino acid change at a conserved alanine (position 446) in RPT1 causes synthetic lethality when combined with rpn12-1, suggesting this region of RPT1 is required for interaction with RPN12 within the 26S proteasome.","method":"Yeast synthetic lethality screen, DNA sequencing of mutant allele, genetic epistasis","journal":"Molecular & general genetics : MGG","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with defined mutation, replicated in yeast as ortholog of PSMC2, single lab","pmids":["10503546"],"is_preprint":false},{"year":2007,"finding":"In Drosophila, loss-of-function of the Rpt1/p48B ATPase subunit (ortholog of PSMC2) impairs 26S proteasome assembly, causes accumulation of multiubiquitinated proteins, alters phosphorylation of the subunit itself, and depletes it from chromatin, establishing its essential role in proteasome integrity and substrate processing.","method":"P-element insertion hypomorphic allele analysis, biochemical fractionation (chromatin depletion), Western blot for ubiquitinated proteins","journal":"Molecular genetics and genomics : MGG","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with multiple orthogonal readouts (proteasome assembly, ubiquitin accumulation, chromatin localization), single lab","pmids":["17429695"],"is_preprint":false},{"year":2013,"finding":"In yeast, the N-terminal Pro residue of Rpt1 (PSMC2 ortholog) undergoes N-terminal methylation (mono- or di-methylation) after removal of the initiator Met; deletion of the Pro-Lys sequence at positions 3–4 abolishes methylation, reduces cell growth, and increases stress sensitivity, indicating that N-terminal methylation of Rpt1 and/or its PK sequence is important for cell growth and stress tolerance.","method":"Mass spectrometry analysis of N-terminal modifications, site-directed mutagenesis (PK deletion), yeast growth and stress assays","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro MS identification of PTM combined with mutagenesis and functional phenotype, single lab","pmids":["24038880"],"is_preprint":false},{"year":2017,"finding":"Knockdown of PSMC2 in osteosarcoma cell lines (SaoS-2 and MG-63) suppresses proliferation, enhances apoptosis, induces G2/M and/or S phase arrest, decreases colony formation, and inhibits migration/invasion in vitro and tumorigenicity in vivo; gene microarray identified downstream genes including ITGA6, FN1, CCND1, CCNE2, and TGFβR2.","method":"RNA interference knockdown, MTT/colony assays, flow cytometry, wound-healing/Transwell assays, nude mouse xenograft, gene microarray, Western blot","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple orthogonal cellular readouts and in vivo validation, single lab","pmids":["27888613"],"is_preprint":false},{"year":2021,"finding":"PSMC2 physically interacts with PLAU (plasminogen activator urokinase) in breast cancer cells, and this PSMC2/PLAU axis promotes breast cancer development and progression; knockdown of PSMC2 suppresses breast cancer cell proliferation, apoptosis resistance, and migration in vitro and tumor growth in vivo.","method":"Co-immunoprecipitation (interaction with PLAU), gene microarray with IPA, loss-of-function knockdown, xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP interaction identified, loss-of-function phenotype, single lab; interaction mechanistic detail limited to abstract","pmids":["34244472"],"is_preprint":false},{"year":2021,"finding":"PSMC2 physically interacts with ITGA6 in hepatocellular carcinoma cells (confirmed by co-IP), and PSMC2 knockdown exhibits mutual regulation with ITGA6; both knockdowns show similar inhibitory effects on HCC proliferation, colony formation, migration, and enhanced apoptosis.","method":"Co-immunoprecipitation, gene microarray with IPA, loss-of-function knockdown, xenograft model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct interaction shown by co-IP, functional epistasis by double knockdown, single lab","pmids":["34413286"],"is_preprint":false},{"year":2021,"finding":"PSMC2 knockdown in ovarian cancer cells decreases colony formation, cell motility, and proliferation while increasing apoptosis; gene microarray identified CCND1 as a downstream effector—knockdown of CCND1 enhances effects of PSMC2 knockdown and CCND1 overexpression reverses them, indicating mutual regulation between PSMC2 and CCND1.","method":"siRNA knockdown, gene microarray, colony/proliferation/apoptosis assays, CCND1 rescue experiment, xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via overexpression rescue and double knockdown, single lab","pmids":["34294689"],"is_preprint":false},{"year":2021,"finding":"PSMC2 promotes prostate cancer cell proliferation, migration, and survival via the Akt/Cyclin D1/CDK6 signaling pathway; knockdown of PSMC2 inhibits these processes and suppresses tumor growth in vivo.","method":"shRNA knockdown, Western blot for pathway proteins, proliferation/apoptosis/migration assays, xenograft","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement inferred from Western blot of downstream proteins after knockdown, single lab, single method for mechanistic claim","pmids":["33902600"],"is_preprint":false},{"year":2021,"finding":"PSMC2 knockdown in skin cutaneous melanoma elevates pro-apoptotic proteins DR6, IGFBP-4, p21, and p53, reduces anti-apoptotic TRAILR-3, and inhibits Wnt signaling pathway proteins, placing PSMC2 as a positive regulator of the Wnt pathway in melanoma.","method":"siRNA knockdown, protein-chip (antibody array), gene set enrichment analysis, flow cytometry, xenograft","journal":"Cell death discovery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — protein array identifies downstream changes but no direct mechanistic connection established, single lab","pmids":["34716318"],"is_preprint":false},{"year":2021,"finding":"PSMC2 knockdown in cholangiocarcinoma cells upregulates Caspase-3 and E-cadherin while downregulating Bcl-2, IGF-II, N-cadherin, and Vimentin; co-IP and RNA-seq identified CDK1 as a direct interaction partner and downstream effector of PSMC2, with mutual regulation of expression between PSMC2 and CDK1.","method":"Co-immunoprecipitation (PSMC2-CDK1 interaction), RNA-seq, qPCR, Western blot, loss-of-function knockdown, xenograft","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP interaction with CDK1 confirmed, functional rescue by double knockdown, single lab","pmids":["34499615"],"is_preprint":false},{"year":2022,"finding":"PSMC2 enhances RPS15A expression by competitively binding (acting as a ceRNA) to hsa-let-7c-3p in gastric cancer, thereby activating the mTOR pathway; RPS15A overexpression reverses the effects of PSMC2 knockdown on proliferation and migration, and the mTOR inhibitor Torin1 partially blocks RPS15A-driven proliferation.","method":"Gene microarray with IPA, dual-luciferase reporter assay (ceRNA/miRNA binding), RPS15A rescue overexpression, Torin1 pharmacological inhibition, loss-of-function knockdown, xenograft","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual-luciferase reporter validates ceRNA mechanism, pathway placement confirmed with pharmacological inhibitor and rescue, single lab","pmids":["35256584"],"is_preprint":false},{"year":2022,"finding":"PSMC2 knockdown in oral squamous cell carcinoma cells downregulates p100, p-Akt, and CDK6, and upregulates MAPK9, placing PSMC2 as a positive regulator of the PI3K/Akt pathway; increased pro-apoptotic proteins were confirmed by antibody array.","method":"Lentiviral shRNA knockdown, human apoptosis antibody array, flow cytometry, Western blot, xenograft","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway proteins measured by Western blot after knockdown, no direct mechanistic link established, single lab","pmids":["34979867"],"is_preprint":false},{"year":2025,"finding":"PSMC2 suppresses JNK-mediated pro-death autophagy in temozolomide-resistant glioblastoma; genetic suppression of PSMC2 activates JNK signaling, causing BCL2 phosphorylation and release of Beclin1 from the BCL2-Beclin1 complex, thereby boosting autophagosome nucleation and restoring apoptosis.","method":"PSMC2 knockdown/overexpression, JNK pathway analysis by Western blot (phospho-BCL2, Beclin1 co-IP/interaction), autophagy assays, MG132 proteasome inhibition","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection with multiple downstream readouts (JNK, BCL2 phosphorylation, Beclin1 release), single lab, single study","pmids":["39824465"],"is_preprint":false},{"year":2025,"finding":"PSMC2 promotes epithelial-to-mesenchymal transition (EMT) in glioblastoma by activating the AKT/GSK3β/β-catenin axis; PSMC2 overexpression leads to AKT-mediated inhibitory phosphorylation of GSK3β, enabling nuclear β-catenin accumulation; LiCl-induced GSK3β phosphorylation reverses effects of PSMC2 knockdown, validating this pathway.","method":"PSMC2 knockdown/overexpression, Western blot (AKT, p-GSK3β, β-catenin nuclear localization), LiCl pharmacological rescue, EMT marker analysis, xenograft","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological rescue validates pathway placement, multiple orthogonal readouts, single lab","pmids":["40233917"],"is_preprint":false},{"year":2026,"finding":"PSMC2 physically interacts with EGFR in hepatocellular carcinoma, stabilizing EGFR protein levels and enhancing phosphorylation of downstream AKT and ERK1/2; knockdown of PSMC2 inhibits HCC proliferation, migration, and invasion in vitro and tumor growth in vivo.","method":"Co-immunoprecipitation (PSMC2-EGFR interaction), immunofluorescence co-localization, Western blot (p-AKT, p-ERK1/2), functional assays, xenograft","journal":"Clinical and experimental medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal co-IP and co-localization establish interaction, downstream signaling confirmed by Western blot, single lab","pmids":["42177695"],"is_preprint":false},{"year":2026,"finding":"PSMC2 physically interacts with EZH2 in glioma cells (confirmed by co-IP and fluorescence co-localization); proteomics analysis identified EZH2 as a PSMC2-interacting partner, and PSMC2 promotes glioma progression through this interaction, modulating EMT and cytoskeletal architecture.","method":"Co-immunoprecipitation, fluorescence co-localization, proteomics, PSMC2 knockdown/overexpression, EMT marker analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and co-localization confirm interaction, proteomics identifies partner, functional consequences shown, single lab","pmids":["41992005"],"is_preprint":false},{"year":2026,"finding":"PSMC2 inhibits ferroptosis in nasopharyngeal carcinoma by activating STAT3 phosphorylation, which upregulates CPT1 and GPX4; PSMC2 knockdown decreases p-STAT3, CPT1, and GPX4 levels, increases ROS, lipid peroxidation, and iron ions, reduces GSH, and increases ferroptosis; these effects are reversed by a STAT3 activator.","method":"PSMC2 knockdown, Western blot (p-STAT3, CPT1, GPX4), ROS/lipid peroxidation assays, GSH measurement, iron ion detection, STAT3 activator rescue, xenograft","journal":"Discover oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological rescue with STAT3 activator validates pathway, multiple orthogonal biochemical readouts, single lab","pmids":["42234270"],"is_preprint":false},{"year":2021,"finding":"PSMC2 silencing in bone marrow stromal cells (BMSCs) from ovariectomized mice promotes osteogenic differentiation in vitro and bone formation in vivo, associated with increased Runx2, PI3K, Wnt3a, and β-catenin protein levels and decreased CTSK.","method":"siRNA knockdown in OVX mouse model, Western blot for osteogenic/pathway markers, histopathology, BMD measurement","journal":"Calcified tissue international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Western blot of downstream pathway proteins after knockdown, no direct mechanistic link established, single lab","pmids":["33625534"],"is_preprint":false}],"current_model":"PSMC2 (RPT1) is an ATPase subunit of the 19S regulatory particle of the 26S proteasome, required for substrate unfolding, translocation, and proteasome assembly; it undergoes N-terminal methylation in yeast, genetically interacts with the lid subunit RPN12, and in cancer cells acts as an oncogenic scaffold that activates multiple downstream pathways (PI3K/AKT, Wnt/β-catenin via AKT/GSK3β, mTOR via RPS15A/ceRNA, JNK-BCL2-Beclin1 autophagy axis, STAT3-GPX4 ferroptosis suppression) through direct physical interactions with partners including PLAU, ITGA6, CDK1, EGFR, and EZH2."},"narrative":{"mechanistic_narrative":"PSMC2 (RPT1) is one of the AAA+ ATPase subunits of the 19S regulatory particle of the 26S proteasome, where it is required for proteasome assembly and processing of ubiquitinated substrates [PMID:17429695]. Genetic and biochemical work in model organisms established its core role: in yeast a conserved-residue mutation in RPT1 is synthetically lethal with the lid subunit RPN12, placing RPT1 in functional contact with the lid within the regulatory particle [PMID:10503546], and in Drosophila loss of the Rpt1 ortholog blocks 26S assembly, causes accumulation of multiubiquitinated proteins, and depletes the subunit from chromatin [PMID:17429695]. The mature yeast subunit also carries an N-terminal proline methylation whose loss reduces growth and stress tolerance [PMID:24038880]. Beyond its proteasomal role, PSMC2 functions as a pro-tumorigenic factor across many cancers; its knockdown consistently suppresses proliferation, colony formation, migration/invasion, and tumor growth while promoting apoptosis [PMID:27888613, PMID:34244472, PMID:34294689]. Mechanistically, PSMC2 physically associates with partners including PLAU [PMID:34244472], ITGA6 [PMID:34413286], CDK1 [PMID:34499615], EGFR [PMID:42177695], and EZH2 [PMID:41992005], and engages multiple downstream programs: it stabilizes EGFR to enhance AKT/ERK signaling [PMID:42177695], drives AKT/GSK3β/β-catenin-mediated EMT [PMID:40233917], activates mTOR through a let-7c-3p ceRNA mechanism that raises RPS15A [PMID:35256584], suppresses JNK-driven pro-death autophagy by maintaining the BCL2–Beclin1 complex [PMID:39824465], and inhibits ferroptosis via STAT3-dependent upregulation of CPT1 and GPX4 [PMID:42234270]. The downstream pathway placements derive largely from knockdown-and-rescue and Western-blot analyses in individual cancer models rather than from reconstituted biochemistry.","teleology":[{"year":1999,"claim":"Established that RPT1/PSMC2 makes a functionally essential contact with the proteasome lid, defining a structural interface within the 19S regulatory particle.","evidence":"Yeast synthetic lethality screen and genetic epistasis between an RPT1 point mutant and rpn12-1","pmids":["10503546"],"confidence":"Medium","gaps":["Physical interaction not directly demonstrated biochemically","Functional consequence in human PSMC2 not tested"]},{"year":2007,"claim":"Demonstrated that the Rpt1 ATPase is required for 26S proteasome integrity and substrate turnover, establishing its core cellular function beyond a structural placeholder.","evidence":"Drosophila hypomorphic allele analysis with proteasome assembly, ubiquitin-accumulation, and chromatin-fractionation readouts","pmids":["17429695"],"confidence":"Medium","gaps":["Mechanism of chromatin depletion unexplained","Significance of subunit phosphorylation not resolved"]},{"year":2013,"claim":"Identified N-terminal proline methylation of Rpt1 and linked it to growth and stress tolerance, revealing a post-translational layer of regulation on the subunit.","evidence":"Mass spectrometry of N-terminal modifications plus PK-deletion mutagenesis and yeast growth/stress assays","pmids":["24038880"],"confidence":"Medium","gaps":["Responsible methyltransferase not identified","Mechanistic link between methylation and proteasome function unknown","Conservation in human PSMC2 untested"]},{"year":2017,"claim":"First positioned PSMC2 as a cancer dependency, showing that its loss impairs tumor cell growth and survival and pointing to candidate downstream genes.","evidence":"RNAi knockdown in osteosarcoma lines with proliferation, apoptosis, cell-cycle, migration, xenograft assays and gene microarray","pmids":["27888613"],"confidence":"Medium","gaps":["Whether phenotype reflects proteasome loss or a distinct function unresolved","Microarray targets not mechanistically validated"]},{"year":2021,"claim":"Defined direct physical partners (PLAU, ITGA6, CDK1) and a downstream effector (CCND1) through which PSMC2 drives tumor phenotypes, advancing from association to candidate molecular partners.","evidence":"Co-IP, gene microarray/RNA-seq, double-knockdown and rescue experiments, and xenografts across breast, hepatocellular, cholangiocarcinoma, and ovarian cancers","pmids":["34244472","34413286","34499615","34294689"],"confidence":"Medium","gaps":["Reciprocal/structural validation of interactions limited","Whether interactions are proteasome-dependent unknown","Direct vs. indirect regulation of CCND1 not separated"]},{"year":2021,"claim":"Linked PSMC2 to AKT-axis and Wnt signaling in prostate cancer, melanoma, and bone marrow stromal cells, broadening its signaling reach but largely by correlation of pathway-protein levels.","evidence":"shRNA/siRNA knockdown with Western blot and antibody-array readouts of pathway proteins; xenograft and OVX-mouse models","pmids":["33902600","34716318","33625534"],"confidence":"Low","gaps":["Pathway placement inferred from downstream protein changes without direct mechanistic link","Single-method mechanistic support","Direction of causality not established"]},{"year":2022,"claim":"Provided a defined non-proteasomal mechanism by showing PSMC2 acts as a ceRNA for let-7c-3p to elevate RPS15A and activate mTOR in gastric cancer.","evidence":"Dual-luciferase reporter assay, RPS15A rescue overexpression, Torin1 inhibition, knockdown, and xenograft","pmids":["35256584"],"confidence":"Medium","gaps":["RNA-level ceRNA activity for a protein-coding mRNA mechanistically unusual and not structurally explained","Generality beyond gastric cancer untested"]},{"year":2025,"claim":"Dissected two signaling mechanisms in glioblastoma: PSMC2 suppression of JNK-driven autophagic cell death and its activation of AKT/GSK3β/β-catenin-mediated EMT.","evidence":"Knockdown/overexpression with phospho-protein Western blots, BCL2-Beclin1 co-IP, autophagy assays, and LiCl pharmacological rescue","pmids":["39824465","40233917"],"confidence":"Medium","gaps":["How PSMC2 restrains JNK upstream not defined","Whether effects depend on proteasomal degradation unresolved"]},{"year":2026,"claim":"Extended the partner network to EGFR and EZH2 and added a ferroptosis-suppression mechanism, consolidating PSMC2 as a hub coupling protein interactions to growth and cell-death pathways.","evidence":"Reciprocal co-IP and co-localization (EGFR, EZH2), proteomics, STAT3-activator rescue, and biochemical ferroptosis readouts (ROS, lipid peroxidation, GSH, iron) with xenografts","pmids":["42177695","41992005","42234270"],"confidence":"Medium","gaps":["Whether PSMC2 stabilizes EGFR via the proteasome or independently unclear","STAT3 activation mechanism not defined","Direct vs. scaffold-mediated effects not separated"]},{"year":null,"claim":"It remains unresolved whether PSMC2's diverse cancer signaling activities are downstream consequences of its core proteasome-ATPase function or reflect a distinct moonlighting role, and no unified molecular mechanism connects its interaction partners to the multiple pathways reported.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of PSMC2-partner interactions","Proteasome-dependence of oncogenic phenotypes untested","Most pathway claims rest on single-lab knockdown studies"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[1]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,13]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,13,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,12]}],"complexes":["26S proteasome 19S regulatory particle"],"partners":["RPN12","PLAU","ITGA6","CDK1","EGFR","EZH2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35998","full_name":"26S proteasome regulatory subunit 7","aliases":["26S proteasome AAA-ATPase subunit RPT1","Proteasome 26S subunit ATPase 2"],"length_aa":433,"mass_kda":48.6,"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. PSMC2 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P35998/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMC2","classification":"Common Essential","n_dependent_lines":1201,"n_total_lines":1208,"dependency_fraction":0.9942052980132451},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000161057","cell_line_id":"CID000116","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"PSMA1","stoichiometry":10.0},{"gene":"PSMA5","stoichiometry":10.0},{"gene":"PSMA6","stoichiometry":10.0},{"gene":"PSMB1","stoichiometry":10.0},{"gene":"PSMB2","stoichiometry":10.0},{"gene":"PSMB3","stoichiometry":10.0},{"gene":"PSMB4","stoichiometry":10.0},{"gene":"PSMB7","stoichiometry":10.0},{"gene":"PSMD12","stoichiometry":10.0},{"gene":"PSMD11","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000116","total_profiled":1310},"omim":[{"mim_id":"618784","title":"PITH DOMAIN-CONTAINING PROTEIN 1; PITHD1","url":"https://www.omim.org/entry/618784"},{"mim_id":"602707","title":"PROTEASOME 26S SUBUNIT, ATPase, 4; PSMC4","url":"https://www.omim.org/entry/602707"},{"mim_id":"602706","title":"PROTEASOME 26S SUBUNIT, ATPase, 1; PSMC1","url":"https://www.omim.org/entry/602706"},{"mim_id":"154365","title":"PROTEASOME 26S SUBUNIT, ATPase, 2; PSMC2","url":"https://www.omim.org/entry/154365"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Cytoplasmic bodies","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSMC2"},"hgnc":{"alias_symbol":["MSS1","S7","Nbla10058","RPT1"],"prev_symbol":[]},"alphafold":{"accession":"P35998","domains":[{"cath_id":"2.40.50.140","chopping":"88-152","consensus_level":"high","plddt":81.2665,"start":88,"end":152},{"cath_id":"3.40.50.300","chopping":"161-341","consensus_level":"high","plddt":82.1422,"start":161,"end":341},{"cath_id":"1.10.8.60","chopping":"347-421","consensus_level":"high","plddt":89.7993,"start":347,"end":421}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35998","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35998-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35998-F1-predicted_aligned_error_v6.png","plddt_mean":80.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMC2","jax_strain_url":"https://www.jax.org/strain/search?query=PSMC2"},"sequence":{"accession":"P35998","fasta_url":"https://rest.uniprot.org/uniprotkb/P35998.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35998/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35998"}},"corpus_meta":[{"pmid":"27888613","id":"PMC_27888613","title":"PSMC2 is up-regulated in osteosarcoma and regulates osteosarcoma cell proliferation, apoptosis and migration.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27888613","citation_count":31,"is_preprint":false},{"pmid":"34244472","id":"PMC_34244472","title":"Overexpression of PSMC2 promotes the tumorigenesis and development of human breast cancer via regulating plasminogen activator urokinase (PLAU).","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34244472","citation_count":28,"is_preprint":false},{"pmid":"35256584","id":"PMC_35256584","title":"PSMC2 promotes the progression of gastric cancer via induction of RPS15A/mTOR pathway.","date":"2022","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/35256584","citation_count":26,"is_preprint":false},{"pmid":"30222246","id":"PMC_30222246","title":"The structure of INI1/hSNF5 RPT1 and its interactions with the c-MYC:MAX heterodimer provide insights into the interplay between MYC and the SWI/SNF chromatin remodeling complex.","date":"2018","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/30222246","citation_count":26,"is_preprint":false},{"pmid":"31598166","id":"PMC_31598166","title":"PSMC2 is Up-regulated in Pancreatic Cancer and Promotes Cancer Cell Proliferation and Inhibits Apoptosis.","date":"2019","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31598166","citation_count":23,"is_preprint":false},{"pmid":"34294689","id":"PMC_34294689","title":"PSMC2/CCND1 axis promotes development of ovarian cancer through regulating cell growth, apoptosis and migration.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34294689","citation_count":22,"is_preprint":false},{"pmid":"34413286","id":"PMC_34413286","title":"PSMC2/ITGA6 axis plays critical role in the development and progression of hepatocellular carcinoma.","date":"2021","source":"Cell death 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progression of oral squamous cell carcinoma by promoting apoptosis via PI3K/Akt pathway.","date":"2022","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/34979867","citation_count":13,"is_preprint":false},{"pmid":"33902600","id":"PMC_33902600","title":"Silencing of PSMC2 inhibits development and metastasis of prostate cancer through regulating proliferation, apoptosis and migration.","date":"2021","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/33902600","citation_count":13,"is_preprint":false},{"pmid":"34716318","id":"PMC_34716318","title":"PSMC2 knockdown suppressed tumor progression of skin cutaneous melanoma.","date":"2021","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/34716318","citation_count":11,"is_preprint":false},{"pmid":"33732365","id":"PMC_33732365","title":"PSMC2, ORC5 and KRTDAP are specific biomarkers for HPV-negative head and neck squamous cell carcinoma.","date":"2021","source":"Oncology 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Tolerance","date":"2025-05-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.27.656411","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16064,"output_tokens":4484,"usd":0.057726,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12608,"output_tokens":3483,"usd":0.075057,"stage2_stop_reason":"end_turn"},"total_usd":0.132783,"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\": 1999,\n      \"finding\": \"Genetic epistasis in yeast shows that RPT1 (PSMC2 ortholog) physically or functionally interacts with RPN12 (a lid component of the 19S regulatory particle): a single amino acid change at a conserved alanine (position 446) in RPT1 causes synthetic lethality when combined with rpn12-1, suggesting this region of RPT1 is required for interaction with RPN12 within the 26S proteasome.\",\n      \"method\": \"Yeast synthetic lethality screen, DNA sequencing of mutant allele, genetic epistasis\",\n      \"journal\": \"Molecular & general genetics : MGG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with defined mutation, replicated in yeast as ortholog of PSMC2, single lab\",\n      \"pmids\": [\"10503546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Drosophila, loss-of-function of the Rpt1/p48B ATPase subunit (ortholog of PSMC2) impairs 26S proteasome assembly, causes accumulation of multiubiquitinated proteins, alters phosphorylation of the subunit itself, and depletes it from chromatin, establishing its essential role in proteasome integrity and substrate processing.\",\n      \"method\": \"P-element insertion hypomorphic allele analysis, biochemical fractionation (chromatin depletion), Western blot for ubiquitinated proteins\",\n      \"journal\": \"Molecular genetics and genomics : MGG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with multiple orthogonal readouts (proteasome assembly, ubiquitin accumulation, chromatin localization), single lab\",\n      \"pmids\": [\"17429695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In yeast, the N-terminal Pro residue of Rpt1 (PSMC2 ortholog) undergoes N-terminal methylation (mono- or di-methylation) after removal of the initiator Met; deletion of the Pro-Lys sequence at positions 3–4 abolishes methylation, reduces cell growth, and increases stress sensitivity, indicating that N-terminal methylation of Rpt1 and/or its PK sequence is important for cell growth and stress tolerance.\",\n      \"method\": \"Mass spectrometry analysis of N-terminal modifications, site-directed mutagenesis (PK deletion), yeast growth and stress assays\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro MS identification of PTM combined with mutagenesis and functional phenotype, single lab\",\n      \"pmids\": [\"24038880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Knockdown of PSMC2 in osteosarcoma cell lines (SaoS-2 and MG-63) suppresses proliferation, enhances apoptosis, induces G2/M and/or S phase arrest, decreases colony formation, and inhibits migration/invasion in vitro and tumorigenicity in vivo; gene microarray identified downstream genes including ITGA6, FN1, CCND1, CCNE2, and TGFβR2.\",\n      \"method\": \"RNA interference knockdown, MTT/colony assays, flow cytometry, wound-healing/Transwell assays, nude mouse xenograft, gene microarray, Western blot\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple orthogonal cellular readouts and in vivo validation, single lab\",\n      \"pmids\": [\"27888613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMC2 physically interacts with PLAU (plasminogen activator urokinase) in breast cancer cells, and this PSMC2/PLAU axis promotes breast cancer development and progression; knockdown of PSMC2 suppresses breast cancer cell proliferation, apoptosis resistance, and migration in vitro and tumor growth in vivo.\",\n      \"method\": \"Co-immunoprecipitation (interaction with PLAU), gene microarray with IPA, loss-of-function knockdown, xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP interaction identified, loss-of-function phenotype, single lab; interaction mechanistic detail limited to abstract\",\n      \"pmids\": [\"34244472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMC2 physically interacts with ITGA6 in hepatocellular carcinoma cells (confirmed by co-IP), and PSMC2 knockdown exhibits mutual regulation with ITGA6; both knockdowns show similar inhibitory effects on HCC proliferation, colony formation, migration, and enhanced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, gene microarray with IPA, loss-of-function knockdown, xenograft model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct interaction shown by co-IP, functional epistasis by double knockdown, single lab\",\n      \"pmids\": [\"34413286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMC2 knockdown in ovarian cancer cells decreases colony formation, cell motility, and proliferation while increasing apoptosis; gene microarray identified CCND1 as a downstream effector—knockdown of CCND1 enhances effects of PSMC2 knockdown and CCND1 overexpression reverses them, indicating mutual regulation between PSMC2 and CCND1.\",\n      \"method\": \"siRNA knockdown, gene microarray, colony/proliferation/apoptosis assays, CCND1 rescue experiment, xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via overexpression rescue and double knockdown, single lab\",\n      \"pmids\": [\"34294689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMC2 promotes prostate cancer cell proliferation, migration, and survival via the Akt/Cyclin D1/CDK6 signaling pathway; knockdown of PSMC2 inhibits these processes and suppresses tumor growth in vivo.\",\n      \"method\": \"shRNA knockdown, Western blot for pathway proteins, proliferation/apoptosis/migration assays, xenograft\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement inferred from Western blot of downstream proteins after knockdown, single lab, single method for mechanistic claim\",\n      \"pmids\": [\"33902600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMC2 knockdown in skin cutaneous melanoma elevates pro-apoptotic proteins DR6, IGFBP-4, p21, and p53, reduces anti-apoptotic TRAILR-3, and inhibits Wnt signaling pathway proteins, placing PSMC2 as a positive regulator of the Wnt pathway in melanoma.\",\n      \"method\": \"siRNA knockdown, protein-chip (antibody array), gene set enrichment analysis, flow cytometry, xenograft\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — protein array identifies downstream changes but no direct mechanistic connection established, single lab\",\n      \"pmids\": [\"34716318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMC2 knockdown in cholangiocarcinoma cells upregulates Caspase-3 and E-cadherin while downregulating Bcl-2, IGF-II, N-cadherin, and Vimentin; co-IP and RNA-seq identified CDK1 as a direct interaction partner and downstream effector of PSMC2, with mutual regulation of expression between PSMC2 and CDK1.\",\n      \"method\": \"Co-immunoprecipitation (PSMC2-CDK1 interaction), RNA-seq, qPCR, Western blot, loss-of-function knockdown, xenograft\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP interaction with CDK1 confirmed, functional rescue by double knockdown, single lab\",\n      \"pmids\": [\"34499615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PSMC2 enhances RPS15A expression by competitively binding (acting as a ceRNA) to hsa-let-7c-3p in gastric cancer, thereby activating the mTOR pathway; RPS15A overexpression reverses the effects of PSMC2 knockdown on proliferation and migration, and the mTOR inhibitor Torin1 partially blocks RPS15A-driven proliferation.\",\n      \"method\": \"Gene microarray with IPA, dual-luciferase reporter assay (ceRNA/miRNA binding), RPS15A rescue overexpression, Torin1 pharmacological inhibition, loss-of-function knockdown, xenograft\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual-luciferase reporter validates ceRNA mechanism, pathway placement confirmed with pharmacological inhibitor and rescue, single lab\",\n      \"pmids\": [\"35256584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PSMC2 knockdown in oral squamous cell carcinoma cells downregulates p100, p-Akt, and CDK6, and upregulates MAPK9, placing PSMC2 as a positive regulator of the PI3K/Akt pathway; increased pro-apoptotic proteins were confirmed by antibody array.\",\n      \"method\": \"Lentiviral shRNA knockdown, human apoptosis antibody array, flow cytometry, Western blot, xenograft\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway proteins measured by Western blot after knockdown, no direct mechanistic link established, single lab\",\n      \"pmids\": [\"34979867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PSMC2 suppresses JNK-mediated pro-death autophagy in temozolomide-resistant glioblastoma; genetic suppression of PSMC2 activates JNK signaling, causing BCL2 phosphorylation and release of Beclin1 from the BCL2-Beclin1 complex, thereby boosting autophagosome nucleation and restoring apoptosis.\",\n      \"method\": \"PSMC2 knockdown/overexpression, JNK pathway analysis by Western blot (phospho-BCL2, Beclin1 co-IP/interaction), autophagy assays, MG132 proteasome inhibition\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection with multiple downstream readouts (JNK, BCL2 phosphorylation, Beclin1 release), single lab, single study\",\n      \"pmids\": [\"39824465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PSMC2 promotes epithelial-to-mesenchymal transition (EMT) in glioblastoma by activating the AKT/GSK3β/β-catenin axis; PSMC2 overexpression leads to AKT-mediated inhibitory phosphorylation of GSK3β, enabling nuclear β-catenin accumulation; LiCl-induced GSK3β phosphorylation reverses effects of PSMC2 knockdown, validating this pathway.\",\n      \"method\": \"PSMC2 knockdown/overexpression, Western blot (AKT, p-GSK3β, β-catenin nuclear localization), LiCl pharmacological rescue, EMT marker analysis, xenograft\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological rescue validates pathway placement, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"40233917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PSMC2 physically interacts with EGFR in hepatocellular carcinoma, stabilizing EGFR protein levels and enhancing phosphorylation of downstream AKT and ERK1/2; knockdown of PSMC2 inhibits HCC proliferation, migration, and invasion in vitro and tumor growth in vivo.\",\n      \"method\": \"Co-immunoprecipitation (PSMC2-EGFR interaction), immunofluorescence co-localization, Western blot (p-AKT, p-ERK1/2), functional assays, xenograft\",\n      \"journal\": \"Clinical and experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal co-IP and co-localization establish interaction, downstream signaling confirmed by Western blot, single lab\",\n      \"pmids\": [\"42177695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PSMC2 physically interacts with EZH2 in glioma cells (confirmed by co-IP and fluorescence co-localization); proteomics analysis identified EZH2 as a PSMC2-interacting partner, and PSMC2 promotes glioma progression through this interaction, modulating EMT and cytoskeletal architecture.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence co-localization, proteomics, PSMC2 knockdown/overexpression, EMT marker analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and co-localization confirm interaction, proteomics identifies partner, functional consequences shown, single lab\",\n      \"pmids\": [\"41992005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PSMC2 inhibits ferroptosis in nasopharyngeal carcinoma by activating STAT3 phosphorylation, which upregulates CPT1 and GPX4; PSMC2 knockdown decreases p-STAT3, CPT1, and GPX4 levels, increases ROS, lipid peroxidation, and iron ions, reduces GSH, and increases ferroptosis; these effects are reversed by a STAT3 activator.\",\n      \"method\": \"PSMC2 knockdown, Western blot (p-STAT3, CPT1, GPX4), ROS/lipid peroxidation assays, GSH measurement, iron ion detection, STAT3 activator rescue, xenograft\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological rescue with STAT3 activator validates pathway, multiple orthogonal biochemical readouts, single lab\",\n      \"pmids\": [\"42234270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMC2 silencing in bone marrow stromal cells (BMSCs) from ovariectomized mice promotes osteogenic differentiation in vitro and bone formation in vivo, associated with increased Runx2, PI3K, Wnt3a, and β-catenin protein levels and decreased CTSK.\",\n      \"method\": \"siRNA knockdown in OVX mouse model, Western blot for osteogenic/pathway markers, histopathology, BMD measurement\",\n      \"journal\": \"Calcified tissue international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Western blot of downstream pathway proteins after knockdown, no direct mechanistic link established, single lab\",\n      \"pmids\": [\"33625534\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMC2 (RPT1) is an ATPase subunit of the 19S regulatory particle of the 26S proteasome, required for substrate unfolding, translocation, and proteasome assembly; it undergoes N-terminal methylation in yeast, genetically interacts with the lid subunit RPN12, and in cancer cells acts as an oncogenic scaffold that activates multiple downstream pathways (PI3K/AKT, Wnt/β-catenin via AKT/GSK3β, mTOR via RPS15A/ceRNA, JNK-BCL2-Beclin1 autophagy axis, STAT3-GPX4 ferroptosis suppression) through direct physical interactions with partners including PLAU, ITGA6, CDK1, EGFR, and EZH2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMC2 (RPT1) is one of the AAA+ ATPase subunits of the 19S regulatory particle of the 26S proteasome, where it is required for proteasome assembly and processing of ubiquitinated substrates [#1]. Genetic and biochemical work in model organisms established its core role: in yeast a conserved-residue mutation in RPT1 is synthetically lethal with the lid subunit RPN12, placing RPT1 in functional contact with the lid within the regulatory particle [#0], and in Drosophila loss of the Rpt1 ortholog blocks 26S assembly, causes accumulation of multiubiquitinated proteins, and depletes the subunit from chromatin [#1]. The mature yeast subunit also carries an N-terminal proline methylation whose loss reduces growth and stress tolerance [#2]. Beyond its proteasomal role, PSMC2 functions as a pro-tumorigenic factor across many cancers; its knockdown consistently suppresses proliferation, colony formation, migration/invasion, and tumor growth while promoting apoptosis [#3, #4, #6]. Mechanistically, PSMC2 physically associates with partners including PLAU [#4], ITGA6 [#5], CDK1 [#9], EGFR [#14], and EZH2 [#15], and engages multiple downstream programs: it stabilizes EGFR to enhance AKT/ERK signaling [#14], drives AKT/GSK3\\u03b2/\\u03b2-catenin-mediated EMT [#13], activates mTOR through a let-7c-3p ceRNA mechanism that raises RPS15A [#10], suppresses JNK-driven pro-death autophagy by maintaining the BCL2\\u2013Beclin1 complex [#12], and inhibits ferroptosis via STAT3-dependent upregulation of CPT1 and GPX4 [#16]. The downstream pathway placements derive largely from knockdown-and-rescue and Western-blot analyses in individual cancer models rather than from reconstituted biochemistry.\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that RPT1/PSMC2 makes a functionally essential contact with the proteasome lid, defining a structural interface within the 19S regulatory particle.\",\n      \"evidence\": \"Yeast synthetic lethality screen and genetic epistasis between an RPT1 point mutant and rpn12-1\",\n      \"pmids\": [\"10503546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physical interaction not directly demonstrated biochemically\", \"Functional consequence in human PSMC2 not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated that the Rpt1 ATPase is required for 26S proteasome integrity and substrate turnover, establishing its core cellular function beyond a structural placeholder.\",\n      \"evidence\": \"Drosophila hypomorphic allele analysis with proteasome assembly, ubiquitin-accumulation, and chromatin-fractionation readouts\",\n      \"pmids\": [\"17429695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of chromatin depletion unexplained\", \"Significance of subunit phosphorylation not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified N-terminal proline methylation of Rpt1 and linked it to growth and stress tolerance, revealing a post-translational layer of regulation on the subunit.\",\n      \"evidence\": \"Mass spectrometry of N-terminal modifications plus PK-deletion mutagenesis and yeast growth/stress assays\",\n      \"pmids\": [\"24038880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Responsible methyltransferase not identified\", \"Mechanistic link between methylation and proteasome function unknown\", \"Conservation in human PSMC2 untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"First positioned PSMC2 as a cancer dependency, showing that its loss impairs tumor cell growth and survival and pointing to candidate downstream genes.\",\n      \"evidence\": \"RNAi knockdown in osteosarcoma lines with proliferation, apoptosis, cell-cycle, migration, xenograft assays and gene microarray\",\n      \"pmids\": [\"27888613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether phenotype reflects proteasome loss or a distinct function unresolved\", \"Microarray targets not mechanistically validated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined direct physical partners (PLAU, ITGA6, CDK1) and a downstream effector (CCND1) through which PSMC2 drives tumor phenotypes, advancing from association to candidate molecular partners.\",\n      \"evidence\": \"Co-IP, gene microarray/RNA-seq, double-knockdown and rescue experiments, and xenografts across breast, hepatocellular, cholangiocarcinoma, and ovarian cancers\",\n      \"pmids\": [\"34244472\", \"34413286\", \"34499615\", \"34294689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal/structural validation of interactions limited\", \"Whether interactions are proteasome-dependent unknown\", \"Direct vs. indirect regulation of CCND1 not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked PSMC2 to AKT-axis and Wnt signaling in prostate cancer, melanoma, and bone marrow stromal cells, broadening its signaling reach but largely by correlation of pathway-protein levels.\",\n      \"evidence\": \"shRNA/siRNA knockdown with Western blot and antibody-array readouts of pathway proteins; xenograft and OVX-mouse models\",\n      \"pmids\": [\"33902600\", \"34716318\", \"33625534\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway placement inferred from downstream protein changes without direct mechanistic link\", \"Single-method mechanistic support\", \"Direction of causality not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided a defined non-proteasomal mechanism by showing PSMC2 acts as a ceRNA for let-7c-3p to elevate RPS15A and activate mTOR in gastric cancer.\",\n      \"evidence\": \"Dual-luciferase reporter assay, RPS15A rescue overexpression, Torin1 inhibition, knockdown, and xenograft\",\n      \"pmids\": [\"35256584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA-level ceRNA activity for a protein-coding mRNA mechanistically unusual and not structurally explained\", \"Generality beyond gastric cancer untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Dissected two signaling mechanisms in glioblastoma: PSMC2 suppression of JNK-driven autophagic cell death and its activation of AKT/GSK3\\u03b2/\\u03b2-catenin-mediated EMT.\",\n      \"evidence\": \"Knockdown/overexpression with phospho-protein Western blots, BCL2-Beclin1 co-IP, autophagy assays, and LiCl pharmacological rescue\",\n      \"pmids\": [\"39824465\", \"40233917\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PSMC2 restrains JNK upstream not defined\", \"Whether effects depend on proteasomal degradation unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended the partner network to EGFR and EZH2 and added a ferroptosis-suppression mechanism, consolidating PSMC2 as a hub coupling protein interactions to growth and cell-death pathways.\",\n      \"evidence\": \"Reciprocal co-IP and co-localization (EGFR, EZH2), proteomics, STAT3-activator rescue, and biochemical ferroptosis readouts (ROS, lipid peroxidation, GSH, iron) with xenografts\",\n      \"pmids\": [\"42177695\", \"41992005\", \"42234270\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PSMC2 stabilizes EGFR via the proteasome or independently unclear\", \"STAT3 activation mechanism not defined\", \"Direct vs. scaffold-mediated effects not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether PSMC2's diverse cancer signaling activities are downstream consequences of its core proteasome-ATPase function or reflect a distinct moonlighting role, and no unified molecular mechanism connects its interaction partners to the multiple pathways reported.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of PSMC2-partner interactions\", \"Proteasome-dependence of oncogenic phenotypes untested\", \"Most pathway claims rest on single-lab knockdown studies\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 13, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 12]}\n    ],\n    \"complexes\": [\"26S proteasome 19S regulatory particle\"],\n    \"partners\": [\"RPN12\", \"PLAU\", \"ITGA6\", \"CDK1\", \"EGFR\", \"EZH2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}