Affinage

PSMC2

26S proteasome regulatory subunit 7 · UniProt P35998

Length
433 aa
Mass
48.6 kDa
Annotated
2026-06-10
27 papers in source corpus 18 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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.

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1999 Medium

    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

    PMID:10503546

    Open questions at the time
    • Physical interaction not directly demonstrated biochemically
    • Functional consequence in human PSMC2 not tested
  2. 2007 Medium

    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

    PMID:17429695

    Open questions at the time
    • Mechanism of chromatin depletion unexplained
    • Significance of subunit phosphorylation not resolved
  3. 2013 Medium

    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

    PMID:24038880

    Open questions at the time
    • Responsible methyltransferase not identified
    • Mechanistic link between methylation and proteasome function unknown
    • Conservation in human PSMC2 untested
  4. 2017 Medium

    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

    PMID:27888613

    Open questions at the time
    • Whether phenotype reflects proteasome loss or a distinct function unresolved
    • Microarray targets not mechanistically validated
  5. 2021 Medium

    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

    PMID:34244472 PMID:34294689 PMID:34413286 PMID:34499615

    Open questions at the time
    • Reciprocal/structural validation of interactions limited
    • Whether interactions are proteasome-dependent unknown
    • Direct vs. indirect regulation of CCND1 not separated
  6. 2021 Low

    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

    PMID:33625534 PMID:33902600 PMID:34716318

    Open questions at the time
    • Pathway placement inferred from downstream protein changes without direct mechanistic link
    • Single-method mechanistic support
    • Direction of causality not established
  7. 2022 Medium

    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

    PMID:35256584

    Open questions at the time
    • RNA-level ceRNA activity for a protein-coding mRNA mechanistically unusual and not structurally explained
    • Generality beyond gastric cancer untested
  8. 2025 Medium

    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

    PMID:39824465 PMID:40233917

    Open questions at the time
    • How PSMC2 restrains JNK upstream not defined
    • Whether effects depend on proteasomal degradation unresolved
  9. 2026 Medium

    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

    PMID:41992005 PMID:42177695 PMID:42234270

    Open questions at the time
    • Whether PSMC2 stabilizes EGFR via the proteasome or independently unclear
    • STAT3 activation mechanism not defined
    • Direct vs. scaffold-mediated effects not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No structural model of PSMC2-partner interactions
  • Proteasome-dependence of oncogenic phenotypes untested
  • Most pathway claims rest on single-lab knockdown studies

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 1
Partners
CDK1EGFREZH2ITGA6PLAURPN12
Complex memberships
26S proteasome 19S regulatory particle

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 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. Yeast synthetic lethality screen, DNA sequencing of mutant allele, genetic epistasis Molecular & general genetics : MGG Medium 10503546
2007 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. P-element insertion hypomorphic allele analysis, biochemical fractionation (chromatin depletion), Western blot for ubiquitinated proteins Molecular genetics and genomics : MGG Medium 17429695
2013 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. Mass spectrometry analysis of N-terminal modifications, site-directed mutagenesis (PK deletion), yeast growth and stress assays Proteomics Medium 24038880
2017 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. RNA interference knockdown, MTT/colony assays, flow cytometry, wound-healing/Transwell assays, nude mouse xenograft, gene microarray, Western blot Oncotarget Medium 27888613
2021 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. Co-immunoprecipitation (interaction with PLAU), gene microarray with IPA, loss-of-function knockdown, xenograft model Cell death & disease Medium 34244472
2021 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. Co-immunoprecipitation, gene microarray with IPA, loss-of-function knockdown, xenograft model Cell death discovery Medium 34413286
2021 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. siRNA knockdown, gene microarray, colony/proliferation/apoptosis assays, CCND1 rescue experiment, xenograft Cell death & disease Medium 34294689
2021 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. shRNA knockdown, Western blot for pathway proteins, proliferation/apoptosis/migration assays, xenograft Cancer cell international Low 33902600
2021 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. siRNA knockdown, protein-chip (antibody array), gene set enrichment analysis, flow cytometry, xenograft Cell death discovery Low 34716318
2021 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. Co-immunoprecipitation (PSMC2-CDK1 interaction), RNA-seq, qPCR, Western blot, loss-of-function knockdown, xenograft Aging Medium 34499615
2022 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. Gene microarray with IPA, dual-luciferase reporter assay (ceRNA/miRNA binding), RPS15A rescue overexpression, Torin1 pharmacological inhibition, loss-of-function knockdown, xenograft Oncogenesis Medium 35256584
2022 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. Lentiviral shRNA knockdown, human apoptosis antibody array, flow cytometry, Western blot, xenograft Cell cycle (Georgetown, Tex.) Low 34979867
2025 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. PSMC2 knockdown/overexpression, JNK pathway analysis by Western blot (phospho-BCL2, Beclin1 co-IP/interaction), autophagy assays, MG132 proteasome inhibition Biochemical pharmacology Medium 39824465
2025 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. PSMC2 knockdown/overexpression, Western blot (AKT, p-GSK3β, β-catenin nuclear localization), LiCl pharmacological rescue, EMT marker analysis, xenograft Cellular signalling Medium 40233917
2026 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. Co-immunoprecipitation (PSMC2-EGFR interaction), immunofluorescence co-localization, Western blot (p-AKT, p-ERK1/2), functional assays, xenograft Clinical and experimental medicine Medium 42177695
2026 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. Co-immunoprecipitation, fluorescence co-localization, proteomics, PSMC2 knockdown/overexpression, EMT marker analysis Scientific reports Medium 41992005
2026 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. PSMC2 knockdown, Western blot (p-STAT3, CPT1, GPX4), ROS/lipid peroxidation assays, GSH measurement, iron ion detection, STAT3 activator rescue, xenograft Discover oncology Medium 42234270
2021 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. siRNA knockdown in OVX mouse model, Western blot for osteogenic/pathway markers, histopathology, BMD measurement Calcified tissue international Low 33625534

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 PSMC2 is up-regulated in osteosarcoma and regulates osteosarcoma cell proliferation, apoptosis and migration. Oncotarget 31 27888613
2021 Overexpression of PSMC2 promotes the tumorigenesis and development of human breast cancer via regulating plasminogen activator urokinase (PLAU). Cell death & disease 28 34244472
2022 PSMC2 promotes the progression of gastric cancer via induction of RPS15A/mTOR pathway. Oncogenesis 26 35256584
2018 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. The FEBS journal 26 30222246
2019 PSMC2 is Up-regulated in Pancreatic Cancer and Promotes Cancer Cell Proliferation and Inhibits Apoptosis. Journal of Cancer 23 31598166
2021 PSMC2/CCND1 axis promotes development of ovarian cancer through regulating cell growth, apoptosis and migration. Cell death & disease 22 34294689
2021 PSMC2/ITGA6 axis plays critical role in the development and progression of hepatocellular carcinoma. Cell death discovery 20 34413286
2021 INI1/SMARCB1 Rpt1 domain mimics TAR RNA in binding to integrase to facilitate HIV-1 replication. Nature communications 19 33980829
2013 N-Terminal methylation of proteasome subunit Rpt1 in yeast. Proteomics 16 24038880
2022 PSMC2 is overexpressed in glioma and promotes proliferation and anti-apoptosis of glioma cells. World journal of surgical oncology 15 35287689
2022 PSMC2 knockdown inhibits the progression of oral squamous cell carcinoma by promoting apoptosis via PI3K/Akt pathway. Cell cycle (Georgetown, Tex.) 13 34979867
2021 Silencing of PSMC2 inhibits development and metastasis of prostate cancer through regulating proliferation, apoptosis and migration. Cancer cell international 13 33902600
2021 PSMC2 knockdown suppressed tumor progression of skin cutaneous melanoma. Cell death discovery 11 34716318
2021 PSMC2, ORC5 and KRTDAP are specific biomarkers for HPV-negative head and neck squamous cell carcinoma. Oncology letters 10 33732365
2025 PSMC2 promotes resistance against temozolomide in glioblastoma via suppressing JNK-mediated autophagic cell death. Biochemical pharmacology 8 39824465
2021 Knockdown of PSMC2 contributes to suppression of cholangiocarcinoma development by regulating CDK1. Aging 8 34499615
1999 Genetic evidence for interaction between components of the yeast 26S proteasome: combination of a mutation in RPN12 (a lid component gene) with mutations in RPT1 (an ATPase gene) causes synthetic lethality. Molecular & general genetics : MGG 8 10503546
2024 PSMC2 knockdown exerts an anti-tumor role in nasopharyngeal carcinoma through regulating AKT signaling pathway. Cell cycle (Georgetown, Tex.) 4 38123344
2024 PSMC2 promotes glioma progression by regulating immune microenvironment and PI3K/AKT/mTOR pathway. Immunobiology 3 38569452
2007 Molecular characterization of the Rpt1/p48B ATPase subunit of the Drosophila melanogaster 26S proteasome. Molecular genetics and genomics : MGG 3 17429695
2025 PSMC2 upregulation enhances epithelial-to-mesenchymal transition in glioblastoma via activating AKT/GSK3β/β-catenin axis. Cellular signalling 2 40233917
2021 Silencing Proteasome 26S Subunit ATPase 2 (PSMC2) Protects the Osteogenic Differentiation In Vitro and Osteogenesis In Vivo. Calcified tissue international 2 33625534
1989 Definition of T-cell specific DNA-binding factors that interact with a 3'-silencer in the CD4+ T-cell gene Rpt-1. Gene 2 2697644
2024 Hsa_circ_0007718 facilitates the progression of colorectal cancer by regulating the miR-1299/PSMC2 axis. International journal of biological macromolecules 1 39396594
2026 PSMC2 serves as a potential regulatory target of EZH2 in promoting glioma progression via epithelial-mesenchymal transition. Scientific reports 0 41992005
2026 PSMC2 promotes hepatocellular carcinoma progression through interaction with EGFR. Clinical and experimental medicine 0 42177695
2026 PSMC2 drives tumor progression in nasopharyngeal carcinoma by inhibiting ferroptosis through STAT3. Discover oncology 0 42234270

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