Affinage

PSMD2

26S proteasome non-ATPase regulatory subunit 2 · UniProt Q13200

Length
908 aa
Mass
100.2 kDa
Annotated
2026-06-10
16 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2011 Medium

    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

    PMID:21465578

    Open questions at the time
    • Did not identify direct substrates
    • Mechanism linking PSMD2 to AKT/p38 not resolved
  2. 2018 Medium

    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

    PMID:29777785

    Open questions at the time
    • Direct vs. proteasome-general effect on p21/p27 not fully separated
    • Binding interface not mapped
  3. 2018 Medium

    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

    PMID:30269947

    Open questions at the time
    • Conservation of ATG16-mediated turnover in mammalian cells not shown
    • Trigger for autophagic delivery unknown
  4. 2019 Medium

    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

    PMID:31136974 PMID:31703613

    Open questions at the time
    • Whether phosphatase suppression is degradation-dependent unclear
    • Mechanism connecting PSMD2 to lipogenic genes not defined
  5. 2023 Medium

    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

    PMID:37848434 PMID:37875476

    Open questions at the time
    • Binding sites for RACK1/β-catenin not structurally resolved
    • Selectivity rules for competitive occupancy unknown
  6. 2023 Medium

    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

    PMID:36998052 PMID:39634424

    Open questions at the time
    • Mechanism upstream of ASS1/mTOR not established
    • Direct vs. indirect AKT regulation unresolved
  7. 2025 High

    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)

    PMID:bio_10.1101_2025.02.22.639686

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Generality of NLS-receptor mode to other substrates untested
  8. 2025 Medium

    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

    PMID:40830962

    Open questions at the time
    • Docking-based interface lacks experimental structure
    • Whether CX26 affects other substrates unknown
  9. 2026 Low

    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

    PMID:41930182

    Open questions at the time
    • Limited mechanistic depth linking PSMD2 to MAPK
    • Direct effector for CXCL14 downregulation not identified
  10. 2026 Medium

    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

    PMID:41789415

    Open questions at the time
    • Downstream proteasomal targets in MASLD not defined
    • Tissue specificity of the axis untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how PSMD2's receptor surface discriminates among substrates and competitive partners, and which interactions reflect direct degradation versus indirect signaling.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005634 nucleus 1 GO:0005764 lysosome 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-9612973 Autophagy 2
Partners
ASPNATG16CX26DIRAS2DNAJA4MIDNOLINMYH9RACK1
Complex memberships
19S regulatory particle26S proteasome

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 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. Co-immunoprecipitation, rescue assays (siRNA knockdown with p21/p27 measurement), in vitro and in vivo functional assays Cancer letters Medium 29777785
2011 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. siRNA knockdown, proteasome activity assay, Western blot for pAKT/p38/p21 Molecular carcinogenesis Medium 21465578
2019 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. Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown epistasis Frontiers in bioscience (Landmark edition) Medium 31136974
2019 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. siRNA knockdown, lipid droplet staining, gene expression analysis of lipid synthesis genes, signaling pathway Western blots BMC molecular biology Medium 31703613
2018 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. Deletion analysis, co-localization (fluorescence microscopy), LysoTracker labeling, proteolytic cleavage assay, genetic knockout (atg16−, atg9−) European journal of cell biology Medium 30269947
2023 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. Co-immunoprecipitation, competitive binding assays, siRNA knockdown, in vitro and in vivo proliferation assays Cell death & disease Medium 37848434
2023 DNAJA4 recruits PSMD2 to facilitate ubiquitin-proteasome-mediated degradation of MYH9, thereby suppressing EMT, migration, and invasion in nasopharyngeal carcinoma. Co-immunoprecipitation, overexpression/knockdown experiments, in vitro migration/invasion assays, in vivo metastasis model, rescue with MYH9 overexpression Cell death & disease Medium 37875476
2022 PSMD2 interacts with DIRAS2 and facilitates its proteasome-mediated degradation in colorectal cancer cells. Co-immunoprecipitation, proteasome inhibitor treatment, knockdown/overexpression functional assays International journal of biological sciences Low 35173535
2023 PSMD2 activates the mTOR pathway by upregulating argininosuccinate synthase 1 (ASS1), thereby inhibiting autophagy and promoting esophageal squamous cell carcinoma cell growth. DIA quantification proteomics, immunoblotting, knockdown/overexpression, autophagy (DAPgreen staining) assays, xenograft model Cell & bioscience Medium 36998052
2024 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. siRNA knockdown, overexpression, immunoblotting of AKT/mTOR pathway, pharmacological rescue with MK-2206, cell viability/apoptosis assays Heliyon Medium 39634424
2025 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. Cryo-EM structural determination, biochemical binding assays, mutagenesis (implied by structural validation), functional nuclear localization assays bioRxivpreprint High bio_10.1101_2025.02.22.639686
2025 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. Co-immunoprecipitation, immunofluorescence, molecular docking, proteomic analysis, in vivo xenograft model Journal of translational medicine Medium 40830962
2026 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. Western blot for MEK/ERK phosphorylation, siRNA knockdown, in vitro/in vivo functional assays, KEGG/GO pathway analysis, CXCL14 measurement Oncology research Low 41930182
2026 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. Luciferase reporter validation, gain/loss-of-function in vivo and in vitro, qPCR, exercise and dietary intervention in mouse models eGastroenterology Medium 41789415

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 PSMD2 regulates breast cancer cell proliferation and cell cycle progression by modulating p21 and p27 proteasomal degradation. Cancer letters 88 29777785
2011 Proteasomal non-catalytic subunit PSMD2 as a potential therapeutic target in association with various clinicopathologic features in lung adenocarcinomas. Molecular carcinogenesis 52 21465578
2019 PSMD1 and PSMD2 regulate HepG2 cell proliferation and apoptosis via modulating cellular lipid droplet metabolism. BMC molecular biology 45 31703613
2019 Asporin promotes cell proliferation via interacting with PSMD2 in gastric cancer. Frontiers in bioscience (Landmark edition) 35 31136974
2023 RACK1 facilitates breast cancer progression by competitively inhibiting the binding of β-catenin to PSMD2 and enhancing the stability of β-catenin. Cell death & disease 23 37848434
2018 ATG16 mediates the autophagic degradation of the 19S proteasomal subunits PSMD1 and PSMD2. European journal of cell biology 23 30269947
2023 DNAJA4 suppresses epithelial-mesenchymal transition and metastasis in nasopharyngeal carcinoma via PSMD2-mediated MYH9 degradation. Cell death & disease 18 37875476
2022 Diverse Ras-related GTPase DIRAS2, downregulated by PSMD2 in a proteasome-mediated way, inhibits colorectal cancer proliferation by blocking NF-κB signaling. International journal of biological sciences 14 35173535
2023 PSMD2 contributes to the progression of esophageal squamous cell carcinoma by repressing autophagy. Cell & bioscience 10 36998052
2021 Proteomic Analysis Reveals That Metformin Suppresses PSMD2, STIP1, and CAP1 for Preventing Gastric Cancer AGS Cell Proliferation and Migration. ACS omega 10 34124444
2024 Identification of PSMD2 as a promising biomarker for pancreatic cancer patients based on comprehensive bioinformatics and in vitro studies. Heliyon 2 39634424
2025 Impact of PSMD2 on Gastric Cancer Tissue Stiffness Investigated via Motor-Piezoceramic Coupled Atomic Force Microscopy. Nano letters 1 40016166
2025 CX26 promotes pancreatic cancer progression by competitively inhibiting interaction of c-Myc with PSMD2 and enhancing c-Myc stability. Journal of translational medicine 1 40830962
2026 Exercise and dietary interventions ameliorate MASLD via the hepatic PPARγ-miR-802-Psmd2 axis. eGastroenterology 0 41789415
2026 De Novo 3q27.1 Microdeletion Refines the Critical Region and Implicates PSMD2 Haploinsufficiency in Growth and Neurodevelopmental Abnormalities. American journal of medical genetics. Part A 0 41804662
2026 PSMD2-Mediated MAPK Signaling Promotes Bladder Cancer Development and Immune Microenvironment Remodeling. Oncology research 0 41930182

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