Affinage

NRBP2

Nuclear receptor-binding protein 2 · UniProt Q9NSY0

Length
501 aa
Mass
57.8 kDa
Annotated
2026-04-29
16 papers in source corpus 8 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NRBP2 is a cytoplasmic pseudokinase that functions as a tumor suppressor and negative regulator of LINE-1 retrotransposition. NRBP2 promotes proteasome-mediated degradation of its paralog NRBP1 through heterodimer formation, thereby disrupting the L1 ribonucleoprotein complex and opposing NRBP1-dependent retrotransposition (PMID:40645931). In cancer contexts, NRBP2 binds Annexin A2 to inhibit Akt/Bad phosphorylation and activates the AMPK/mTOR axis to suppress proliferation, invasion, and epithelial-to-mesenchymal transition (PMID:27634758, PMID:33816275). NRBP2 expression is epigenetically silenced by GATA1-recruited HDAC2-mediated histone deacetylation at its promoter and post-transcriptionally suppressed by exosomal miR-25-5p (PMID:35491849, PMID:41223004).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2008 Medium

    Establishing that NRBP2 is a cytoplasmic protein with a functional role in cell survival addressed the basic question of where it localizes and what happens when it is lost — revealing that neural progenitor cells become vulnerable to apoptosis upon NRBP2 depletion.

    Evidence siRNA knockdown, subcellular fractionation/immunostaining, and cell viability assays in neural progenitor cells

    PMID:18619852

    Open questions at the time
    • Mechanism by which NRBP2 suppresses apoptosis not identified
    • No direct binding partner or signaling target defined
    • Single cell type tested
  2. 2016 Medium

    Identification of ANXA2 as a direct binding partner and downstream effector resolved how NRBP2 connects to pro-survival signaling — NRBP2 suppresses ANXA2 expression and thereby inhibits Akt/Bad phosphorylation, establishing a molecular mechanism for its tumor-suppressive activity.

    Evidence Co-immunoprecipitation, overexpression with ANXA2 rescue, and phosphorylation assays in hepatocellular carcinoma cells

    PMID:27634758

    Open questions at the time
    • Mechanism by which NRBP2 binding leads to ANXA2 downregulation unclear
    • No structural basis for NRBP2–ANXA2 interaction
    • Not validated outside hepatocellular carcinoma
  3. 2021 Medium

    Demonstrating AMPK/mTOR pathway engagement expanded NRBP2's tumor-suppressive mechanism beyond Akt — pharmacological epistasis showed that NRBP2 activates AMPK to suppress mTOR, inhibiting EMT and invasion in breast cancer.

    Evidence Overexpression/knockdown with AMPK and mTOR pharmacological inhibitors, invasion assays, and orthotopic xenograft model in breast cancer

    PMID:33816275

    Open questions at the time
    • Direct molecular target through which NRBP2 activates AMPK not identified
    • Relationship between AMPK/mTOR and ANXA2/Akt arms of NRBP2 signaling unresolved
    • No kinase-dead mutant analysis despite pseudokinase status
  4. 2022 Medium

    Identifying GATA1/HDAC2-mediated epigenetic silencing of the NRBP2 promoter explained how tumor cells downregulate NRBP2 expression, resolving the regulatory question of why NRBP2 is frequently lost in cancers.

    Evidence ChIP for GATA1 and HDAC2 at NRBP2 promoter, promoter-reporter assays, overexpression/rescue in thyroid carcinoma cells

    PMID:35491849

    Open questions at the time
    • Whether GATA1/HDAC2-mediated silencing operates in cancer types beyond thyroid carcinoma unknown
    • No genome-wide analysis of NRBP2 promoter methylation or acetylation states
    • Upstream signals activating GATA1 in this context not defined
  5. 2025 High

    Discovery that NRBP2 promotes proteasome-mediated degradation of its paralog NRBP1 via heterodimer formation provided the first defined enzymatic-level mechanism for NRBP2 and revealed its role as a negative regulator of LINE-1 retrotransposition — a fundamentally distinct function from its tumor-suppressive signaling roles.

    Evidence Co-immunoprecipitation, proteasome inhibition (MG132), retrotransposition reporter assays, heterodimer formation experiments, phylogenetic analysis in Nature Communications

    PMID:40645931

    Open questions at the time
    • E3 ubiquitin ligase mediating NRBP1 ubiquitination not identified
    • Whether NRBP2-driven NRBP1 degradation contributes to tumor suppression is untested
    • Structural basis for NRBP1–NRBP2 heterodimerization unresolved
  6. 2025 Medium

    Validation that exosomal miR-25-5p directly targets NRBP2 mRNA established a post-transcriptional regulatory axis, showing NRBP2 suppression modulates PI3K/AKT signaling and pyroptosis in alveolar epithelial cells during bronchopulmonary dysplasia.

    Evidence Luciferase reporter assay for miR-25-5p–NRBP2 interaction, PI3K inhibitor rescue, macrophage exosome co-culture, in vivo BPD rat model

    PMID:41223004

    Open questions at the time
    • Whether miR-25-5p regulation of NRBP2 is relevant in cancer contexts unknown
    • NRBP2 relationship to pyroptosis machinery not mechanistically defined
    • Single disease model tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the E3 ligase mediating NRBP2-triggered NRBP1 degradation, the structural basis for NRBP1–NRBP2 heterodimerization, and whether NRBP2's pseudokinase domain retains any catalytic or allosteric function relevant to its diverse signaling outputs.
  • No E3 ligase identified for NRBP1 degradation pathway
  • No crystal or cryo-EM structure of NRBP2 or NRBP1–NRBP2 complex
  • Pseudokinase domain function uncharacterized — no kinase-dead mutant analysis reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3
Partners
ANXA2NRBP1

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 NRBP2 is a 55-60 kDa protein with mainly cytoplasmic localization, and its downregulation by siRNA renders neural progenitor cells more vulnerable to apoptosis, indicating a role in neural progenitor cell survival. siRNA knockdown, subcellular fractionation/immunostaining, cell viability assays Molecular and cellular neurosciences Medium 18619852
2016 NRBP2 binds to Annexin A2 (ANXA2) via co-immunoprecipitation, inhibits ANXA2 expression, and thereby downregulates Akt and Bad phosphorylation, increasing chemosensitivity of hepatocellular carcinoma cells. Co-immunoprecipitation, overexpression, rescue experiments with ANXA2 co-expression, phosphorylation assays Cancer research Medium 27634758
2021 NRBP2 overexpression activates the AMPK/mTOR signaling pathway to suppress breast cancer cell proliferation, invasion, and epithelial-to-mesenchymal transition (EMT); an AMPK inhibitor partially rescues NRBP2 overexpression effects, and mTOR inhibitors eliminate NRBP2 knockdown effects. Overexpression and knockdown (KD/OE), pharmacological inhibition of AMPK and mTOR, in vitro invasion/proliferation assays, in vivo orthotopic model Frontiers in oncology Medium 33816275
2022 GATA1 recruits histone deacetylase 2 (HDAC2) to the NRBP2 promoter to trigger histone deacetylation and suppress NRBP2 expression in thyroid carcinoma cells. Chromatin immunoprecipitation, overexpression of GATA1/HDAC2, promoter-reporter assays, rescue experiments Bioengineered Medium 35491849
2024 NRBP2 in cancer-associated fibroblasts (CAFs) inhibits the Akt signaling pathway, thereby suppressing CAF-induced chemoresistance in breast cancer cells. Overexpression/knockdown in CAFs, co-culture experiments, immunoblotting of Akt pathway components, apoptosis assays Toxicology research Low 39664500
2025 NRBP2 targets its paralog NRBP1 for proteasome-mediated degradation, likely through heterodimer formation, and thereby opposes NRBP1's role in promoting L1 retrotransposition by disrupting the L1 ribonucleoprotein complex. Co-immunoprecipitation, proteasome inhibition assays, retrotransposition reporter assays, heterodimer formation experiments, phylogenetic analysis Nature communications High 40645931
2025 Exosomal miR-25-5p from M2 macrophages targets NRBP2, downregulating NRBP2 expression and inhibiting the PI3K/AKT pathway to protect alveolar epithelial cells from pyroptosis in bronchopulmonary dysplasia. Luciferase reporter assay (miRNA-target validation), PI3K inhibitor rescue, miR-25-5p knockdown, co-culture of macrophage-derived exosomes with alveolar epithelial cells, in vivo BPD rat model FASEB journal Medium 41223004
2024 NRBP2 targets NRBP1 for proteasome-mediated decay through heterodimer formation, and their opposing roles in regulating LINE1 retrotransposition arise from NRBP2-driven degradation of NRBP1 rather than competition for common binding partners. Co-immunoprecipitation, proteasome inhibition, retrotransposition reporter assays, pulldown experiments bioRxivpreprint Medium
2025 NRBP1 and its close homolog NRBP2 are predicted to function as upstream activators of the WNK kinase pathway, based on structural similarity including a CCT domain, and NRBP1 can directly activate WNK4 in vitro. AlphaFold-3 structural modeling, proximity labeling, immunoprecipitation, in vitro kinase activation assay, NRBP1 knockdown/knockout Science advances Low 40668933

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 SCRIB and PUF60 are primary drivers of the multisystemic phenotypes of the 8q24.3 copy-number variant. American journal of human genetics 78 24140112
2020 DNA-dependent protein kinase regulates lysosomal AMP-dependent protein kinase activation and autophagy. Autophagy 45 31983282
2016 NRBP2 Overexpression Increases the Chemosensitivity of Hepatocellular Carcinoma Cells via Akt Signaling. Cancer research 39 27634758
2014 Mechanisms of nanosized titanium dioxide-induced testicular oxidative stress and apoptosis in male mice. Particle and fibre toxicology 23 25209749
2020 miR-146b-5p Plays a Critical Role in the Regulation of Autophagy in ∆per Brucella melitensis-Infected RAW264.7 Cells. BioMed research international 17 32051823
2019 The altered expression of autophagy-related genes participates in heart failure: NRBP2 and CALCOCO2 are associated with left ventricular dysfunction parameters in human dilated cardiomyopathy. PloS one 17 31009519
2018 Role of PUF60 gene in Verheij syndrome: a case report of the first Chinese Han patient with a de novo pathogenic variant and review of the literature. BMC medical genomics 17 30352594
2008 Nuclear receptor binding protein 2 is induced during neural progenitor differentiation and affects cell survival. Molecular and cellular neurosciences 12 18619852
2022 Proteomic profiling reveals antitumor effects of RT2 peptide on a human colon carcinoma xenograft mouse model. European journal of pharmacology 9 35032485
2022 GATA binding protein 1 recruits histone deacetylase 2 to the promoter region of nuclear receptor binding protein 2 to affect the tumor microenvironment and malignancy of thyroid carcinoma. Bioengineered 9 35491849
2020 Nuclear Receptor Binding Protein 2 Is Downregulated in Medulloblastoma, and Reduces Tumor Cell Survival upon Overexpression. Cancers 6 32517178
2021 NRBP2 Functions as a Tumor Suppressor and Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer. Frontiers in oncology 5 33816275
2025 NRBP1 pseudokinase binds to and activates the WNK pathway in response to osmotic stress. Science advances 3 40668933
2025 Opposing roles of pseudokinases NRBP1 and NRBP2 in regulating L1 retrotransposition. Nature communications 0 40645931
2025 Lipoxin A4 Regulates M2 Macrophage-Derived Exosomal miR-25-5p to Protect Cell Pyroptosis in Bronchopulmonary Dysplasia. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41223004
2024 Cancer-associated fibroblasts affect breast cancer cell sensitivity to chemotherapeutic agents by regulating NRBP2. Toxicology research 0 39664500