Affinage

NRBP1

Nuclear receptor-binding protein · UniProt Q9UHY1

Length
535 aa
Mass
59.8 kDa
Annotated
2026-06-10
28 papers in source corpus 18 papers cited in narrative 18 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

NRBP1 is a multidomain pseudokinase/adapter protein that integrates ubiquitin-dependent protein turnover, small-GTPase signaling, and osmotic stress sensing, having been originally characterized as a putative adapter bearing LXXLL nuclear-receptor-binding motifs, a kinase-like domain, and a bipartite NLS (PMID:10843813). As a substrate receptor, dimerized NRBP1 assembles a heterodimeric Cul2/Cul4A Cullin-RING ubiquitin ligase whose formation is enhanced by the chaperone-like activity of TSC22D3/TSC22D4, targeting BRI2 and BRI3 for degradation and thereby controlling Aβ production (PMID:32160551); the same E3 activity drives ubiquitination and degradation of the stemness factor SALL4 (PMID:31864704, PMID:35317026). NRBP1 also acts as a scaffold for Rho-family GTPase signaling, binding P-Rex1, Rac1, and Cdc42 to promote Rac1/Cdc42 activation, ROS generation, and cell migration and invasion in a P-Rex1-dependent manner (PMID:36693952). In the WNK-SPAK/OSR1 osmotic stress pathway, NRBP1 uses a CCT-like domain to bind TSC22D scaffold proteins through conserved RΦ-motifs and, together with WNK1 and TSC22D2/4, condenses into intrinsically-disordered-region-dependent biomolecular condensates (WNK bodies) within seconds of hyperosmotic stress (PMID:38980795, PMID:40668933, PMID:40668923); recombinant NRBP1 directly activates WNK4 in vitro and is required for basal and sorbitol-induced WNK1-SPAK/OXSR1 activation, and DCT-specific deletion in mice reduces NCC phosphorylation and Na+ reabsorption (PMID:40668933, PMID:40668923). NRBP1 additionally inhibits Jab1/CSN5-induced c-Jun phosphorylation and AP-1 activation (PMID:17052710). NRBP1 abundance is itself controlled by TRIM24-mediated, S42-phosphorylation-dependent ubiquitination at K430 and by NRBP2, which antagonizes NRBP1 via heterodimer-driven degradation (PMID:41430038, PMID:40645931).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2000 Medium

    Established NRBP1 as a candidate multidomain adapter, defining the domain architecture (LXXLL motifs, pseudokinase domain, NLS) that framed all subsequent functional hypotheses.

    Evidence cDNA cloning, in vitro translation, and domain analysis

    PMID:10843813

    Open questions at the time
    • No binding partners or catalytic activity demonstrated
    • Functional role unaddressed
  2. 2002 Medium

    First linked NRBP1 to Rho-family GTPase signaling and secretory trafficking, showing it associates with activated Rac3 and alters ER-to-Golgi transport.

    Evidence Co-IP with V12Rac3, kinase activity assay, and immunocytochemistry in COS-1 cells

    PMID:11956649

    Open questions at the time
    • Source of associated kinase activity not resolved
    • Mechanism linking GTPase binding to trafficking unclear
  3. 2006 Medium

    Identified a transcriptional regulatory role, showing NRBP1 binds Jab1/CSN5 and suppresses AP-1 activation.

    Evidence In vivo Co-IP and AP-1 reporter / c-Jun phosphorylation assays

    PMID:17052710

    Open questions at the time
    • Structural basis of Jab1 interaction unknown
    • Relationship to NRBP1's other functions unexplored
  4. 2020 High

    Defined NRBP1 as a CRL substrate receptor, reconstituting a heterodimeric Cul2/Cul4A ligase that degrades BRI2/BRI3 and showing TSC22D3/4 act as assembly chaperones — linking NRBP1 to Aβ production.

    Evidence CRL reconstitution, MS interactome, RNAi knockdown with Aβ readout

    PMID:32160551

    Open questions at the time
    • In vivo relevance to amyloid pathology not tested
    • Full substrate repertoire undefined
  5. 2019 Medium

    Extended NRBP1's E3 substrate-receptor role to oncogenesis by showing it ubiquitinates SALL4, with THG-1 competing to stabilize SALL4 and promote tumor stemness.

    Evidence Ubiquitination and competitive binding assays, tumorsphere formation in ESCC cells

    PMID:31864704

    Open questions at the time
    • Cullin scaffold used for SALL4 not directly identified
    • Single cancer context
  6. 2023 High

    Established NRBP1 as a scaffold that drives Rac1/Cdc42 activation and oncogenic migration/invasion through P-Rex1.

    Evidence BioID/MS, Co-IP, GTPase pull-down activity assays, P-Rex1-dependent rescue, ROS measurement, xenografts

    PMID:36693952

    Open questions at the time
    • Whether NRBP1 directly activates P-Rex1 GEF activity not resolved
    • Connection to its E3 functions unknown
  7. 2024 High

    Resolved the molecular basis of NRBP1 recruitment to the WNK osmotic-stress pathway, identifying CCT/NbrT domain-motif binding to TSC22D and rapid IDR-dependent condensate formation with WNK1.

    Evidence Co-essentiality analysis, live-cell condensate imaging, co-IP, domain mapping, phylogenetics; in vitro CCT-motif binding (one preprint)

    PMID:38980795 PMID:bio_10.1101_2024.06.26.600905

    Open questions at the time
    • Functional consequence of condensation for kinase activity not yet shown in these reports
    • Stoichiometry of the condensate undefined
  8. 2025 High

    Demonstrated NRBP1 is a direct activator of WNK kinases and a physiological regulator of renal Na+ handling, showing recombinant NRBP1 activates WNK4 in vitro and DCT-specific deletion reduces NCC phosphorylation.

    Evidence In vitro WNK4 activation with recombinant NRBP1, proximity labeling/Co-IP/MS, CRISPR knockout, AlphaFold-3 modeling, DCT-specific knockout mice with NCC phosphorylation readout

    PMID:40668923 PMID:40668933

    Open questions at the time
    • Mechanism by which a pseudokinase activates WNK4 catalysis is unresolved
    • Whether the same activity governs WNK signaling in non-renal tissues untested
  9. 2025 Medium

    Identified upstream control of NRBP1 abundance, showing TRIM24 mediates S42-phosphorylation-dependent K430 ubiquitination and NRBP2 antagonizes NRBP1 by heterodimer-driven degradation.

    Evidence Co-IP, ubiquitination assays, site-directed mutagenesis, L1 retrotransposition assays, NRBP1/NRBP2 perturbation

    PMID:40645931 PMID:41430038

    Open questions at the time
    • Kinase phosphorylating S42 not identified
    • Physiological trigger of TRIM24/NRBP2-mediated turnover unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NRBP1's distinct activities — CRL substrate receptor, GTPase scaffold, and WNK pathway activator — are coordinated or partitioned within a cell remains unknown.
  • No structural model integrating the multiple functional modules
  • Unknown whether condensate localization gates E3 versus GTPase functions
  • Catalytic mechanism of pseudokinase-driven WNK activation unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-392499 Metabolism of proteins 2
Partners
JAB1P-REX1RAC1TRIM24TSC22D2TSC22D3TSC22D4WNK1
Complex memberships
Cul2/Cul4A heterodimeric Cullin-RING ligaseWNK body / NRBP1-WNK1-TSC22D condensate

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 NRBP1 (NRBP) was identified as a multidomain putative adapter protein containing two LXXLL nuclear receptor binding motifs, a putative SH2 domain-binding domain, a kinase-like domain, a bipartite nuclear localization signal, and PEST sequences. In vitro translation revealed three products of 60, 51, and 43 kDa, suggesting multiple translation initiation sites. cDNA cloning, in vitro translation, domain analysis Genomics Medium 10843813
2002 NRBP1 forms a complex with constitutively activated Rac3 (V12Rac3) and exhibits an associated kinase activity. NRBP and activated Rac3 co-localize to endomembranes and at the cell periphery in lamellipodia. Overexpression of NRBP caused redistribution of Golgi-associated marker p58 to more peripheral locations, consistent with impairment of ER-to-Golgi transport, suggesting a role in subcellular trafficking. Co-IP/pulldown with V12Rac3, kinase activity assay, immunocytochemistry, overexpression in COS-1 cells International journal of molecular medicine Medium 11956649
2006 NRBP1 interacts in vivo with Jab1 (the fifth component of the COP9 signalosome complex) and inhibits Jab1-induced phosphorylation of c-Jun and AP-1 activation. Overexpression of NRBP1 in mammalian cells specifically inhibits AP-1 activation by various stimuli. Co-IP in vivo, AP-1 reporter assay, c-Jun phosphorylation assay, overexpression FEBS letters Medium 17052710
2020 NRBP1 functions as a substrate receptor of a Cullin-RING ubiquitin ligase (CRL) complex targeting BRI2 and BRI3 for degradation. Dimerized NRBP1 assembles into a functional heterodimeric CRL containing both Cul2 and Cul4A through its BC-box and an overlapping cryptic H-box. Formation of the NRBP1 heterodimeric CRL is strongly enhanced by chaperone-like function of TSC22D3 and TSC22D4. NRBP1 knockdown in neuronal cells increases BRI2 and BRI3 abundance and significantly reduces Aβ production. Co-IP, mass spectrometry, reconstitution of CRL complex, RNAi knockdown, Aβ measurement Cell reports High 32160551
2019 NRBP1 induces ubiquitination of SALL4, targeting it for degradation. THG-1 (a NRBP1 binding protein) competes with SALL4 for NRBP1 binding, thereby blocking NRBP1-mediated ubiquitination of SALL4 and stabilizing it to promote stemness gene expression (NANOG, OCT4) and tumorsphere growth in esophageal squamous cell carcinoma cells. Knockdown and overexpression, ubiquitination assay, competitive binding assay, tumorsphere formation assay Biochemical and biophysical research communications Medium 31864704
2021 NRBP1 is localized in microglia and neurons (not astrocytes) in mouse medial prefrontal cortex. (R)-ketamine increases NRBP1 expression in primary microglia cultures through ERK activation, and NRBP1 participates in an ERK-NRBP1-CREB-BDNF signaling cascade. Microglial depletion blocked the antidepressant-like effects of (R)-ketamine. Isobaric quantitative proteomics (iTRAQ), immunofluorescence/immunohistochemistry for localization, primary microglia culture, ERK inhibition, intracerebroventricular HDO injection, microglial depletion (PLX3397, MCLs) Molecular psychiatry Medium 34819637
2022 Drosophila Madm (ortholog of NRBP1) is required presynaptically to maintain synaptic stability and coordinate synaptic growth and function by controlling cap-dependent translation via the TOR effector 4E-BP/Thor. Postsynaptic Madm induces a compensatory transsynaptic signal using the presynaptic homeostatic potentiation (PHP) machinery to offset synaptic release deficits at degenerating neuromuscular synapses, acting via regulation of cap-dependent translation regulators 4E-BP/Thor and S6-kinase. Genetic loss-of-function (presynaptic and postsynaptic specific knockdown), electrophysiology, imaging of neuromuscular junction, epistasis with TOR pathway components Cell reports High 36450258
2023 NRBP1 (pseudokinase) acts as a scaffold that binds P-Rex1 (a guanine nucleotide exchange factor for Rac1), Rac1, and Cdc42. NRBP1 overexpression enhances GTP-bound Rac1 and Cdc42 levels in a P-Rex1-dependent manner, while NRBP1 knockdown reduces their activation. NRBP1-mediated promotion of cell migration and invasion is P-Rex1-dependent. Generation of reactive oxygen species via a NRBP1/P-Rex1 pathway is implicated in oncogenic roles. BioID/MS proximity labeling, Co-IP, GTP-Rac1/Cdc42 pull-down activity assays, siRNA knockdown, P-Rex1-dependent rescue experiments, ROS measurement, xenograft models Oncogene High 36693952
2024 NRBP1 promotes GBM malignant phenotypes (proliferation, invasion, migration, apoptosis resistance) through activation of the PI3K/Akt signaling pathway. The effects of NRBP1 knockout and overexpression on GBM cells were rescued by PI3K/Akt inhibitor MK-2206 and activator SC79, respectively, establishing epistatic placement of NRBP1 upstream of PI3K/Akt. NRBP1 knockout and overexpression, pharmacological epistasis (MK-2206, SC79), cell proliferation/invasion/migration assays, mouse tumor model Cancer medicine Medium 39149873
2024 NRBP1, TSC22D2, and WNK1 physically associate into biomolecular condensates within seconds of hyperosmotic stress, dependent on intrinsically disordered regions (IDRs). NRBP1 contains a domain (NbrT, NRBP binding region with TSC22D) that specifically evolved to bind TSC22D proteins, co-evolving with WNK IDR expansion in metazoans. All three gene families are functionally buffered for osmo-sensing and cell volume control. Gene co-essentiality analysis, live-cell imaging of condensate formation, co-IP, domain mapping (NbrT identification), phylogenetic analysis Cell reports High 38980795
2024 The NRBP1 CCT-like domain binds TSC22D1 via the same R-F-x-V/I or R-x-F-x-V/I motif used by OSR1 and SPAK, identifying NRBP1 as a WNK pathway component that interacts with TSC22D scaffold proteins through conserved CCT domain-motif interactions. Computational motif prediction, in vitro binding assays, comparison with known CCT domain interactions bioRxivpreprint Medium bio_10.1101_2024.06.26.600905
2025 NRBP1 pseudokinase directly activates WNK4 in vitro and is required for basal and sorbitol-induced activation of WNK1 and downstream SPAK/OXSR1 components. NRBP1 associates with WNK1 and TSC22D2/4 following osmotic stress (confirmed by immunoprecipitation, MS, immunoblotting). NRBP1 contains a CCT domain that, per AlphaFold-3 modeling, interacts with TSC22D4 RΦ-motifs alongside WNK1 CCTL1 domain in a multi-protein complex. NRBP1 knockdown or knockout markedly inhibits WNK pathway activation. Proximity labeling, Co-IP, mass spectrometry, immunoblotting, in vitro WNK4 activation assay with recombinant NRBP1, siRNA/CRISPR knockout, AlphaFold-3 structural modeling Science advances High 40668933
2025 NRBP1 and long TSC22D isoforms (TSC22D1.1, TSC22D2) are localized in WNK bodies (cytoplasmic biomolecular condensates) in the distal convoluted tubule (DCT). NRBP1 and long TSC22D isoforms increase WNK4 activity in HEK293 cells. DCT-specific NRBP1 knockout mice show reduced NCC phosphorylation and activate a compensatory response, demonstrating that NRBP1 modulates Na+ reabsorption in the kidney. Immunofluorescence/localization in DCT, HEK293 cell WNK4 activity assays, DCT-specific NRBP1 knockout mouse model, NCC phosphorylation measurement Science advances High 40668923
2025 TRIM24 binds NRBP1 and enhances its ubiquitination and subsequent degradation. NRBP1 phosphorylation at residue S42 is crucial for TRIM24-mediated ubiquitination, and K430 is the specific ubiquitination site targeted by TRIM24. Co-IP, ubiquitination assays, site-directed mutagenesis (S42, K430), siRNA knockdown, Western blot Cell death & disease Medium 41430038
2025 NRBP1 positively regulates L1 retrotransposition by influencing integrity of the L1 ribonucleoprotein complex. NRBP2 antagonizes NRBP1 function by targeting NRBP1 for degradation, probably through heterodimer formation, rather than by competing for common interaction partners. L1 retrotransposition assay, NRBP1/NRBP2 overexpression and knockdown, heterodimer formation analysis, phylogenetic analysis Nature communications Medium 40645931
2017 DNA methylation at the NRBP1 promoter region (B1 site, 72 bp upstream of TSS) regulates TFAP2A binding. Hypomethylation reduces TFAP2A binding to B1, leading to increased NRBP1 expression. Methylation increases TFAP2A binding and suppresses gene expression, as shown by luciferase reporter assay and protein pulldown. Luciferase reporter assay, protein pulldown assay, bisulfite pyrosequencing Clinical epigenetics Medium 28932319
2022 NRBP1 negatively regulates SALL4 protein stability in breast cancer cells, and overexpression of SALL4 reverses the NRBP1-overexpression-induced suppression of invasion, migration, apoptosis, and chemotherapy drug sensitivity, establishing NRBP1 acts upstream of SALL4. NRBP1 overexpression, SALL4 overexpression rescue experiment, Transwell invasion/migration assay, apoptosis assay, drug sensitivity assay (doxorubicin, cisplatin) Oncology letters Medium 35317026
2022 NRBP1 modulates ABCG2 (urate transporter) expression in HK-2 kidney cells via activation of the Wnt/β-catenin pathway. Knockdown of NRBP1 increased ABCG2 expression, and this effect was blocked by a β-catenin inhibitor (21H7), demonstrating pathway dependence. Lentiviral overexpression, siRNA knockdown, qRT-PCR, Western blot, immunofluorescence, β-catenin inhibitor (21H7) epistasis Nefrologia Low 36437206

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Microglial ERK-NRBP1-CREB-BDNF signaling in sustained antidepressant actions of (R)-ketamine. Molecular psychiatry 176 34819637
2020 NRBP1-Containing CRL2/CRL4A Regulates Amyloid β Production by Targeting BRI2 and BRI3 for Degradation. Cell reports 36 32160551
2000 Cloning of the cDNA and localization of the gene encoding human NRBP, a ubiquitously expressed, multidomain putative adapter protein. Genomics 32 10843813
2017 DNA hypomethylation of a transcription factor binding site within the promoter of a gout risk gene NRBP1 upregulates its expression by inhibition of TFAP2A binding. Clinical epigenetics 28 28932319
2002 Interaction of the small GTPase Rac3 with NRBP, a protein with a kinase-homology domain. International journal of molecular medicine 26 11956649
2015 NRBP1 is downregulated in breast cancer and NRBP1 overexpression inhibits cancer cell proliferation through Wnt/β-catenin signaling pathway. OncoTargets and therapy 24 26715855
2012 High NRBP1 expression in prostate cancer is linked with poor clinical outcomes and increased cancer cell growth. The Prostate 24 22473923
2006 Adapter protein NRBP associates with Jab1 and negatively regulates AP-1 activity. FEBS letters 18 17052710
2024 The TSC22D, WNK, and NRBP gene families exhibit functional buffering and evolved with Metazoa for cell volume regulation. Cell reports 15 38980795
2023 The pseudokinase NRBP1 activates Rac1/Cdc42 via P-Rex1 to drive oncogenic signalling in triple-negative breast cancer. Oncogene 13 36693952
2020 Puerarin Inhibits the Progression of Bladder Cancer by Regulating circ_0020394/miR-328-3p/NRBP1 Axis. Cancer biotherapy & radiopharmaceuticals 13 33016781
2018 MiR-519d inhibits prostate cancer cell proliferation, cycle and invasion via targeting NRBP1. European review for medical and pharmacological sciences 13 29863241
2021 CircLRP6 contributes to prostate cancer growth and metastasis by binding to miR-330-5p to up-regulate NRBP1. World journal of surgical oncology 12 34158077
2019 THG-1 suppresses SALL4 degradation to induce stemness genes and tumorsphere formation through antagonizing NRBP1 in squamous cell carcinoma cells. Biochemical and biophysical research communications 11 31864704
2024 NRBP1 promotes malignant phenotypes of glioblastoma by regulating PI3K/Akt activation. Cancer medicine 9 39149873
2022 NRBP1 negatively regulates SALL4 to reduce the invasion and migration, promote apoptosis and increase the sensitivity to chemotherapy drugs of breast cancer cells. Oncology letters 8 35317026
2021 Circular RNA circ_0062019 exerts oncogenic properties in prostate cancer via mediating miR-1253/NRBP1 axis. Andrologia 8 34866220
2022 NRBP1 modulates uric acid transporter ABCG2 expression by activating the Wnt/β-catenin pathway in HK-2 cells. Nefrologia 7 36437206
2025 NRBP1 pseudokinase binds to and activates the WNK pathway in response to osmotic stress. Science advances 4 40668933
2023 The Circular RNA Circ_0085494 Regulates Prostate Cancer Progression Through NRBP1/miR-497-5p Axis. Biochemical genetics 4 36790665
2025 NRBP1 and TSC22D proteins affect distal convoluted tubule physiology through modulation of the WNK pathway. Science advances 3 40668923
2022 Madm/NRBP1 mediates synaptic maintenance and neurodegeneration-induced presynaptic homeostatic potentiation. Cell reports 2 36450258
2025 Silencing NRBP1 Gene with shRNA Improves Cognitive Function and Pathological Features in AD Rat Model. Biochemical genetics 1 40616751
2024 NRBP1 and TSC22D proteins impact distal convoluted tubule physiology through modulation of the WNK pathway. bioRxiv : the preprint server for biology 1 39764004
2026 DNA Methylation Regulates CDK5R1 and NRBP1 to Exert Effects on Alcohol Dependence: Insights From Mendelian Randomization. Addiction biology 0 42025296
2025 Opposing roles of pseudokinases NRBP1 and NRBP2 in regulating L1 retrotransposition. Nature communications 0 40645931
2025 WNK kinase activity is modulated by the pseudokinase NRBP1 and the scaffold proteins of the TSC22D family. Current opinion in nephrology and hypertension 0 40726374
2025 TRIM24 promotes proliferation and metastasis of gastric cancer via mediating NRBP1 ubiquitination. Cell death & disease 0 41430038

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