Affinage

CUL2

Cullin-2 · UniProt Q13617

Length
745 aa
Mass
87.0 kDa
Annotated
2026-06-09
48 papers in source corpus 26 papers cited in narrative 26 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

CUL2 is the scaffold subunit of a family of multisubunit Cullin-RING E3 ubiquitin ligases (CRL2s) that direct substrate-specific ubiquitylation across cell-cycle control, hypoxia signaling, DNA replication, and proteostasis (PMID:9122164, PMID:15601820, PMID:33590678). It bridges the catalytic RING subunit Rbx1 to an Elongin B/Elongin C adaptor, which in turn docks variable substrate-recognition subunits via a BC box plus a downstream 'Cul2 box'; domain-swap and structural analyses establish that these short Cul2-box versus Cul5-box determinants encode whether a receptor assembles with Cul2-Rbx1 or Cul5-Rbx2 (PMID:15601820, PMID:18187417, PMID:25661653, PMID:28591624). The reconstituted Cul2/Rbx1 module is enzymatically active, conjugating ubiquitin to substrates through E2 enzymes and accepting NEDD8/Rub1 modification on Cul2 itself; this neddylation is required to activate the assembled ligase for substrate ubiquitylation (PMID:10579999, PMID:17132228, PMID:34045610). Through the VHL substrate receptor, CRL2 targets HIF-α for oxygen-dependent proteasomal degradation, and disruption of the Cul2-VHL interaction accounts for a large fraction of cancer-predisposing VHL mutations (PMID:9122164, PMID:9447969, PMID:15601820). Distinct substrate receptors route CUL2 to functionally diverse targets: ZYG-11 and FEM-1 direct degradation of cyclin B1, the sex-determining factor TRA-1, and the polarity protein PAR-6 to govern meiotic progression, sex determination, and embryonic polarity (PMID:15215208, PMID:15215209, PMID:17609115, PMID:18502413); LRR1 directs ubiquitylation of the CMG helicase subunit MCM7 to drive replisome disassembly at replication termination, a reaction opposed by the deubiquitylase USP37 (PMID:33590678, PMID:40411782); and FEM1 paralogs recognize C-terminal arginine (Arg/C) degrons (PMID:33398168). Additional receptor-defined activities include PRAME- and PRAMEL7-directed chromatin functions that regulate transcription and pluripotency, and degradation of misfolded TDP-43, viral dengue NS3, and Sirt2 (PMID:21822215, PMID:38332149, PMID:26751167, PMID:36126167, PMID:41932528).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1997 High

    Established CUL2 as a physical component of the VHL tumor-suppressor complex, linking a cullin to human cancer predisposition for the first time.

    Evidence in vivo and in vitro Co-IP showing trimeric VBC-dependent association, with disease-mutant analysis

    PMID:9122164

    Open questions at the time
    • Did not define the enzymatic output of the complex
    • Did not identify substrates
  2. 1998 High

    Placed CUL2 functionally in the VHL ubiquitin ligase pathway controlling hypoxia-inducible gene expression by mapping the pVHL-CUL2 bridge through Elongin C.

    Evidence Co-IP, chromatographic co-purification, and VHL mutant functional assays in native cells

    PMID:9447969

    Open questions at the time
    • Direct ubiquitylation of HIF substrate not yet demonstrated
    • Did not address oxygen-sensing mechanism
  3. 1999 High

    Demonstrated that the Cul2/Rbx1 module is an active ubiquitin-conjugating machine and is itself modified by the ubiquitin-like protein Rub1, defining its enzymatic core.

    Evidence in vitro reconstituted ubiquitination and Rub1-conjugation assays with multiple E2 enzymes

    PMID:10579999

    Open questions at the time
    • Physiological substrates not identified in this assay
    • Role of neddylation in activation not yet shown
  4. 1999 High

    Connected CUL2 to in vivo cell-cycle control, showing it acts at the G1/S transition and in mitotic chromosome condensation via CDK-inhibitor turnover.

    Evidence C. elegans cul-2 loss-of-function with cell-cycle phenotypes and CKI-1 protein-level readout

    PMID:10587644

    Open questions at the time
    • Did not establish CKI-1 as a direct ubiquitylation substrate
    • Substrate receptor for cell-cycle role unidentified
  5. 2004 High

    Defined the molecular code for cullin selectivity, showing Cul2-box versus Cul5-box sequences determine whether a BC-box receptor assembles with Cul2-Rbx1 or Cul5-Rbx2, with functional consequences for HIF-2α degradation.

    Evidence endogenous Co-IP, domain-swap mutagenesis, and RNAi with HIF-2α degradation readout

    PMID:15601820

    Open questions at the time
    • Structural basis of box recognition not yet resolved
    • Did not catalog the full receptor repertoire
  6. 2004 High

    Identified ZYG-11 as a CUL-2 substrate receptor driving meiotic cyclin B turnover and showed CUL-2 controls meiotic exit and embryonic polarity, expanding its substrate range beyond HIF.

    Evidence C. elegans RNAi with cyclin B (CYB-3) levels, PAR-protein localization, and epistasis including cyclin B1 inactivation rescue

    PMID:15215208 PMID:15215209

    Open questions at the time
    • Direct ubiquitylation of cyclin B by CUL-2 not biochemically reconstituted
    • Mammalian conservation of this meiotic role untested
  7. 2006 Medium

    Showed that NEDD8 modification of Cul2 activates the ECV ligase and that HIFα recognition triggers Rbx1-dependent neddylation and a specific E2 (UbcH5a) for substrate ubiquitylation, defining the activation switch.

    Evidence cell-based neddylation pathway manipulation and biochemical E2-preference assays

    PMID:17132228

    Open questions at the time
    • Single-lab study
    • Quantitative kinetics of neddylation-coupled activation not established
  8. 2007 High

    Established CUL-2 substrate receptors FEM-1 and ZYG-11 as the specificity determinants targeting the Gli factor TRA-1 for sex determination, with cross-species validation in human cells.

    Evidence Co-IP, genetic epistasis, proteasome inhibition, and heterologous expression in human cells; VHL-box motif mapping for ZYG-11

    PMID:17304241 PMID:17609115

    Open questions at the time
    • Human orthologous substrate of ZYG11/FEM not identified
    • Direct ubiquitylation site on TRA-1 not mapped
  9. 2008 Medium

    Extended CRL2 receptor logic with detailed Cul2-box assembly rules and revealed a VHL-independent CUL2 role supporting HIF transcriptional activity through ARNT and vasculogenesis.

    Evidence biochemical complex purification with mutagenesis; siRNA with VEGF reporter, ARNT Westerns, and zebrafish morpholino vasculogenesis assay; PAR-6 Co-IP and epistasis

    PMID:18187417 PMID:18372249 PMID:18502413

    Open questions at the time
    • Mechanism by which CUL2 controls ARNT levels unresolved
    • Single-lab findings for the VHL-independent transcriptional role
  10. 2011 Medium

    Identified PRAME as a CUL2 substrate receptor with chromatin-targeting capacity, linking the ligase to transcriptional regulation at active promoters.

    Evidence affinity purification/mass spectrometry, genome-wide ChIP, and in vitro DNA binding

    PMID:21822215

    Open questions at the time
    • Chromatin-associated ubiquitylation substrate of PRAME-CUL2 not defined
    • Single-lab study
  11. 2015 High

    Provided the first structural view of how Cul2 engages VHL-EloBC, revealing BC-box, cullin-box, and a novel EloC contact site and electrostatic determinants of cullin selectivity.

    Evidence X-ray crystallography of the Cul2 N-terminal domain with VHL-EloB-EloC and comparative analysis

    PMID:25661653

    Open questions at the time
    • Full-length cullin conformation not captured
    • Catalytic geometry with Rbx1 and substrate not visualized
  12. 2017 High

    Resolved the full pentameric CRL2VHL architecture, capturing a closed Cul2 conformation and an intermediate Rbx1 pose, and pinpointed interface hotspots that act as a Cul2/Cul5 selectivity switch.

    Evidence X-ray crystallography with ITC/SPR binding thermodynamics and selectivity-determinant mutagenesis

    PMID:28591624

    Open questions at the time
    • Dynamics of the closed-to-open transition during catalysis not directly observed
    • Substrate-bound ubiquitin-transfer state not resolved
  13. 2021 High

    Defined CUL2LRR1 as the S-phase ligase that ubiquitylates the CMG subunit MCM7 to drive p97-mediated replisome disassembly at replication termination, distinct from a mitotic TRAIP pathway.

    Evidence loss-of-function in mouse ES cells, ubiquitylation assays, and chromatin fractionation

    PMID:33590678

    Open questions at the time
    • Trigger that activates CUL2LRR1 at termination not fully defined
    • Regulatory coupling to other termination factors unresolved
  14. 2021 High

    Established the structural basis of Arg/C-degron recognition by FEM1 paralog substrate adapters, defining how CRL2FEM1 complexes achieve degron-class selectivity, and confirmed in vitro enzymatic activity of recombinant Cul2-Rbx1.

    Evidence crystal structures of FEM1A/B/C with degron substrates plus GPS proteome-wide analysis; recombinant Cul2-Rbx1 ubiquitination assays

    PMID:33398168 PMID:34045610

    Open questions at the time
    • Endogenous physiological Arg/C-degron substrates for each FEM1 paralog incompletely cataloged
  15. 2022 Medium

    Broadened CUL2 function into antiviral immunity and germline differentiation through ubiquitylation of dengue NS3 and Drosophila Bam.

    Evidence Co-IP, K48-linkage ubiquitination assays, and loss-of-function with viral replication readouts; Drosophila genetic epistasis with Bam lysine mutagenesis

    PMID:36126167 PMID:36423673

    Open questions at the time
    • Substrate receptor mediating NS3 and Bam recognition not fully defined
    • Single-lab findings
  16. 2024 Medium

    Identified PRAMEL7 as a CUL2 receptor that degrades NuRD components to antagonize repression of pluripotency genes, linking CUL2 to ground-state pluripotency.

    Evidence Co-IP, chromatin fractionation, proteasome inhibition, and loss-of-function rescue

    PMID:38332149

    Open questions at the time
    • Direct ubiquitylation sites on NuRD subunits not mapped
    • Single-lab study
  17. 2025 High

    Refined replication-termination control by showing USP37 deubiquitylates CMG to oppose CUL2LRR1 and prevent premature replisome disassembly, and added Sirt2 and a KEAP1-NRF2 axis to the CUL2 repertoire in infection and cancer.

    Evidence USP37-CMG Co-IP, structure-guided mutagenesis, and CUL2LRR1-depletion epistasis; K48 ubiquitination and knockdown assays for Sirt2; Co-IP, fractionation, and ferroptosis/xenograft assays for NRF2

    PMID:40411782 PMID:41402811 PMID:41932528

    Open questions at the time
    • Whether the KEAP1-NRF2 competition reflects ligase activity or non-catalytic sequestration not resolved
    • Substrate receptors for Sirt2 degradation not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full mammalian substrate-receptor repertoire and the in vivo physiological substrate set for many human CRL2 complexes (e.g., ZYG11, PRAME) remain to be comprehensively defined.
  • Human orthologous substrates for several non-VHL receptors uncharacterized
  • Regulation of receptor exchange on the shared Cul2 scaffold not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016874 ligase activity 4 GO:0060090 molecular adaptor activity 4 GO:0005198 structural molecule activity 3
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 2 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1640170 Cell Cycle 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-69306 DNA Replication 2
Partners
ELONGIN B (TCEB2)ELONGIN C (TCEB1)FEM-1LRR1PRAMERBX1VHLZYG-11
Complex memberships
CRL2 (Cullin2-RING E3 ubiquitin ligase)CRL2-FEM1CRL2-LRR1CRL2-VHL (ElonginBC-Cul2-VHL / ECV)

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 CUL2 (Hs-CUL-2) specifically associates with the trimeric pVHL-Elongin B-Elongin C (VBC) complex both in vitro and in vivo; this association is strictly dependent on the integrity of the trimeric VBC complex, and ~70% of cancer-predisposing VHL mutations disrupt this interaction. CUL2 is a cytosolic protein that can be translocated to the nucleus by pVHL. Co-immunoprecipitation in vivo and in vitro binding assays; immunofluorescence for localization Proceedings of the National Academy of Sciences of the United States of America High 9122164
1998 pVHL binds to human CUL2 via Elongin C; pVHL-CUL2 complexes exist in native cells, and pVHL mutants unable to bind Elongin C/CUL2 are likewise unable to inhibit accumulation of hypoxia-inducible mRNAs under normoxia, placing CUL2 in the VHL ubiquitin ligase pathway controlling HIF target gene expression. Co-immunoprecipitation; chromatographic co-purification; functional assays with VHL mutants Molecular and cellular biology High 9447969
1999 The Cul2/Rbx1 module (alongside Cdc53/Rbx1 of SCF) activates ubiquitin conjugation to target proteins via E2 enzymes Cdc34 and Ubc5, and also activates conjugation of the ubiquitin-like protein Rub1 to Cul2 itself via the dedicated E2 Ubc12; Rbx1 is the common component mediating both ubiquitin and Rub1 modification. In vitro ubiquitination and Rub1-conjugation assays with reconstituted Cul2/Rbx1 module Genes & development High 10579999
1999 In C. elegans, cul-2 is required at two distinct cell-cycle points: the G1-to-S-phase transition and mitotic chromosome condensation. Loss of cul-2 causes G1 arrest correlating with accumulation of the CDK inhibitor CKI-1, and prevents mitotic chromosome condensation, leading to unequal DNA segregation and chromosome bridging. Genetic loss-of-function (cul-2 mutants) in C. elegans with cell-cycle phenotype readouts; CKI-1 protein level analysis Nature cell biology High 10587644
2004 VHL-box proteins (containing a BC box plus a downstream Cul2 box) specifically interact with Cul2-Rbx1, whereas SOCS-box proteins (BC box plus Cul5 box) interact with Cul5-Rbx2. Domain-swapping analyses showed Cul2 and Cul5 box sequences determine this specificity. RNAi knockdown of Cul2-Rbx1 inhibited VHL-mediated degradation of HIF-2α, while knockdown of Cul5-Rbx2 did not. Co-immunoprecipitation of endogenous complexes; domain-swap mutagenesis; RNAi knockdown with HIF-2α degradation readout Genes & development High 15601820
2004 ZYG-11 and CUL-2 promote the metaphase-to-anaphase transition and M phase exit at meiosis II in C. elegans by acting together in a CUL-2-based E3 ligase; loss of either gene causes accumulation of cyclin CYB-3, delayed meiotic exit, and inverted embryonic polarity (PAR proteins, P granules, pronuclear migration). RNAi loss-of-function in C. elegans; analysis of cyclin B levels, PAR protein localization, cell-cycle progression Development (Cambridge, England) High 15215208 15215209
2004 CUL-2 is required for degradation of cyclin B1 during C. elegans meiosis; loss of cul-2 delays or abolishes meiotic anaphase II (not anaphase I) without preventing cohesin REC-8 removal or sister chromatid separation, indicating a specific defect in chromosome movement. Partial rescue of meiotic delay by cyclin B1 inactivation confirms cyclin B1 is a CUL-2 target. Genetic loss-of-function with epistasis (cul-2 mutant × cyclin B1 inactivation); cytological analysis of chromosome behavior and REC-8 localization Development (Cambridge, England) High 15215209
2006 NEDD8 modification (neddylation) of Cul2 is required for activation of the ECV (ElonginBC-Cul2-VHL) E3 ubiquitin ligase. Oxygen-dependent recognition of HIFα by VHL triggers Rbx1-dependent neddylation of Cul2, which preferentially engages the E2 ubiquitin-conjugating enzyme UbcH5a to ubiquitylate HIFα. Cell-based assays; manipulation of neddylation pathway; identification of E2 preference by biochemical assays Neoplasia (New York, N.Y.) Medium 17132228
2007 In C. elegans, CUL-2-based ubiquitin ligase containing FEM-1 (substrate-recognition subunit), FEM-2, and FEM-3 (cofactors) degrades the Gli-family transcription factor TRA-1 to regulate sex determination. CUL-2 physically associates with FEM-1 and TRA-1 in vivo; when FEM proteins are expressed in human cells, they interact with human CUL2 and induce proteasome-dependent TRA-1 degradation. Co-immunoprecipitation in vivo; genetic epistasis; proteasome inhibitor experiments; heterologous expression in human cells Developmental cell High 17609115
2007 ZYG-11 is the substrate-recognition subunit for a CUL-2-based E3 ubiquitin ligase complex in C. elegans; ZYG-11 interacts with CUL-2 in vivo and binds the adaptor protein Elongin C via a nematode variant of the VHL-box motif. Members of the ZYG11 gene family across metazoa (including humans) are conserved CUL2-based ubiquitin ligase components. Co-immunoprecipitation in vivo; sequence/domain analysis; conservation mapping EMBO reports Medium 17304241
2008 CUL-2/FEM-1 ubiquitin ligase (CBC(FEM-1)) regulates PAR-6 protein levels in C. elegans; PAR-6 physically interacts with FEM-1, and CUL-2 is required for degradation of PAR-6 to control cell polarity. Genetic epistasis (nos-3; par-2 suppression); Co-immunoprecipitation (PAR-6 with FEM-1); protein level analysis Developmental biology Medium 18502413
2008 CUL2 characterization of Cul2-box sequences: the spacing between BC-box and Cullin-box is flexible (3 to ~80 aa); the LPPhiP motif conserved in most Cul5-boxes is also compatible with Cul2 interaction; residues conserved in the Cul2-box are a subset of those conserved in the Cul5-box. These structure-function studies define the rules for assembly of BC-box proteins with Cul2-Rbx1 versus Cul5-Rbx2 modules. Purification of BC-box protein complexes; structure-function/mutagenesis analysis; mass spectrometry-based interactome The Journal of biological chemistry Medium 18187417
2008 CUL2 is required for HIF transcriptional activity in a manner distinct from its known role in HIFα degradation: CUL2 siRNA inhibits HIFα-mediated VEGF promoter activation and reduces ARNT expression; ectopic ARNT rescues HIF activity, placing CUL2 upstream of ARNT. In VHL-null cells (786-O), Cul2 siRNA still suppresses ARNT and VEGF, indicating this function is VHL-independent. In zebrafish, zCul2 morpholino blocks embryonic vasculogenesis. siRNA knockdown with VEGF promoter reporter assay; Western blot for ARNT; zebrafish morpholino knockdown with vasculogenesis readout The Journal of biological chemistry Medium 18372249
2011 PRAME (preferentially expressed antigen of melanoma) is a substrate-recognition subunit of a Cul2-based E3 ubiquitin ligase. PRAME can be recruited to DNA in vitro and is specifically enriched genome-wide at transcriptionally active NFY-bound promoters and enhancers. Protein complex purification (affinity purification/mass spectrometry); chromatin immunoprecipitation (genome-wide); in vitro DNA binding The EMBO journal Medium 21822215
2015 Crystal structure of VHL bound to the Cul2 N-terminal domain, Elongin B, and Elongin C reveals that Cul2 interacts with both the VHL BC box and cullin box and a novel EloC site. Cullin selectivity is influenced by distinct electrostatic interactions between cullin and substrate receptor. X-ray crystallography; comparative structural analysis with other cullin E3 ligase structures Structure (London, England : 1993) High 25661653
2016 CUL2 E3 ubiquitin ligase (with VHL as substrate-binding component) recognizes misfolded/fragmented TDP-43 at Glu246 in RRM2 and mediates its degradation. Excess VHL paradoxically stabilizes TDP-43 and promotes inclusion formation at the juxtanuclear protein quality control center. CUL2 also ubiquitylates mutant SOD1. Recombinant protein structural fragility assay; site-directed identification of VHL recognition residue (Glu246); cell-based overexpression/knockdown; immunohistochemistry of ALS spinal cord Scientific reports Medium 26751167
2017 Crystal structure of the full pentameric CRL2VHL complex (Cul2-Rbx1-EloB-EloC-pVHL) reveals a closed conformation of full-length Cul2 and a new Rbx1 pose in trajectory from closed to open. Hotspot residues at the Cul2/pVHL-EloBC interface are characterized; mutations at specific positions create a selectivity switch between Cul2 and Cul5 recognition. X-ray crystallography; thermodynamic binding analyses (ITC/SPR); mutagenesis of selectivity determinants Structure (London, England : 1993) High 28591624
2021 CUL2LRR1 ubiquitin ligase is required for ubiquitylation of the CMG helicase MCM7 subunit during S-phase in mammalian cells, leading to replisome disassembly by the p97 ATPase. A second mitotic pathway of CMG disassembly is dependent on the TRAIP ubiquitin ligase. Loss-of-function studies in mouse embryonic stem cells; ubiquitylation assays; chromatin fractionation EMBO reports High 33590678
2021 Crystal structures of FEM1A, FEM1B, and FEM1C (substrate adapters of CRL2) in complex with Arg/C-degron-bearing substrates reveal the molecular mechanism of C-terminal arginine degron recognition. FEM1A/C and FEM1B selectively target distinct subclasses of Arg/C-degrons, providing the structural basis for substrate selectivity in CRL2FEM1 complexes. X-ray crystallography; in vitro binding assays; global protein stability (GPS) analysis Nature chemical biology High 33398168
2021 Functional recombinant CUL2·RBX1 complex purified from E. coli is enzymatically active in transferring ubiquitin (and ubiquitin-like proteins) to substrates in vitro and can bind substrate receptor modules (e.g., VHL-EloBC for HIF1α ubiquitination). Recombinant protein expression/purification; in vitro ubiquitination assay; substrate receptor binding assay Scientific reports Medium 34045610
2022 NLRC5 recruits CUL2 to catalyze K48-linked poly-ubiquitination of the dengue virus NS3 protease domain, targeting NS3 for selective autophagic degradation via the cargo receptor TOLLIP, thereby restricting DENV infection. Co-immunoprecipitation; ubiquitination assays (K48-linkage specific); NLRC5/CUL2 knockdown/knockout with viral replication readout; autophagy flux assays Autophagy Medium 36126167
2022 Drosophila Cul2 mediates ubiquitination of Bam (bag-of-marbles) protein at multiple lysine residues in its C-terminal region, promoting Bam turnover; genetic evidence shows Cul2-mediated Bam ubiquitination is essential for germline stem cell maintenance and proper germ cell differentiation. Ubiquitination assays; genetic epistasis in Drosophila; site-directed mutagenesis of Bam lysine residues Developmental biology Medium 36423673
2024 PRAMEL7 associates with CUL2 and recruits it to chromatin; PRAMEL7-CUL2 targets NuRD complex components for proteasomal degradation, decreasing NuRD stability and its promoter association, thereby antagonizing NuRD-mediated repression of pluripotency genes and establishing ground-state pluripotency. Co-immunoprecipitation; chromatin fractionation; proteasome inhibitor experiments; loss-of-function rescue assays EMBO reports Medium 38332149
2025 USP37 deubiquitylase binds the CMG helicase (via CDC45) at replication forks and counteracts CUL2LRR1-mediated ubiquitylation of CMG, preventing premature replisome disassembly. Structure-guided mutations displacing USP37 from CMG sensitize cells to DNA synthesis defects; depletion of CUL2LRR1 suppresses this sensitivity. Co-immunoprecipitation (USP37–CMG); structure-guided mutagenesis; genetic epistasis (USP37 mutant × CUL2LRR1 depletion); DNA damage sensitivity assays Cell reports High 40411782
2025 CUL2 mediates K48-linked ubiquitination of Sirt2, targeting it for proteasomal degradation; silencing CUL2 stabilizes Sirt2 protein levels, reduces NF-κB pathway activation, and preserves lung epithelial barrier protein expression (Occludin, Claudin-1, ZO-1) during S. aureus infection. Co-immunoprecipitation; ubiquitination linkage assay (K48-specific); CUL2 siRNA knockdown with Sirt2 protein level and NF-κB readouts; Western blot and immunofluorescence Biochimica et biophysica acta. Molecular basis of disease Medium 41932528
2025 CUL2 competes with NRF2 for KEAP1 binding, preventing KEAP1-mediated NRF2 degradation and promoting NRF2 nuclear translocation; this CUL2-NRF2 axis suppresses ferroptosis and confers gemcitabine resistance in pancreatic cancer cells and xenografts. Co-immunoprecipitation; subcellular fractionation; proteasome inhibitor (MG132) assay; gain- and loss-of-function in vitro and xenograft studies; ferroptosis assays Cancer cell international Medium 41402811

Source papers

Stage 0 corpus · 48 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. Proceedings of the National Academy of Sciences of the United States of America 417 9122164
2004 VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases. Genes & development 411 15601820
1998 Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2. Molecular and cellular biology 320 9447969
2018 Twist1 Regulates Vimentin through Cul2 Circular RNA to Promote EMT in Hepatocellular Carcinoma. Cancer research 269 29844124
1999 The Rbx1 subunit of SCF and VHL E3 ubiquitin ligase activates Rub1 modification of cullins Cdc53 and Cul2. Genes & development 238 10579999
2008 Characterization of Cullin-box sequences that direct recruitment of Cul2-Rbx1 and Cul5-Rbx2 modules to Elongin BC-based ubiquitin ligases. The Journal of biological chemistry 168 18187417
2017 Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex. Structure (London, England : 1993) 122 28591624
2007 A CUL-2 ubiquitin ligase containing three FEM proteins degrades TRA-1 to regulate C. elegans sex determination. Developmental cell 122 17609115
1999 CUL-2 is required for the G1-to-S-phase transition and mitotic chromosome condensation in Caenorhabditis elegans. Nature cell biology 112 10587644
2004 Zyg-11 and cul-2 regulate progression through meiosis II and polarity establishment in C. elegans. Development (Cambridge, England) 108 15215208
2004 CUL-2 and ZYG-11 promote meiotic anaphase II and the proper placement of the anterior-posterior axis in C. elegans. Development (Cambridge, England) 77 15215209
2002 Mammalian mediator subunit mMED8 is an Elongin BC-interacting protein that can assemble with Cul2 and Rbx1 to reconstitute a ubiquitin ligase. Proceedings of the National Academy of Sciences of the United States of America 75 12149480
2015 Insights into Cullin-RING E3 ubiquitin ligase recruitment: structure of the VHL-EloBC-Cul2 complex. Structure (London, England : 1993) 74 25661653
2022 CircSTX6 promotes pancreatic ductal adenocarcinoma progression by sponging miR-449b-5p and interacting with CUL2. Molecular cancer 62 35650603
2011 The tumour antigen PRAME is a subunit of a Cul2 ubiquitin ligase and associates with active NFY promoters. The EMBO journal 60 21822215
2021 Molecular basis for arginine C-terminal degron recognition by Cul2FEM1 E3 ligase. Nature chemical biology 50 33398168
2007 The Caenorhabditis elegans cell-cycle regulator ZYG-11 defines a conserved family of CUL-2 complex components. EMBO reports 47 17304241
2003 Genetic and morphological characterization of the barley uniculm2 (cul2) mutant. TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 43 12647059
2000 Familial clear cell renal cell carcinoma (FCRC): clinical features and mutation analysis of the VHL, MET, and CUL2 candidate genes. Journal of medical genetics 42 10807693
2006 Role of the NEDD8 modification of Cul2 in the sequential activation of ECV complex. Neoplasia (New York, N.Y.) 34 17132228
2021 CUL2LRR1 , TRAIP and p97 control CMG helicase disassembly in the mammalian cell cycle. EMBO reports 32 33590678
2022 Circular RNA CUL2 regulates the development of colorectal cancer by modulating apoptosis and autophagy via miR-208a-3p/PPP6C. Aging 31 35027503
2022 NLRC5 restricts dengue virus infection by promoting the autophagic degradation of viral NS3 through E3 ligase CUL2 (cullin 2). Autophagy 30 36126167
2016 CUL2-mediated clearance of misfolded TDP-43 is paradoxically affected by VHL in oligodendrocytes in ALS. Scientific reports 30 26751167
2002 Study on the interactions between CuL(2) and Morin with DNA. Journal of inorganic biochemistry 29 12175939
2020 microRNA-322/424 promotes liver fibrosis by regulating angiogenesis through targeting CUL2/HIF-1α pathway. Life sciences 27 33333053
2008 CUL2 is required for the activity of hypoxia-inducible factor and vasculogenesis. The Journal of biological chemistry 26 18372249
2020 MicroRNA-154-5p regulates the HPV16 E7-pRb pathway in Cervical Carcinogenesis by targeting CUL2. Journal of Cancer 22 32742484
2016 CUL2 overexpression driven by CUL2/E2F1/miR-424 regulatory loop promotes HPV16 E7 induced cervical carcinogenesis. Oncotarget 21 27153550
1999 Genomic organization and chromosomal localization of the human CUL2 gene and the role of von Hippel-Lindau tumor suppressor-binding protein (CUL2 and VBP1) mutation and loss in renal-cell carcinoma development. Genes, chromosomes & cancer 18 10441001
2010 CUL2 and STK11 as novel response-predictive genes for neoadjuvant radiochemotherapy in esophageal cancer. Pharmacogenomics 17 20712528
2009 Mutational analysis of hypoxia-related genes HIF1alpha and CUL2 in common human cancers. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 17 20078552
2008 PAR-6 levels are regulated by NOS-3 in a CUL-2 dependent manner in Caenorhabditiselegans. Developmental biology 16 18502413
2005 Multiple roles of Rbx1 in the VBC-Cul2 ubiquitin ligase complex. Genes to cells : devoted to molecular & cellular mechanisms 16 15966899
2022 Circ-CUL2/microRNA-888-5p/RB1CC1 axis participates in cisplatin resistance in NSCLC via repressing cell advancement. Bioengineered 14 35068326
2022 E3 ligase Cul2 mediates Drosophila early germ cell differentiation through targeting Bam. Developmental biology 11 36423673
2021 Expression and purification of functional recombinant CUL2•RBX1 from E. coli. Scientific reports 11 34045610
2021 LINC00997/MicroRNA 574-3p/CUL2 Promotes Cervical Cancer Development via Mitogen-Activated Protein Kinase Signaling. Molecular and cellular biology 10 34031216
2005 Synthesis, characterization and antitumor activity of copper(II) complexes, [CuL2] [HL1-3=N,N-diethyl-N'-(R-benzoyl)thiourea (R=H, o-Cl and p-NO2)]. Bioinorganic chemistry and applications 10 18365106
1999 Differences in allelic distribution of two polymorphisms in the VHL-associated gene CUL2 in pheochromocytoma patients without somatic CUL2 mutations. The Journal of clinical endocrinology and metabolism 8 10487688
2021 MicroRNA-574-3p Regulates HIF-α Isoforms Promoting Gastric Cancer Epithelial-Mesenchymal Transition via Targeting CUL2. Digestive diseases and sciences 7 34655362
2021 Immunoexpression of HSPA9 and CUL2 in prostatic tissue and adenocarcinoma. Annals of diagnostic pathology 5 34717191
2025 USP37 protects mammalian cells during DNA replication stress by counteracting CUL2LRR1 and TRAIP. Cell reports 4 40411782
2024 PRAMEL7 and CUL2 decrease NuRD stability to establish ground-state pluripotency. EMBO reports 4 38332149
2025 Cul2 Is Essential for the Drosophila IMD Signaling-Mediated Antimicrobial Immune Defense. International journal of molecular sciences 3 40141268
2025 Identification and validation of USP15 and CUL2 as ubiquitination related biomarker in chronic obstructive pulmonary disease. Hereditas 2 40413536
2026 Dysregulation of the CUL2-Sirt2 axis exacerbates lung epithelial barrier injury in Staphylococcus aureus-induced pneumonia. Biochimica et biophysica acta. Molecular basis of disease 0 41932528
2025 CUL2 confers ferroptosis resistance in pancreatic cancer by disrupting KEAP1-mediated NRF2 degradation. Cancer cell international 0 41402811

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