CUL2

Summary

CUL2 (cullin 2, HGNC:2552) is a protein-coding gene on chromosome 10p11.21, encoding Cullin-2 (Q13617). Core component of multiple cullin-RING-based ECS (ElonginB/C-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of target proteins. It is a selective cancer dependency (DepMap: 64.0% of cell lines).

Enables ubiquitin ligase complex scaffold activity and ubiquitin protein ligase binding activity. Involved in ubiquitin-dependent protein catabolic process via the C-end degron rule pathway. Located in nucleoplasm. Part of Cul2-RING ubiquitin ligase complex.

Source: NCBI Gene 8453 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 109 total — 1 likely-pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 64.0% of screened cell lines
• MANE Select transcript: NM_003591

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2552
Approved symbol	CUL2
Name	cullin 2
Location	10p11.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000108094
Ensembl biotype	protein_coding
OMIM	603135
Entrez	8453

Gene structure

Transcript identifiers

Ensembl transcripts: 63 — 37 protein_coding, 17 nonsense_mediated_decay, 9 retained_intron

ENST00000374746, ENST00000374748, ENST00000374749, ENST00000374751, ENST00000374754, ENST00000421317, ENST00000468804, ENST00000478044, ENST00000537177, ENST00000626172, ENST00000673636, ENST00000684955, ENST00000684965, ENST00000685421, ENST00000685488, ENST00000685681, ENST00000686156, ENST00000686271, ENST00000686302, ENST00000686748, ENST00000686903, ENST00000687194, ENST00000687282, ENST00000687524, ENST00000688044, ENST00000688252, ENST00000688390, ENST00000688541, ENST00000688571, ENST00000688705, ENST00000688736, ENST00000689036, ENST00000689330, ENST00000689705, ENST00000690092, ENST00000690123, ENST00000690393, ENST00000690789, ENST00000691201, ENST00000691263, ENST00000691272, ENST00000691457, ENST00000691635, ENST00000691858, ENST00000691962, ENST00000691974, ENST00000692456, ENST00000692866, ENST00000693739, ENST00000859693, ENST00000859694, ENST00000859695, ENST00000859696, ENST00000859697, ENST00000859698, ENST00000859699, ENST00000970358, ENST00000970359, ENST00000970360, ENST00000970361, ENST00000970362, ENST00000970363, ENST00000970364

RefSeq mRNA: 6 — MANE Select: NM_003591 NM_001198777, NM_001198778, NM_001198779, NM_001324375, NM_001324376, NM_003591

CCDS: CCDS55709, CCDS7179, CCDS73086, CCDS91236

Canonical transcript exons

ENST00000374749 — 21 exons

Exon	Start	End
ENSE00001464519	35090179	35090341
ENSE00003477507	35013699	35013800
ENSE00003486185	35008551	35010442
ENSE00003496584	35031300	35031386
ENSE00003497075	35054434	35054539
ENSE00003503083	35062960	35063062
ENSE00003515307	35031491	35031619
ENSE00003524671	35044566	35044676
ENSE00003537027	35049683	35049765
ENSE00003552445	35025132	35025198
ENSE00003562211	35035172	35035296
ENSE00003593546	35033166	35033273
ENSE00003595254	35029488	35029640
ENSE00003605025	35038920	35039082
ENSE00003609367	35060874	35060968
ENSE00003620460	35028810	35028887
ENSE00003637414	35032435	35032494
ENSE00003643673	35016192	35016394
ENSE00003653466	35044772	35044868
ENSE00003670896	35011848	35011964
ENSE00003692474	35071199	35071339

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 95.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.0359 / max 310.2371, expressed in 1816 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
109096	16.8823	1800
109100	4.9759	1663
109099	4.6524	1618
109097	0.7593	478
109098	0.7445	436
109095	0.0215	4

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	95.93	gold quality
male germ cell	CL:0000015	93.51	gold quality
cortical plate	UBERON:0005343	93.27	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.50	gold quality
muscle of leg	UBERON:0001383	92.14	gold quality
gastrocnemius	UBERON:0001388	92.13	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.75	gold quality
calcaneal tendon	UBERON:0003701	90.39	gold quality
ventricular zone	UBERON:0003053	90.18	gold quality
stromal cell of endometrium	CL:0002255	90.12	gold quality
islet of Langerhans	UBERON:0000006	90.08	gold quality
ganglionic eminence	UBERON:0004023	89.91	gold quality
muscle organ	UBERON:0001630	89.71	gold quality
adrenal tissue	UBERON:0018303	89.35	gold quality
biceps brachii	UBERON:0001507	89.22	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	89.07	gold quality
right testis	UBERON:0004534	88.52	gold quality
left testis	UBERON:0004533	88.37	gold quality
testis	UBERON:0000473	88.01	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	87.99	gold quality
rectum	UBERON:0001052	87.23	gold quality
prefrontal cortex	UBERON:0000451	87.17	gold quality
deltoid	UBERON:0001476	86.96	gold quality
colonic epithelium	UBERON:0000397	86.79	gold quality
smooth muscle tissue	UBERON:0001135	86.47	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.40	gold quality
embryo	UBERON:0000922	86.38	gold quality
skeletal muscle tissue	UBERON:0001134	86.31	gold quality
right adrenal gland	UBERON:0001233	85.99	gold quality
visceral pleura	UBERON:0002401	85.97	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.58

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ARNT

miRNA regulators (miRDB)

131 targeting CUL2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-329-3P	99.91	66.56	1234

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 64.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 25)

• Cullin selection is determined by specific Elongin C and Skp1 sequences (PMID:15280393)
• the HPV16 E7-associated cullin 2 ubiquitin ligase complex contributes to aberrant degradation of the pRB tumor suppressor in HPV16 E7-expressing cells. (PMID:17609271)
• CUL2 is required for normal vasculogenesis, at least in part mediated by its regulation of HIF-mediated transcription. (PMID:18372249)
• The data suggest that neither HIF1alpha nor CUL2 mutation may play a central role in HIF1alpha activation in gastric, colorectal, breast, lung and hepatocellular carcinomas, and acute leukemias. (PMID:20078552)
• The authors applied protein-complex purification strategies and identified PRAME as a substrate recognition subunit of a Cullin2-based E3 ubiquitin ligase. (PMID:21822215)
• Study finds that UBXN7 over-expression converts CUL2 to its neddylated form and causes the accumulation of non-ubiquitylated HIF1alpha. (PMID:22537386)
• a novel link between the oncoprotein PRAME and the conserved EKC complex (PMID:22912744)
• Nevertheless, the identification of the Cul2 box may allow prediction of Cullin specificity for all E4orf6-containing Adenoviridae. (PMID:24453364)
• Cullins are a family of NEDD8 targets important in the stabilization and degradation of proteins, such as hypoxia-inducible factor (HIF1A), via Cullin-2. (PMID:25326537)
• misfolded TDP-43 is cleared by VHL/CUL2 in a step-wise manner via fragmentation. (PMID:26751167)
• Results suggest that E7 recruited CUL2, driven by CUL2/E2F1/miR-424 regulatory loop, is overexpressed and accelerates HPV16-induced cervical carcinogenesis. (PMID:27153550)
• The crystal structure of a pentameric CRL2(VHL) complex, composed of Cul2, Rbx1, Elongin B, Elongin C, and pVHL reveals hydrophobic contact residues critical for the Cul2 interactions. (PMID:28591624)
• direct evidence that both A3A and HPV16 E7 interact with CUL2, suggesting that the E7-CUL2 complex formed during HPV infection may regulate A3A protein levels in the cell. (PMID:29367246)
• Twist1 bound the Cul2 promoter. (PMID:29844124)
• Roles of Cullin-2 E3 Ubiquitin Ligase Complex in Cancer (PMID:31898228)
• Integrating cullin2-RING E3 ligase as a potential biomarker for glioblastoma multiforme prognosis and radiosensitivity profiling. (PMID:32918970)
• ORF10-Cullin-2-ZYG11B complex is not required for SARS-CoV-2 infection. (PMID:33827988)
• Reconstitution of human CMG helicase ubiquitylation by CUL2LRR1 and multiple E2 enzymes. (PMID:34195792)
• MicroRNA-574-3p Regulates HIF-alpha Isoforms Promoting Gastric Cancer Epithelial-Mesenchymal Transition via Targeting CUL2. (PMID:34655362)
• Immunoexpression of HSPA9 and CUL2 in prostatic tissue and adenocarcinoma. (PMID:34717191)
• CircSTX6 promotes pancreatic ductal adenocarcinoma progression by sponging miR-449b-5p and interacting with CUL2. (PMID:35650603)
• A close shave: How SARS-CoV-2 induces the loss of cilia. (PMID:35695891)
• MicroRNA-154-5p suppresses cervical carcinoma growth and metastasis by silencing Cullin2 in vitro and in vivo. (PMID:37397007)
• Comprehensive prognostic and immunological analysis of Cullin2 in pan-cancer and its identification in hepatocellular carcinoma. (PMID:38787355)
• TRAF2 associates with cullin neddylation complex assembly. (PMID:38978293)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cul2	ENSDARG00000013965
mus_musculus	Cul2	ENSMUSG00000024231
rattus_norvegicus	Cul2	ENSRNOG00000015292
drosophila_melanogaster	Cul2	FBGN0032956
caenorhabditis_elegans		WBGENE00000837

Paralogs (7): CUL3 (ENSG00000036257), CUL1 (ENSG00000055130), CUL4A (ENSG00000139842), CACUL1 (ENSG00000151893), CUL4B (ENSG00000158290), CUL5 (ENSG00000166266), ANAPC2 (ENSG00000176248)

Protein

Protein identifiers

Cullin-2 — Q13617 (reviewed: Q13617)

All UniProt accessions (29): Q13617, A0A0A0MTN0, A0A0D9SET6, A0A140VKB1, A0A8I5KP04, A0A8I5KPX0, A0A8I5KQQ5, A0A8I5KR51, A0A8I5KS98, A0A8I5KSW7, A0A8I5KTY2, A0A8I5KTY5, A0A8I5KU22, A0A8I5KUA0, A0A8I5KUA9, A0A8I5KV54, A0A8I5KVE2, A0A8I5KVR3, A0A8I5KWB8, A0A8I5KXB2, A0A8I5KY75, A0A8I5KYA3, A0A8I5KYM7, A0A8I5KYP8, A0A8I5KYZ8, A0A8I5QJI3, A0A8I5QKN3, Q5T2B5, Q5T2B7

UniProt curated annotations — full annotation on UniProt →

Function. Core component of multiple cullin-RING-based ECS (ElonginB/C-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of target proteins. CUL2 serves as a rigid scaffold in the complex and may contribute to catalysis through positioning of the substrate and the E2 ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1. The functional specificity of the ECS complex depends on the substrate recognition component. ECS(VHL) mediates the ubiquitination of hypoxia-inducible factor (HIF). A number of ECS complexes (containing either KLHDC2, KLHDC3, KLHDC10, APPBP2, FEM1A, FEM1B or FEM1C as substrate-recognition component) are part of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. ECS complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins. ECS(LRR1) ubiquitinates MCM7 and promotes CMG replisome disassembly by VCP and chromatin extraction during S-phase.

Subunit / interactions. Component of multiple Cul2-RING (CRL2) E3 ubiquitin-protein ligase complexes consisting of CUL2, Elongin BC (ELOB and ELOC), RBX1 and a variable substrate-specific adapter; this complex is also known as ECS (Elongin BC-CUL2/5-SOCS-box protein) complex and may consist of CUL2 or CUL5. Component of a ECS(VHL) or CBC(VHL) complex containing CUL2, RBX1, ELOB, ELOC and VHL. Component of the ECS(MED8) complex with the probable substrate recognition component MED8. Component of multiple ECS complexes part of the DesCEND (destruction via C-end degrons) pathway, which contain either KLHDC2, KLHDC3, KLHDC10, APPBP2, FEM1A, FEM1B or FEM1C as substrate-recognition component. Component of the ECS(LRR1) complex with the probable substrate recognition component LRR1. Component of a CRL2(FEM1B) complex containing CUL2, RBX1, ELOB, ELOC and FEM1B. Component of a CRL2(FEM1C) complex containing CUL2, RBX1, ELOB, ELOC and FEM1C. Part of an E3 ubiquitin-protein ligase complex including ZYG11B, CUL2 and Elongin BC. Part of an E3 ubiquitin-protein ligase complex including ZER1, CUL2 and Elongin BC. Interacts with RBX1, RNF7, FEM1B and TIP120A/CAND1. Found in a complex composed of LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2. Interacts (when neddylated) with ARIH1; leading to activate the E3 ligase activity of ARIH1. Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation. Component of VCB (elongins BC/CUL2/VHL) complex that contains at least DCUN1D1, CUL2 and VHL; this complex triggers CUL2 neddylation and consequently cullin ring ligase (CRL) substrates polyubiquitination. (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein NS1.

Subcellular location. Nucleus.

Post-translational modifications. Neddylated; which enhances the ubiquitination activity of ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes. Neddylation leads to structural rearrangment in the complex that allows interaction between the E2 ubiquitin-conjugating enzyme and the acceptor ubiquitin. CBC(VHL) complex formation seems to promote neddylation. Deneddylated via its interaction with the COP9 signalosome (CSN) complex.

Domain organisation. The Cullin neddylation domain restrains the RING domain of RBX1 in the E3 ubiquitin-protein ligase complex; this restraint is removed upon neddylation of the cullin.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the cullin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13617-1	1	yes
Q13617-2	2

RefSeq proteins (6): NP_001185706, NP_001185707, NP_001185708, NP_001311304, NP_001311305, NP_003582* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001373	Cullin_N	Domain
IPR016157	Cullin_CS	Conserved_site
IPR016158	Cullin_homology	Domain
IPR016159	Cullin_repeat-like_dom_sf	Homologous_superfamily
IPR019559	Cullin_neddylation_domain	Domain
IPR036317	Cullin_homology_sf	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR045093	Cullin	Family
IPR059120	Cullin-like_AB	Domain

Pfam: PF00888, PF10557, PF26557

Enzyme classification (BRENDA):

• EC 2.3.2.32 — cullin-RING-type E3 NEDD8 transferase (BRENDA: 6 organisms, 26 substrates, 31 inhibitors, 0 Km, 0 kcat entries)

UniProt features (83 total): helix 35, strand 23, turn 9, mutagenesis site 6, sequence conflict 3, modified residue 2, chain 1, domain 1, cross-link 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

42 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7PLO	ELECTRON MICROSCOPY	2.8
9EFQ	ELECTRON MICROSCOPY	2.96
4WQO	X-RAY DIFFRACTION	3.2
8JAU	ELECTRON MICROSCOPY	3.22
8JAQ	ELECTRON MICROSCOPY	3.26
8WQF	ELECTRON MICROSCOPY	3.27
9UA3	ELECTRON MICROSCOPY	3.28
8JAL	ELECTRON MICROSCOPY	3.3
8JAR	ELECTRON MICROSCOPY	3.3
8WQB	ELECTRON MICROSCOPY	3.37
8WQE	ELECTRON MICROSCOPY	3.38
8WQA	ELECTRON MICROSCOPY	3.39
8JAV	ELECTRON MICROSCOPY	3.44
8R5H	ELECTRON MICROSCOPY	3.44
8WQH	ELECTRON MICROSCOPY	3.44
8QU8	ELECTRON MICROSCOPY	3.5
8JAS	ELECTRON MICROSCOPY	3.54
8WQC	ELECTRON MICROSCOPY	3.54
9J77	ELECTRON MICROSCOPY	3.56
8JE2	ELECTRON MICROSCOPY	3.63
8WDK	ELECTRON MICROSCOPY	3.64
8RX0	ELECTRON MICROSCOPY	3.7
8Q7R	ELECTRON MICROSCOPY	3.71
8PQL	ELECTRON MICROSCOPY	3.76
9BJ8	ELECTRON MICROSCOPY	3.78
9J78	ELECTRON MICROSCOPY	3.88
5N4W	X-RAY DIFFRACTION	3.9
9J63	ELECTRON MICROSCOPY	3.93
9LKY	ELECTRON MICROSCOPY	3.93
8JE1	ELECTRON MICROSCOPY	3.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13617-F1	86.02	0.40

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 393, 661, 689

Mutagenesis-validated functional residues (6):

Position	Phenotype
675	activates ube2r2-mediated ubiquitin chain extension in the absence of neddylation; when associated with k-660 and k-664.
689	loss of conjugation with nedd8.
719	no effect on conjugation with nedd8.
621	no effect on conjugation with nedd8.
660	activates ube2r2-mediated ubiquitin chain extension in the absence of neddylation; when associated with k-664 and k-675.
664	activates ube2r2-mediated ubiquitin chain extension in the absence of neddylation; when associated with k-660 and k-675.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1234176	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha
R-HSA-8951664	Neddylation
R-HSA-9010553	Regulation of expression of SLITs and ROBOs
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-9954709	Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide

MSigDB gene sets: 275 (showing top): GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, TAATAAT_MIR126, GOBP_REGULATION_OF_DNA_TEMPLATED_DNA_REPLICATION, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, MIDORIKAWA_AMPLIFIED_IN_LIVER_CANCER, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, GOBP_NEGATIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_CELL_CYCLE_PHASE_TRANSITION, MAZ_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, AACYNNNNTTCCS_UNKNOWN

GO Biological Process (10): G1/S transition of mitotic cell cycle (GO:0000082), protein ubiquitination (GO:0016567), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), intrinsic apoptotic signaling pathway (GO:0097193), ubiquitin-dependent protein catabolic process via the C-end degron rule pathway (GO:0140627), negative regulation of beige fat cell differentiation (GO:0160276), ubiquitin-dependent protein catabolic process (GO:0006511), proteasomal protein catabolic process (GO:0010498), protein catabolic process (GO:0030163)

GO Molecular Function (5): ubiquitin-protein transferase activity (GO:0004842), protein-macromolecule adaptor activity (GO:0030674), ubiquitin protein ligase binding (GO:0031625), ubiquitin ligase complex scaffold activity (GO:0160072), protein binding (GO:0005515)

GO Cellular Component (8): nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytosol (GO:0005829), SCF ubiquitin ligase complex (GO:0019005), Cul2-RING ubiquitin ligase complex (GO:0031462), nucleus (GO:0005634), cullin-RING ubiquitin ligase complex (GO:0031461), nuclear lumen (GO:0031981)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Cellular response to hypoxia	1
Post-translational protein modification	1
Signaling by ROBO receptors	1
Class I MHC mediated antigen processing & presentation	1
Ribosome-associated quality control	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
proteasome-mediated ubiquitin-dependent protein catabolic process	2
nuclear lumen	2
cellular anatomical structure	2
cullin-RING ubiquitin ligase complex	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G1/S phase transition	1
protein modification by small protein conjugation	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
intracellular signal transduction	1
apoptotic signaling pathway	1
negative regulation of fat cell differentiation	1
beige fat cell differentiation	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
protein catabolic process	1
macromolecule catabolic process	1
protein metabolic process	1
ubiquitin-like protein transferase activity	1
protein binding	1
molecular adaptor activity	1
ubiquitin-like protein ligase binding	1
protein complex scaffold activity	1
binding	1
intracellular membraneless organelle	1
cytoplasm	1
intracellular membrane-bounded organelle	1
ubiquitin ligase complex	1
nucleus	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2368 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CUL2	RBX1	P62877	999
CUL2	ELOB	Q15370	999
CUL2	ELOC	Q15369	999
CUL2	VHL	P40337	998
CUL2	RNF7	Q9UBF6	996
CUL2	COMMD1	Q8N668	991
CUL2	CUL3	Q13618	983
CUL2	SOCS1	O15524	980
CUL2	NEDD8	Q15843	975
CUL2	SKP1	P34991	974
CUL2	CUL4A	Q13619	972
CUL2	CISH	Q9NSE2	960
CUL2	CUL7	Q14999	959
CUL2	HIF1A	Q16665	958
CUL2	CUL5	Q93034	950

IntAct

257 interactions, top by confidence:

A	B	Type	Score
COMMD1	CCDC22	psi-mi:“MI:0914”(association)	0.970
CUL2	VHL	psi-mi:“MI:0915”(physical association)	0.940
VHL	CUL2	psi-mi:“MI:0914”(association)	0.940
CUL2	VHL	psi-mi:“MI:0914”(association)	0.940
NEDD8	UBE2M	psi-mi:“MI:0914”(association)	0.940
COPS8	COPS2	psi-mi:“MI:0914”(association)	0.850
RBX1	CUL2	psi-mi:“MI:0915”(physical association)	0.850
PRAME	CUL2	psi-mi:“MI:0914”(association)	0.830
UBXN7	VCP	psi-mi:“MI:0914”(association)	0.820
VCP	UBXN7	psi-mi:“MI:0914”(association)	0.820
CUL2	ELOC	psi-mi:“MI:0914”(association)	0.800
KLHDC3	CUL2	psi-mi:“MI:0914”(association)	0.770
KLHDC3	CUL2	psi-mi:“MI:0915”(physical association)	0.770
COPS6	RHOBTB1	psi-mi:“MI:0914”(association)	0.730
KLHDC2	CUL2	psi-mi:“MI:0914”(association)	0.730
UBXN7	CUL2	psi-mi:“MI:0914”(association)	0.710
UBXN7	CUL2	psi-mi:“MI:0915”(physical association)	0.710
CUL2	UBXN7	psi-mi:“MI:0914”(association)	0.710

BioGRID (1021): CUL2 (Affinity Capture-RNA), CUL2 (Affinity Capture-RNA), CUL2 (Affinity Capture-RNA), CUL2 (Affinity Capture-Western), CUL2 (Affinity Capture-Western), CUL2 (Biochemical Activity), CUL2 (Biochemical Activity), CUL2 (Biochemical Activity), CUL2 (Biochemical Activity), CUL2 (Affinity Capture-Western), CUL2 (Reconstituted Complex), CUL2 (Biochemical Activity), CUL2 (Biochemical Activity), CUL2 (Biochemical Activity), CUL2 (Biochemical Activity)

ESM2 similar proteins: A4IHP4, B5DF89, B5DFC8, O13790, O14122, O43747, O60999, P0CH31, P22892, P34561, Q09760, Q12018, Q13617, Q13618, Q17389, Q17390, Q17391, Q17392, Q1MTP1, Q20938, Q21346, Q23639, Q24311, Q2TBL4, Q54NZ5, Q54XF7, Q5B3U7, Q5R5M2, Q5RAT8, Q5RCF3, Q5ZC88, Q6DE95, Q6GPF3, Q7SI58, Q8LGH4, Q8LPK4, Q8LPL6, Q8R1B4, Q8VWK0, Q94AH6

Diamond homologs: A2A432, O13790, O60999, Q12018, Q13616, Q13617, Q13619, Q13620, Q17389, Q17390, Q21346, Q24311, Q3TCH7, Q54NZ5, Q5R4G6, Q5RCF3, Q8LGH4, Q9C9L0, Q9D4H8, Q9SZ75, Q9WTX6, Q9XZJ3, A4IHP4, B5DF89, P0CH31, Q09760, Q13618, Q54CS2, Q54XF7, Q6DE95, Q6GPF3, Q94AH6, Q9JLV5, Q9ZVH4, Q23639, Q5RB36, Q5ZC88, Q93034, Q9SRZ0, O14122

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
NAE	“up-regulates activity”	CUL2	neddylation
CUL2	“down-regulates quantity by destabilization”	APOBEC3A	ubiquitination
CUL2	“up-regulates activity”	ARIH1	binding
CUL2	“form complex”	“BAF250b E3 ligase”	binding
CUL2	“form complex”	VCB-Cul2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 167 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
DNA Damage Recognition in GG-NER	10	25.9×	8e-10
Formation of TC-NER Pre-Incision Complex	11	21.1×	8e-10
Iron uptake and transport	5	15.7×	1e-03
Neddylation	34	14.7×	5e-28
Cargo recognition for clathrin-mediated endocytosis	12	11.4×	9e-08
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	5	10.8×	6e-03
Antigen processing: Ubiquitination & Proteasome degradation	14	4.7×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
regulation of protein neddylation	12	77.0×	1e-18
protein neddylation	13	62.5×	1e-18
ubiquitin-dependent protein catabolic process via the C-end degron rule pathway	7	53.9×	3e-09
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	5	12.8×	4e-03
proteasome-mediated ubiquitin-dependent protein catabolic process	27	9.7×	1e-16
protein ubiquitination	22	6.2×	1e-09
ubiquitin-dependent protein catabolic process	10	5.1×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

109 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	70
Likely benign	3
Benign	4

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
982195	NM_003591.4(CUL2):c.2192T>C (p.Ile731Thr)	Likely pathogenic

SpliceAI

3577 predictions. Top by Δscore:

Variant	Effect	Δscore
10:35011843:TTTA:T	donor_loss	1.0000
10:35011844:TTACC:T	donor_loss	1.0000
10:35011845:TA:T	donor_loss	1.0000
10:35011846:AC:A	donor_loss	1.0000
10:35011847:C:A	donor_loss	1.0000
10:35011847:CCT:C	donor_gain	1.0000
10:35011849:T:TA	donor_gain	1.0000
10:35011960:ATTTC:A	acceptor_gain	1.0000
10:35011961:TTTC:T	acceptor_gain	1.0000
10:35011962:TTC:T	acceptor_gain	1.0000
10:35011963:TC:T	acceptor_gain	1.0000
10:35011963:TCC:T	acceptor_loss	1.0000
10:35011964:CCTGT:C	acceptor_gain	1.0000
10:35011965:C:CA	acceptor_loss	1.0000
10:35011965:C:CC	acceptor_gain	1.0000
10:35011970:T:C	acceptor_gain	1.0000
10:35011970:T:TC	acceptor_gain	1.0000
10:35011973:C:CT	acceptor_gain	1.0000
10:35011974:A:T	acceptor_gain	1.0000
10:35013691:GCACT:G	donor_loss	1.0000
10:35013692:CACTT:C	donor_loss	1.0000
10:35013693:ACTT:A	donor_loss	1.0000
10:35013694:CT:C	donor_loss	1.0000
10:35013695:TT:T	donor_loss	1.0000
10:35013696:TAC:T	donor_loss	1.0000
10:35013697:A:AC	donor_gain	1.0000
10:35013697:ACTTG:A	donor_loss	1.0000
10:35013698:C:CC	donor_gain	1.0000
10:35013698:C:T	donor_loss	1.0000
10:35016188:ATACC:A	donor_loss	1.0000

AlphaMissense

4996 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:35010322:A:G	Y743H	1.000
10:35010328:A:G	Y741H	1.000
10:35010352:G:T	R733S	1.000
10:35010361:A:G	Y730H	1.000
10:35010375:A:G	L725P	1.000
10:35010392:C:A	K719N	1.000
10:35010392:C:G	K719N	1.000
10:35010416:A:C	F711L	1.000
10:35010416:A:T	F711L	1.000
10:35010418:A:G	F711L	1.000
10:35011858:A:G	L699P	1.000
10:35011858:A:T	L699H	1.000
10:35011868:G:C	H696D	1.000
10:35011887:T:A	K689N	1.000
10:35011887:T:G	K689N	1.000
10:35011888:T:A	K689I	1.000
10:35011889:T:C	K689E	1.000
10:35011898:G:T	R686S	1.000
10:35011900:A:T	V685D	1.000
10:35011903:A:T	I684K	1.000
10:35011907:C:G	A683P	1.000
10:35011909:G:T	A682D	1.000
10:35011910:C:G	A682P	1.000
10:35011915:A:G	L680P	1.000
10:35011927:C:G	R676P	1.000
10:35013744:T:A	R648S	1.000
10:35013744:T:G	R648S	1.000
10:35013745:C:G	R648T	1.000
10:35025136:A:C	C560W	1.000
10:35025138:A:G	C560R	1.000

dbSNP variants (sampled 300 via entrez): RS1000047087 (10:35031626 T>C), RS1000062757 (10:35050942 T>C), RS1000069706 (10:35126713 C>T), RS1000085188 (10:35093015 A>G), RS1000097402 (10:35091750 A>C), RS1000116365 (10:35027611 T>C), RS1000141789 (10:35051642 T>A,C), RS1000170539 (10:35027311 A>G), RS1000171007 (10:35069596 A>G), RS1000173906 (10:35069611 G>A,C), RS1000210786 (10:35072438 G>A), RS1000218352 (10:35108367 G>A), RS1000221322 (10:35115105 G>A), RS1000247867 (10:35117405 T>C), RS1000268797 (10:35075520 TC>T)

Disease associations

OMIM: gene MIM:603135 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (1): Moyamoya angiopathy (Orphanet:477768)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004131_87	Inflammatory bowel disease	6.000000e-12
GCST004132_106	Crohn’s disease	4.000000e-14

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4523754 (PROTEIN-PROTEIN INTERACTION), CHEMBL6067537 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.60	Kd	2512	nM	CHEMBL5653589
5.45	ED50	3530	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 140 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148181: Binding affinity to human CUL2 incubated for 45 mins by Kinobead based pull down assay	kd	2.5122	uM

CTD chemical–gene interactions

41 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Valproic Acid	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
aflatoxin B2	increases methylation	1
dinophysistoxin 1	increases expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	affects reaction, increases ubiquitination	1
CGP 52608	increases reaction, affects binding	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	increases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Arsenic	affects methylation	1
Benztropine	increases expression	1
Cannabinoids	affects methylation, increases abundance	1
Clozapine	increases expression	1
Cycloheximide	affects reaction, increases degradation	1
Diethylstilbestrol	increases expression	1

ChEMBL screening assays

31 unique, capped per target: 31 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4370954	Binding	Protac activity against VHL/cullin2/ERalpha in human MCF7 cells assessed as ERalpha degradation by measuring ER protein/GADPH ratio at 1 nM after 4 hrs by Western blot analysis relative to control	Discovery of ERD-308 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Estrogen Receptor (ER). — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B7WV	Abcam Raji CUL2 KO	Cancer cell line	Male
CVCL_B9XF	Abcam THP-1 CUL2 KO	Cancer cell line	Male
CVCL_C6ZB	Abcam PC-3 CUL2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.