CUL3 Gene: Cullin-3, a Key Regulator of Ubiquitination and Disease
Comprehensive genomic, functional, and clinical insights into CUL3, a component of the ubiquitin-proteasome system implicated in hypertension, neurodevelopmental disorders, and cancer.
Gene Information Card
| Symbol | CUL3 |
|---|---|
| Full Name | Cullin 3 |
| Gene Type | Protein coding |
| Chromosomal Location | 2q36.2 |
| NCBI Gene ID | 8452 ncbi.nlm.nih.gov/gene/8452 |
| Ensembl ID | ENSG00000036257 |
| UniProt ID | Q13618 |
| OMIM ID | 603136 |
| HGNC ID | 2553 |
| Aliases | CUL-3, MGC138479, MGC138481 |
Description
CUL3 encodes cullin-3, a core component of the Cullin-RING E3 ubiquitin ligase complex (CRL3). This complex targets specific substrates for ubiquitination and subsequent proteasomal degradation, regulating diverse cellular processes including cell cycle, transcription, and signal transduction. CUL3 is essential for proper development and its dysfunction is linked to several diseases.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Pseudohypoaldosteronism type II (PHA2, Gordon syndrome) | Mutations in CUL3 lead to loss of function of the CRL3 complex, impairing degradation of WNK kinases. Accumulation of WNK1/WNK4 causes overactivation of the Na-Cl cotransporter (NCC) in the distal nephron, leading to hypertension and hyperkalemia. | OMIM #614496; multiple studies (e.g., Boyden et al., 2012) |
| Neurodevelopmental disorders (including autism, intellectual disability) | De novo heterozygous mutations in CUL3 are associated with neurodevelopmental phenotypes. The mechanism likely involves altered ubiquitination of synaptic proteins and disrupted neuronal development. | ClinVar; Deciphering Developmental Disorders Study (2017) |
| Cancers (e.g., lung, breast, renal) | CUL3 mutations or dysregulation can lead to aberrant degradation of tumor suppressors or oncogenes. For example, loss of CUL3 function stabilizes NRF2, promoting antioxidant response and tumor growth. | COSMIC; multiple cancer genomics studies |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 17.2 | Medium |
| Kidney | 12.5 | Medium |
| Liver | 10.8 | Medium |
| Testis | 9.3 | Low |
| Lung | 8.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa (cervical cancer) | 15.0 | High expression |
| A549 (lung cancer) | 12.3 | Medium expression |
| MCF7 (breast cancer) | 10.5 | Medium expression |
| HEK293 (embryonic kidney) | 14.2 | High expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1390C>T (p.Arg464Ter) | Nonsense | Rare (germline) | Loss of function; associated with PHA2 |
| c.1517A>G (p.Asp506Gly) | Missense | Rare (germline) | Loss of function; associated with PHA2 |
| c.1183C>T (p.Arg395Trp) | Missense | De novo (neurodevelopmental) | Likely loss of function; altered substrate binding |
| c.1661A>G (p.Tyr554Cys) | Missense | Somatic (cancer) | Gain of function?; may affect substrate specificity |
Mutation functional classification
Loss of Function (LOF)
Most CUL3 mutations, especially truncating or missense in the cullin domain, result in loss of E3 ligase activity, leading to substrate accumulation (e.g., WNK kinases, NRF2).
Gain of Function (GOF)
Some somatic missense mutations may alter substrate specificity or enhance ligase activity, potentially promoting oncogenic pathways, though this is less well characterized.
Dominant Negative (DN)
Heterozygous mutations in CUL3 can exert a dominant-negative effect by forming inactive complexes with other cullins or sequestering adaptors, as seen in PHA2.
View complete mutation data：
Gene Ontology (GO)
| • ubiquitin-protein transferase activity | • protein ubiquitination |
| • ubiquitin-dependent protein catabolic process | • cullin-RING ubiquitin ligase complex |
| • cell cycle | • response to oxidative stress |
Pathways
• Cullin-RING ubiquitin ligase (CRL3) pathway
• Ubiquitin-proteasome system
• WNK signaling in hypertension
• NRF2-ARE pathway (oxidative stress response)
• Cell cycle regulation (via cyclin E degradation)
Protein Summary
Cullin-3 is a scaffold protein that assembles a multi-subunit E3 ubiquitin ligase complex. It binds to BTB-domain-containing adaptor proteins, which recruit specific substrates for ubiquitination. CUL3 is involved in the degradation of key regulatory proteins such as WNK kinases, NRF2, and cyclin E. Its activity is crucial for maintaining cellular homeostasis, and its dysregulation contributes to hypertension, neurodevelopmental disorders, and cancer.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| CUL3 Overexpression MARC-145 Stable Cell Line | EDC90138 | African green monkey | 707550 | Details Get a Quote |
| CUL3 Knockout HEK293 Cell Line | EDJ-KQ78101 | Human | 8452 | Details Get a Quote |
| CUL3 Knockout NCI-H82 Cell Line | EDJ-KQ78102 | Human | 8452 | Details Get a Quote |
| CUL3 Knockout HEK293T Cell Line | EDJ-KQ78127 | Human | 8452 | Details Get a Quote |
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