KEAP1 Gene: Structure, Function, and Clinical Significance
A comprehensive overview of the KEAP1 gene, its protein product, associated diseases, expression patterns, and mutations.
Gene Information Card
| Symbol | KEAP1 |
|---|---|
| Full Name | Kelch-like ECH-associated protein 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 19p13.2 |
| NCBI Gene ID | 9817 ncbi.nlm.nih.gov/gene/9817 |
| Ensembl ID | ENSG00000079999 |
| UniProt ID | Q14145 |
| OMIM ID | 606016 |
| HGNC ID | 6340 |
| Aliases | INRF2, KLHL19, MGC111110 |
Description
The KEAP1 gene encodes a cytoplasmic protein that acts as a substrate adaptor for a CUL3-based E3 ubiquitin ligase complex. It negatively regulates the transcription factor NRF2 (NFE2L2) by targeting it for ubiquitination and proteasomal degradation under basal conditions. Upon oxidative or electrophilic stress, KEAP1 undergoes conformational changes, leading to NRF2 stabilization and activation of antioxidant response element (ARE)-dependent genes. KEAP1 is critical for cellular defense against oxidative stress and xenobiotic insults.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Non-small cell lung cancer | Loss-of-function mutations in KEAP1 lead to constitutive NRF2 activation, promoting tumorigenesis and chemoresistance. | COSMIC; ClinVar; multiple studies |
| Hepatocellular carcinoma | Somatic mutations and promoter hypermethylation of KEAP1 result in NRF2 accumulation, contributing to cancer progression. | COSMIC; ClinVar |
| Gallbladder cancer | KEAP1 mutations are recurrent and associated with poor prognosis. | COSMIC |
| Chronic obstructive pulmonary disease (COPD) | Polymorphisms in KEAP1 may affect oxidative stress response in lung tissue. | ClinVar; literature |
| Type 2 diabetes | KEAP1 variants may influence oxidative stress and insulin resistance. | ClinVar; literature |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 12.5 | Medium |
| Kidney | 10.2 | Medium |
| Lung | 8.7 | Medium |
| Brain | 6.3 | Low |
| Heart | 5.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| A549 (Lung carcinoma) | 15.3 | High expression; often used in KEAP1/NRF2 studies |
| HepG2 (Liver carcinoma) | 12.8 | Moderate expression |
| MCF7 (Breast carcinoma) | 7.2 | Low expression |
| HeLa (Cervical carcinoma) | 9.4 | Moderate expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Gly333Cys | Missense | ~2% in lung cancer | Impairs KEAP1-NRF2 interaction, leading to NRF2 stabilization |
| p.Arg320Gln | Missense | ~1% in various cancers | Disrupts Kelch domain, reducing NRF2 binding |
| p.Asp236Tyr | Missense | Rare | Alters protein conformation and function |
| c.1559+1G>A | Splice site | Rare | Splicing defect, likely loss-of-function |
Mutation functional classification
Loss of Function (LOF)
Most KEAP1 mutations in cancer are loss-of-function, leading to reduced NRF2 ubiquitination and constitutive activation of antioxidant response.
Gain of Function (GOF)
Gain-of-function mutations are rare and not well characterized; some may affect protein stability or interactions.
Dominant Negative (DN)
Certain missense mutations may act in a dominant-negative manner, interfering with wild-type KEAP1 function in heterozygous state.
View complete mutation data：
Gene Ontology (GO)
| • ubiquitin-protein transferase activity | • protein binding |
| • actin binding | • response to oxidative stress |
| • negative regulation of transcription by RNA polymerase II | • protein ubiquitination |
Pathways
• NRF2-ARE signaling pathway
• Oxidative stress response
• Ubiquitin-proteasome pathway
• p53-independent DNA damage response
Protein Summary
KEAP1 is a 69 kDa protein with a BTB/POZ domain, a BACK domain, and six Kelch repeats. It forms a homodimer and interacts with CUL3 and RBX1 to assemble an E3 ubiquitin ligase complex. The Kelch domain binds to NRF2, presenting it for ubiquitination. Under oxidative stress, critical cysteine residues (e.g., Cys151, Cys273, Cys288) are modified, causing conformational changes that release NRF2. KEAP1 is also involved in autophagy and regulation of other substrates.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| keap1（p.C364S） Point Mutation in R28 Cell Line | EDC03012 | Rat | 117519 | Details Get a Quote |
| KEAP1 Knockout HEK293 Cell Line | EDJ-KQ3528 | Human | 9817 | Details Get a Quote |
| KEAP1 Knockout Hela Cell Line | EDJ-KQ23990 | Human | 9817 | Details Get a Quote |
| KEAP1 Knockout A549 Cell Line | EDJ-KQ25367 | Human | 9817 | Details Get a Quote |
| KEAP1 Knockout HCT 116 Cell Line | EDJ-KQ25368 | Human | 9817 | Details Get a Quote |
| KEAP1 Knockout T24 Cell Line | EDJ-KQ78099 | Human | 9817 | Details Get a Quote |
| KEAP1 Knockout HAP1 Cell Line | EDJ-KQ78100 | Human | 9817 | Details Get a Quote |
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