Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that regulates the response to oxidative stress by targeting NFE2L2/NRF2 for ubiquitination (PubMed:14585973, PubMed:15379550, PubMed:15572695, PubMed:15601839, PubMed:15983046, PubMed:37339955). KEAP1 acts as a key sensor of oxidative and electrophilic stress: in normal conditions, the BCR(KEAP1) complex mediates ubiquitination and degradation of NFE2L2/NRF2, a transcription factor regulating expression of many cytoprotective genes (PubMed:15601839, PubMed:16006525). In response to oxidative stress, different electrophile metabolites trigger non-enzymatic covalent modifications of highly reactive cysteine residues in KEAP1, leading to inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes (PubMed:16006525, PubMed:17127771, PubMed:18251510, PubMed:19489739, PubMed:29590092).
In response to selective autophagy, KEAP1 is sequestered in inclusion bodies following its interaction with SQSTM1/p62, leading to inactivation of the BCR(KEAP1) complex and activation of NFE2L2/NRF2 (PubMed:20452972). The BCR(KEAP1) complex also mediates ubiquitination of SQSTM1/p62, increasing SQSTM1/p62 sequestering activity and degradation (PubMed:28380357). The BCR(KEAP1) complex also targets BPTF and PGAM5 for ubiquitination and degradation by the proteasome (PubMed:15379550, PubMed:17046835)
Component of the BCR(KEAP1) E3 ubiquitin ligase complex, at least composed of 2 molecules of CUL3, 2 molecules of KEAP1, and RBX1 (PubMed:15572695, PubMed:15601839, PubMed:15983046, PubMed:17127771, PubMed:18251510, PubMed:24896564). Interacts with NFE2L2/NRF2; the interaction is direct (PubMed:15379550, PubMed:15601839, PubMed:16006525, PubMed:16888629, PubMed:18387606). Forms a ternary complex with NFE2L2/NRF2 and PGAM5 (PubMed:17046835).
Interacts with (phosphorylated) SQSTM1/p62; the interaction is direct and inactivates the BCR(KEAP1) complex by sequestering it in inclusion bodies, promoting its degradation (PubMed:20452972, PubMed:20495340). Interacts with NFE2L1 (PubMed:16687406). Interacts with BPTF and PTMA (PubMed:15657435).
Interacts with MAP1LC3B (PubMed:24089205). Interacts indirectly with ENC1 (PubMed:19424503). Interacts with SESN1 and SESN2 (PubMed:23274085).
Interacts with HSP90AA1 and HSP90AB1 (PubMed:26517842). Interacts with PGCKA1; this interaction prevents the ubiquitination of KEAP1 by TRIM25, thus protecting KEAP1 from degradation (PubMed:36882524)
(Microbial infection) Interacts with ebolavirus protein VP24; this interaction activates transcription factor NFE2L2/NRF2 by blocking its interaction with KEAP1
Broadly expressed, with highest levels in skeletal muscle
KEAP1 contains reactive cysteine residues that act as sensors for endogenously produced and exogenously encountered small molecules, which react with sulfhydryl groups and modify the cysteine sensors, leading to impair ability of the BCR(KEAP1) complex to ubiquitinate target proteins
The Kelch repeats mediate interaction with NFE2L2/NRF2, BPTF and PGAM5
| Cancer Type | Mutation Percentage |
|---|---|
| Central Nervous System Astrocytoma Grade Iv | 0.28% |
| Lung Adenocarcinoma | 13.44% |
| Lung Small Cell Carcinoma | 2.37% |
| Lung Squamous Cell Carcinoma | 9.80% |
| Oesophagus Adenocarcinoma | 0.62% |
| Oesophagus Squamous Cell Carcinoma | 2.34% |
| Pancreas Ductal Carcinoma | 0.57% |
Genes with an experimentally identified or computationally predicted synthetic-lethal relationship to KEAP1, aggregated across our SSL data sources. Click any partner node to view that gene’s page.
Nodes and edges are coloured by the SSL data source. Partners appearing in more than one source are shown in grey.
Total Trials Found: 51
| NCT ID | Condition | Brief Title | Phase | Status |
|---|---|---|---|---|
| NCT05180799 | NSCLC, Melanoma | A Phase 1/2 Study of BA3071 in Patients With Solid Tumors | PHASE1, PHASE2 | ACTIVE_NOT_RECRUITING |
| NCT06128551 | Non-Small Cell Lung Cancer (NSCLC), Colorectal Cancer, Pancreatic Ductal Adenocarcinoma | Study of Elironrasib and Daraxonrasib as Monotherapies and Combination Therapy in Participants With Advanced KRAS G12C Mutant Solid Tumors | PHASE1, PHASE2 | RECRUITING |
| NCT04267913 | Lung Squamous Cell Carcinoma, Recurrent Lung Carcinoma, Stage IV Lung Cancer AJCC v8, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8 | Testing of TAK228 (MLN0128, Sapanisertib) Plus Docetaxel to the Usual Standard of Care for Advanced Squamous Cell Lung Cancer (A Lung-MAP Treatment Trial) | PHASE2 | WITHDRAWN |
| NCT05996263 | Lung Cancer Stage III, Lung Cancer Stage IV | Prognostic Value of Combined Approach Based on KEAP1/NFE2L2 Mutations and Pre-therapeutic FDG-PET/CT Radiomic Analysis in Advanced Non-small-cell Lung Cancer PDL1 ≥ 50% Treated With Pembrolizumab (PEMBROMIC) | N/A | UNKNOWN |
| NCT03872427 | Advanced Malignant Solid Neoplasm, Metastatic Malignant Solid Neoplasm, NF1 Mutation Positive Malignant Peripheral Nerve Sheath Tumor, Unresectable Malignant Solid Neoplasm | Testing Whether Cancers With Specific Mutations Respond Better to Glutaminase Inhibitor, Telaglenastat Hydrochloride, Anti-Cancer Treatment, BeGIN Study | PHASE2 | ACTIVE_NOT_RECRUITING |
| NCT02417701 | Recurrent Lung Squamous Cell Carcinoma, Stage IV Lung Squamous Cell Carcinoma AJCC v7 | Sapanisertib in Treating Patients With Stage IV or Recurrent Lung Cancer | PHASE2 | COMPLETED |
| NCT05054725 | Non-Small Cell Lung Cancer | Combination Study of RMC-4630 and Sotorasib for NSCLC Subjects With KRASG12C Mutation After Failure of Prior Standard Therapies | PHASE2 | COMPLETED |
| NCT06008093 | Carcinoma, Non-Small-Cell Lung | A Study to Investigate the Efficacy of Durvalumab Plus Tremelimumab in Combination With Chemotherapy Compared With Pembrolizumab in Combination With Chemotherapy in Metastatic NSCLC Patients With Non-squamous Histology Who Have Mutations and/or Co-mutations in STK11, KEAP1, or KRAS | PHASE2 | ACTIVE_NOT_RECRUITING |
| NCT05275868 | Non-small Cell Lung Cancer | Study of MGY825 in Patients With Advanced Non-small Cell Lung Cancer | PHASE1 | TERMINATED |
| NCT06341660 | Non-small Cell Lung Cancer | To Evaluate the Safety and Tolerability of Carbognilumab Combined With Chemotherapy as the First-line Treatment for Patients With KEAP1 Mutated Advanced or Postoperative Recurrent Non-small Cell Lung Cancer (NSCLC) | PHASE2 | UNKNOWN |