KEAP1
KEAP1 (Kelch-like ECH-associated protein 1) is a gene whose normal job is to hold cell growth in check. The public catalogues list it as a drug target, an oncogene driver, a tumour suppressor and a biomarker, and clinical evidence ties its variants to diagnosis, prognosis or drug response. Tied to Lung cancer, Hepatocellular carcinoma, Nasopharyngeal carcinoma and 3 more.
Overview
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. 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. 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.
CIViC holds 6 clinical evidence items and 0 assertions across 2 variants, naming Cisplatin/Pembrolizumab/Pemetrexed Regimen, Chemotherapy, Palliative Radiation Therapy and Durvalumab Regimen and others. Open Targets scores its association with cancer at 0.76 (direct and indirect evidence; datatypes clinical 0.14, literature 0.99, genetic association 0.18, somatic mutation 0.96, animal model 0.37). IntOGen calls it a driver in 14 cohorts (7 activating, 7 loss-of-function), covering Cholangiocarcinoma, Hepatocellular Carcinoma, Lung Adenocarcinoma, Lung Squamous Cell Carcinoma, Nasopharyngeal Carcinoma, Non-Small Cell Lung Cancer.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
In plain words · KEAP1 (Kelch-like ECH-associated protein 1) is a gene whose normal job is to hold cell growth in check. The public catalogues list it as a drug target, an oncogene driver, a tumour suppressor and a biomarker, and clinical evidence ties its variants to diagnosis, prognosis or drug response. Tied to Lung cancer, Hepatocellular carcinoma, Nasopharyngeal carcinoma and 3 more.
- 1 · What it is
KEAP1 (Kelch-like ECH-associated protein 1) is a gene whose normal job is to hold cell growth in check. The public catalogues list it as a drug target, an oncogene driver, a tumour suppressor and a biomarker, and clinical evidence ties its variants to diagnosis, prognosis or drug response. Tied to Lung cancer, Hepatocellular carcinoma, Nasopharyngeal carcinoma and 3 more.
- 2 · What goes wrong in cancer
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.
- 3 · How drugs use it
No product in this corpus aims at KEAP1 yet. Because the protein is lost rather than overactive, drugs either restore its function or exploit the weakness its loss leaves (synthetic lethality).
External identifiers
Sources: HGNC HGNC:23177 (approved symbol, name, aliases, locus and cross-references (hgnc_complete_set.txt)); UniProt Q14145 (protein name, function text, keywords and locations (REST API)); CIViC gene KEAP1 (6 evidence items, 0 assertions, 2 variants; diseases: Lung Non-small Cell Carcinoma (GraphQL API, CC0)); Open Targets ENSG00000079999 (association with cancer (MONDO_0004992) 0.76; per-cancer scores at or above 0.5: non-small cell lung carcinoma 0.69, neuroendocrine neoplasm 0.52, lung cancer 0.72 (GraphQL API, CC0)); IntOGen KEAP1 (driver in 14 cohorts (Act 7, LoF 7); Compendium_Cancer_Genes.tsv release 20240920, CC0 1.0)
Biology
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. 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. 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. 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. The BCR(KEAP1) complex also mediates ubiquitination of SQSTM1/p62, increasing SQSTM1/p62 sequestering activity and degradation. The BCR(KEAP1) complex also targets BPTF and PGAM5 for ubiquitination and degradation by the proteasome. Location: Cytoplasm; Nucleus (UniProt). Locus 19p13.2 (HGNC).
- Lung cancer: Open Targets association 0.72 with lung cancer (MONDO_0008903)
- Hepatocellular carcinoma: IntOGen driver in 2 cohorts (HCC)
- Nasopharyngeal carcinoma: IntOGen driver in 1 cohort (NPC)
- Neuroendocrine tumours: Open Targets association 0.52 with neuroendocrine neoplasm (MONDO_0019496)
- Non-small-cell lung cancer: Open Targets association 0.69 with non-small cell lung carcinoma (MONDO_0005233); CIViC evidence names this disease
- Biliary tract cancer: IntOGen driver in 1 cohort (CHOL)
Notes
top- Written by scripts/fetch-cancer-genes.ts from CIViC, Open Targets, IntOGen, HGNC and UniProt; the function text is UniProt's, condensed and in UK spelling. Roles: Open Targets known-drug datatype score 0.14; IntOGen calls it an activating (Act) driver in 7 cohorts; IntOGen calls it a loss-of-function (LoF) driver in 7 cohorts; CIViC holds 6 clinical evidence items on its variants. Evidence tier "clinical-evidence" is the strongest of those signals.
- Prevalence not recorded: none of the sources gives a positivity rate.
Latest papers
topQuery for this target: (TITLE:"KEAP1" OR ABSTRACT:"KEAP1" OR TITLE:"kelch like ECH associated protein 1" OR ABSTRACT:"kelch like ECH associated protein 1" OR TITLE:"Kelch-like ECH-associated protein 1" OR ABSTRACT:"Kelch-like ECH-associated protein 1" OR TITLE:"KIAA0132" OR ABSTRACT:"KIAA0132" OR TITLE:"MGC10630" OR ABSTRACT:"MGC10630" OR TITLE:"MGC1114" OR ABSTRACT:"MGC1114") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about KEAP1, not a curated reading list.
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