KEAP1
a substrate adapter protein for the E3 ubiquitin ligase complex formed by CUL3 and RBX1. Has tumor suppressor activity. Retains NRF2, BPTF and PGAM5 in the cytosol. Targets NRF2 for ubiquitination and degradation by the proteasome, thus resulting in the suppression of its transcriptional activity and of antioxidant response element-mediated detoxifying enzyme gene expression. Somatic mutations of KEAP1 or NRF2 commonly occur in solid cancers, irrespective of histological type, resulting in the constitutive transcription of cytoprotective genes. Genetic disruption of the KEAP1/CUL3 E3 ubiquitin ligase complex leads to the activation of the NF-kappaB pathway in lung cancer. Alternative activation of the cytoprotective NRF2 pathway exist in the absence of mutations in KEAP1 and HRF2: WTX, PALB2, SQSTM1, and DPP3 can competitively bind KEAP1. These proteins and others that bind KEAP1 contain an ¿ETGE¿ amino acid motif, which matches the KEAP1 interaction motif found in NRF2. Binding of these ¿ETGE¿-containing proteins can displace NRF2, freeing it to translocate to the nucleus and implement its cytoprotective transcriptional pathway. The DPP3 gene is frequently overexpressed in squamous cell lung carcinomas with high wt NRF2 activity. Its expression level significantly correlates with the response rate and progression-free survival of platinum-based first-line chemotherapy. May be a useful biomarker for predicting the chemosensitivity of patients with advanced-stage NSCLC. Broadly expressed, with highest levels in skeletal muscle. Ubiquitination and subsequent degradation of PGAM5 is inhibited by oxidative stress and sulforaphane. Note: This description may include information from UniProtKB.
Protein type: Ubiquitin conjugating system; Transcription regulation; Endoplasmic reticulum; Motility/polarity/chemotaxis
SS: The number of records in which this modification site was determined using site-specific methods. SS methods include amino acid sequencing, site-directed mutagenesis, modification site-specific antibodies, specific MS strategies, etc.
