Under the basal resting conditions, cytosolic Nuclear factor erythroid 2-related NFE2L2 (NRF2) is maintained at low basal levels by constitutive proteasomal degradation. Kelch-like ECH associated protein 1 (KEAP1), which is a substrate adaptor protein for the Cullin 3 (CUL3)-dependent E3 ubiquitin ligase complex binds with and represses NFE2L2 by promoting its ubiquitination and subsequent proteasomal degradation (Itoh et al. 1999, Cullinan et al. 2004, Kobayashi et al. 2004, Zhang et al. 2004, Furukawa & Xiong 2005). Therefore, the KEAP1–CUL3–E3 ubiquitin ligase complex tightly regulates NFE2L2 protein to maintain it at a low level. NFE2L2 contains seven functional domains, known as Neh1-Neh7. Neh2 domain contains two motifs termed ETGE and DLG are involved in interacting with KEAP1.
KEAP1 and NFE2L2 mutations occur in several tumour types and KEAP1 and NFE2L2 mutations occur at a frequency of around 25% in lung cancer. The NFE2L2 pathway has multiple pro-tumorigenic functions, and NFE2L2 levels are increased in head and neck squamous cell carcinoma (HNSCC). KEAP1 somatic mutant C23Y is observed in tumors from approximately 15% of patients with lung cancer (Hayes & McMahon 2009).