NFE2L2 binds KEAP1:CUL3:RBX1

Stable Identifier
R-HSA-8932327
Type
Reaction [binding]
Species
Homo sapiens
Compartment
Synonyms
NRF2 binds KEAP1 E3 complex
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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).

Literature References
PubMed ID Title Journal Year
15282312 Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2

Kobayashi, A, Kang, MI, Okawa, H, Ohtsuji, M, Zenke, Y, Chiba, T, Igarashi, K, Yamamoto, M

Mol. Cell. Biol. 2004
15367669 The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase

Cullinan, SB, Gordan, JD, Jin, J, Harper, JW, Diehl, JA

Mol. Cell. Biol. 2004
9887101 Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain

Itoh, K, Wakabayashi, N, Katoh, Y, Ishii, T, Igarashi, K, Engel, JD, Yamamoto, M

Genes Dev. 1999
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