Reactome | KEAP1-NFE2L2 pathway

KEAP1-NFE2L2 pathway

Stable Identifier

R-HSA-9755511

DOI

10.3180/R-HSA-9755511.1

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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The KEAP1:NFE2L2 (KEAP1-NRF2, Kelch-like ECH-associated protein 1-Nuclear Factor (erythroid-derived 2)-like 2) regulatory pathway plays a central role in protecting cells against multiple homeostatic responses including adaptation to oxidative, inflammatory, metabolic, proteotoxic and xenobiotic stresses. The NFE2L2 transcriptome has been implicated in protection against many chronic diseases including cardiovascular, metabolic, neurodgenerative and respiratory diseases (reviewed in Cuadrado et al, 2018; Baird and Yamamoto, 2020). In cancer, NFE2L2 plays a critical role in the metabolic reprogramming, directing metabolic intermediates into the Warburg and pentose phosphate pathways to support proliferative growth and redox homeostasis (reviewed in He et al, 2020; Ge et al, 2020; Hayes et al, 2020; Kitamura and Hotomashi, 2018)

KEAP1 is a redox sensor that together with CUL3/RBX1 forms part of an E3 ubiquitin ligase, which tightly regulates the activity of the transcription factor NFE2L2 by targeting it for ubiquitination and proteasome-dependent degradation. Oxidative modifications or electrophile adduct formation with redox-sensitive cysteines within KEAP1 renders this protein unable to target bound NFE2L2 for ubiquitination and allows newly translated NFE2L2 to accumulate within the cell and translocate to the nucleus where it can promote its transcriptional program (reviewed in Cuadrado et al, 2019; Baird and Yamamoto, 2020).

Literature References

PubMed ID	Title	Journal	Year
30610225	Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases Wells, G, Cousin, SP, Franklin, S, Cuadrado, A, Rojo, AI, Hayes, JD, Rumsey, WL, Levonen, AL, Dinkova-Kostova, AT, Kensler, TW, Attucks, OC	Nat Rev Drug Discov	2019
32640524	NRF2, a Transcription Factor for Stress Response and Beyond He, F, Wen, T, Ru, X	Int J Mol Sci	2020
32582032	The Role of the Pentose Phosphate Pathway in Diabetes and Cancer Ge, T, Yang, J, Tong, X, Wang, Y, Zhou, S, Li, Y	Front Endocrinol (Lausanne)	2020
32284348	The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway Yamamoto, M, Baird, L	Mol Cell Biol	2020
29507103	Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach Alcaraz, MJ, Pajares, M, León, R, Robledinos-Antón, N, Valverde, AM, López, MG, Manda, G, Guney, E, Oliva, B, Cuadrado, A, Schmidt, HHHW, Ghezzi, P, Rojo, AI, Hassan, A, Barbas, C, Daiber, A	Pharmacol Rev	2018
29450944	NRF2 addiction in cancer cells Motohashi, H, Kitamura, H	Cancer Sci	2018
32649885	Oxidative Stress in Cancer Hayes, JD, Tew, KD, Dinkova-Kostova, AT	Cancer Cell	2020