Reactome | NFE2L2 translocates from cytosol to nucleoplasm

NFE2L2 translocates from cytosol to nucleoplasm

Stable Identifier

R-HSA-8932309

Type

Reaction [omitted]

Species

Homo sapiens

Compartment

cytosol, nucleoplasm

Synonyms

NRF2 translocates into nucleus

ReviewStatus

5/5

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NFE2L2 translocates from cytosol to nucleoplasm

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Upon activation by electrophiles or reactive oxygen species Nuclear factor erythroid 2-related (NFE2L2, NRF2) accumulates in the nucleus. The mechanism by which this translocation occurs is not entirely elucidated. NFE2L2 possess two functional nuclear localization signals (NLS) one near the N-terminal region (murine NFE2L2 42-53 aa) and the other (residues 587-593) in the C-terminal region which may function in the nuclear import. It has also been demonstrated that importins might be involved in the nuclear translocation of NFE2L2. NFE2L2 associates especially with importin alpha 5 and beta 1 (Theodore et al. 2008). Nuclear import of NFE2L2 has been shown to be stimulated downstream of active PI3K signaling (Joung et al, 2007; Li et al, 2006; Martin et al, 2004). Similarly, activation of the NFE2L2 pathway has been observed downstream of some oncogenes (Best et al, 2021; Tang et al, 2021; Mitsuishi et al, 2012; De Nicola et al, 2011; Wakabayashi et al, 2014; reviewed in He et al, 2020; Kitamura and Motohashi, 2018). NFE2L2 contributes to oncogenesis through metabolic reprogramming to support proliferation and through enhanced detoxification and antioxidation capabilities (reviewed in He et al, 2020; Kitamura and Motohashi, 2018). Activation of the PI3K pathway through inactivation of PTEN and KEAP1 increases the levels of T308 phosphorylated AKT, and promotes the nuclear accumulation of NFE2L2, stimulating expression of target genes (Mitsuishi et al, 2012; Best et al, 2021).

Literature References

PubMed ID	Title	Journal	Year
17979524	Capsaicin induces heme oxygenase-1 expression in HepG2 cells via activation of PI3K-Nrf2 signaling: NAD(P)H:quinone oxidoreductase as a potential target Joung, EJ, Li, MH, Lee, HG, Somparn, N, Jung, YS, Na, HK, Kim, SH, Cha, YN, Surh, YJ	Antioxid Redox Signal	2007
16962933	Peroxynitrite induces HO-1 expression via PI3K/Akt-dependent activation of NF-E2-related factor 2 in PC12 cells Li, MH, Cha, YN, Surh, YJ	Free Radic Biol Med	2006
29526543	Synergy between the KEAP1/NRF2 and PI3K Pathways Drives Non-Small-Cell Lung Cancer with an Altered Immune Microenvironment Best, SA, De Souza, DP, Kersbergen, A, Policheni, AN, Dayalan, S, Tull, D, Rathi, V, Gray, DH, Ritchie, ME, McConville, MJ, Sutherland, KD	Cell Metab	2018
14688281	Regulation of heme oxygenase-1 expression through the phosphatidylinositol 3-kinase/Akt pathway and the Nrf2 transcription factor in response to the antioxidant phytochemical carnosol Martin, D, Rojo, AI, Salinas, M, Diaz, R, Gallardo, G, Alam, J, De Galarreta, CM, Cuadrado, A	J Biol Chem	2004
32640524	NRF2, a Transcription Factor for Stress Response and Beyond He, F, Ru, X, Wen, T	Int J Mol Sci	2020
24298019	Notch-Nrf2 axis: regulation of Nrf2 gene expression and cytoprotection by notch signaling Wakabayashi, N, Skoko, JJ, Chartoumpekis, DV, Kimura, S, Slocum, SL, Noda, K, Palliyaguru, DL, Fujimuro, M, Boley, PA, Tanaka, Y, Shigemura, N, Biswal, S, Yamamoto, M, Kensler, TW	Mol Cell Biol	2014
22789539	Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming Mitsuishi, Y, Taguchi, K, Kawatani, Y, Shibata, T, Nukiwa, T, Aburatani, H, Yamamoto, M, Motohashi, H	Cancer Cell	2012
33859744	c-MYC-directed NRF2 drives malignant progression of head and neck cancer via glucose-6-phosphate dehydrogenase and transketolase activation Tang, YC, Hsiao, JR, Jiang, SS, Chang, JY, Chu, PY, Liu, KJ, Fang, HL, Lin, LM, Chen, HH, Huang, YW, Chen, YT, Tsai, FY, Lin, SF, Chuang, YJ, Kuo, CC	Theranostics	2021
21734707	Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis DeNicola, GM, Karreth, FA, Humpton, TJ, Gopinathan, A, Wei, C, Frese, K, Mangal, D, Yu, KH, Yeo, CJ, Calhoun, ES, Scrimieri, F, Winter, JM, Hruban, RH, Iacobuzio-Donahue, C, Kern, SE, Blair, IA, Tuveson, DA	Nature	2011
29450944	NRF2 addiction in cancer cells Kitamura, H, Motohashi, H	Cancer Sci	2018
18238777	Multiple nuclear localization signals function in the nuclear import of the transcription factor Nrf2 Theodore, M, Kawai, Y, Yang, J, Kleshchenko, Y, Reddy, SP, Villalta, F, Arinze, IJ	J. Biol. Chem.	2008