NFE2L2 translocates from cytosol to nucleoplasm

Stable Identifier
R-HSA-8932309
Type
Reaction [BlackBoxEvent]
Species
Homo sapiens
Compartment
Synonyms
NRF2 translocates into nucleus
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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

Na, HK, Lee, HG, Surh, YJ, Kim, SH, Cha, YN, Somparn, N, Jung, YS, Li, MH, Joung, EJ

Antioxid Redox Signal 2007
16962933 Peroxynitrite induces HO-1 expression via PI3K/Akt-dependent activation of NF-E2-related factor 2 in PC12 cells

Surh, YJ, Cha, YN, Li, MH

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

Rathi, V, Ritchie, ME, Policheni, AN, De Souza, DP, Best, SA, Sutherland, KD, Tull, D, McConville, MJ, Gray, DH, Dayalan, S, Kersbergen, A

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

Alam, J, Martin, D, De Galarreta, CM, Cuadrado, A, Gallardo, G, Rojo, AI, Diaz, R, Salinas, M

J Biol Chem 2004
32640524 NRF2, a Transcription Factor for Stress Response and Beyond

He, F, Wen, T, Ru, X

Int J Mol Sci 2020
24298019 Notch-Nrf2 axis: regulation of Nrf2 gene expression and cytoprotection by notch signaling

Palliyaguru, DL, Fujimuro, M, Noda, K, Kimura, S, Slocum, SL, Shigemura, N, Chartoumpekis, DV, Tanaka, Y, Boley, PA, Yamamoto, M, Wakabayashi, N, Biswal, S, Skoko, JJ, Kensler, TW

Mol Cell Biol 2014
22789539 Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming

Motohashi, H, Yamamoto, M, Nukiwa, T, Aburatani, H, Kawatani, Y, Shibata, T, Mitsuishi, Y, Taguchi, K

Cancer Cell 2012
33859744 c-MYC-directed NRF2 drives malignant progression of head and neck cancer via glucose-6-phosphate dehydrogenase and transketolase activation

Chu, PY, Chen, HH, Lin, LM, Chang, JY, Lin, SF, Chen, YT, Liu, KJ, Huang, YW, Chuang, YJ, Kuo, CC, Tsai, FY, Fang, HL, Hsiao, JR, Jiang, SS, Tang, YC

Theranostics 2021
21734707 Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis

Calhoun, ES, Hruban, RH, Blair, IA, Yu, KH, Gopinathan, A, Frese, K, Scrimieri, F, Yeo, CJ, DeNicola, GM, Winter, JM, Mangal, D, Wei, C, Iacobuzio-Donahue, C, Kern, SE, Humpton, TJ, Karreth, FA, Tuveson, DA

Nature 2011
29450944 NRF2 addiction in cancer cells

Motohashi, H, Kitamura, H

Cancer Sci 2018
18238777 Multiple nuclear localization signals function in the nuclear import of the transcription factor Nrf2

Reddy, SP, Kawai, Y, Yang, J, Kleshchenko, Y, Theodore, M, Villalta, F, Arinze, IJ

J. Biol. Chem. 2008
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