Reactome | GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2

GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2

Stable Identifier

R-HSA-9762114

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2

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In addition to KEAP1:CUL3-mediated degradation in the cytosol, NFE2L2 appears to also be subject to degradation by a BTRC:CUL1 E3 ligase (reviewed in Cuadrado, 2015; Baird and Yamamoto, 2020; Yamamoto et al, 2018). Degradation by the BTRC:CUL1 pathway is mediated by interaction with the NFE2L2 Neh6 domain, and is stimulated by GSK3B-mediated phosphorylation of the Neh6 DSGIS motif. GSK3B-dependent Neh6 phosphorylation is primed by the phosphorylation of a cluster of adjacent serines by unknown kinase(s) (Salazar et al, 2006; Rada et al, 2011; Rada et L, 2012; Rojo et al, 2012; Chen et al, 2017; reviewed in Baird and Yamamoto, 2020). Inhibitory phosphorylation of GSK3B by activated PI3K/AKT signaling relieves BTRC:CUL1-mediated NFE2L2 degradation and provides a biochemical link between activated PI3K signaling and increased NFE2L2 pathway activity (reviewed in Cuadrado, 2015; Baird and Yamamoto, 2020; Yamamoto et al, 2018).

Literature References

PubMed ID	Title	Journal	Year
29717933	The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis Yamamoto, M, Kensler, TW, Motohashi, H	Physiol Rev	2018
21245377	SCF/{beta}-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner Rada, P, Rojo, AI, Chowdhry, S, McMahon, M, Hayes, JD, Cuadrado, A	Mol Cell Biol	2011
32284348	The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway Baird, L, Yamamoto, M	Mol Cell Biol	2020
31945188	c-Jun NH₂ -Terminal Protein Kinase Phosphorylates the Nrf2-ECH Homology 6 Domain of Nuclear Factor Erythroid 2-Related Factor 2 and Downregulates Cytoprotective Genes in Acetaminophen-Induced Liver Injury in Mice Chen, Y, Liu, K, Zhang, J, Hai, Y, Wang, P, Wang, H, Liu, Q, Wong, CCL, Yao, J, Gao, Y, Liao, Y, Tang, X, Wang, XJ	Hepatology	2020
22751928	Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP axis Rada, P, Rojo, AI, Evrard-Todeschi, N, Innamorato, NG, Cotte, A, Jaworski, T, Tobón-Velasco, JC, Devijver, H, Garcia-Mayoral, MF, Van Leuven, F, Hayes, JD, Bertho, G, Cuadrado, A	Mol Cell Biol	2012
16551619	Glycogen synthase kinase-3beta inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2 Salazar, M, Rojo, AI, Velasco, D, de Sagarra, RM, Cuadrado, A	J Biol Chem	2006
25937177	Structural and functional characterization of Nrf2 degradation by glycogen synthase kinase 3/β-TrCP Cuadrado, A	Free Radic Biol Med	2015
22142471	Signaling pathways activated by the phytochemical nordihydroguaiaretic acid contribute to a Keap1-independent regulation of Nrf2 stability: Role of glycogen synthase kinase-3 Rojo, AI, Medina-Campos, ON, Rada, P, Zúñiga-Toalá, A, López-Gazcón, A, Espada, S, Pedraza-Chaverri, J, Cuadrado, A	Free Radic Biol Med	2012