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 Motohashi, H, Yamamoto, M, Kensler, TW	Physiol Rev	2018
21245377	SCF/{beta}-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner Cuadrado, A, Chowdhry, S, Rojo, AI, Rada, P, Hayes, JD, McMahon, M	Mol Cell Biol	2011
32284348	The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway Yamamoto, M, Baird, L	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 Wang, P, Liao, Y, Liu, K, Wang, H, Gao, Y, Chen, Y, Yao, J, Zhang, J, Liu, Q, Wang, XJ, Tang, X, Wong, CCL, Hai, Y	Hepatology	2020
22751928	Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP axis Rada, P, Garcia-Mayoral, MF, Cotte, A, Innamorato, NG, Van Leuven, F, Cuadrado, A, Devijver, H, Rojo, AI, Evrard-Todeschi, N, Hayes, JD, Tobón-Velasco, JC, Jaworski, T, Bertho, G	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 de Sagarra, RM, Velasco, D, Cuadrado, A, Salazar, M, Rojo, AI	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 Cuadrado, A, Medina-Campos, ON, Pedraza-Chaverri, J, Rojo, AI, Rada, P, Zúñiga-Toalá, A, Espada, S, López-Gazcón, A	Free Radic Biol Med	2012