GSK3B phosphorylates p-NFE2L2

Stable Identifier
Reaction [transition]
Homo sapiens
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GSK3B promotes the nuclear, KEAP1-independent degradation of NFE2L2 by the BTRC:CUL1 E3 ligase (reviewed in Baird and Yamamoto, 2020; Yamamoto et al, 2018). In contrast to the KEAP1:CUL3 degradation, which makes use of an NFE2L2 degron in Neh2, the nuclear GSK3B-CUL1 degron of NFE2L2 is located in Neh6. This domain contains a DSGIS motif at residues 334-338 that is phosphorylated in vitro and in vivo by GSK3B to promote NFE2L2 ubiquitination and subsequent degradation (Salazar et al, 2006; Rada et al, 2011; Rada et al, 2012; Rojo et al, 2012; Chowdhry et al, 2013). Inhibitory phosphorylation of GSK3B by active PI3K/AKT signaling abrogates this nuclear degradation of NFE2L2 (Salazar et al, 2006; Rada et al, 2011; Chowdhry et al, 2013; Rojo et al, 2012; reviewed in Baird and Yamamoto, 2020; Yamamoto et al, 2018).
Literature References
PubMed ID Title Journal Year
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
29717933 The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis

Motohashi, H, Yamamoto, M, Kensler, TW

Physiol Rev 2018
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
32284348 The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway

Yamamoto, M, Baird, L

Mol Cell Biol 2020
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
22964642 Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity

McMahon, M, Cuadrado, A, Zhang, Y, Hayes, JD, Chowdhry, S, Sutherland, C

Oncogene 2013
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
Catalyst Activity

protein serine/threonine kinase activity of GSK3B [nucleoplasm]

Orthologous Events
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